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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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RTS,S/AS01, RTS,S Mosquirix


 The World Health Organization (WHO) has announced that the Government of Malawi has immunized the first children with RTS,S/AS01 (RTS,S), the world’s first malaria vaccine, according to the World Record Academy.

Sequence:

1MMAPDPNANP NANPNANPNA NPNANPNANP NANPNANPNA NPNANPNANP51NANPNANPNA NPNANPNANP NANPNANPNA NPNKNNQGNG QGHNMPNDPN101RNVDENANAN NAVKNNNNEE PSDKHIEQYL KKIKNSISTE WSPCSVTCGN151GIQVRIKPGS ANKPKDELDY ENDIEKKICK MEKCSSVFNV VNSRPVTNME201NITSGFLGPL LVLQAGFFLL TRILTIPQSL DSWWTSLNFL GGSPVCLGQN251SQSPTSNHSP TSCPPICPGY RWMCLRRFII FLFILLLCLI FLLVLLDYQG301MLPVCPLIPG STTTNTGPCK TCTTPAQGNS MFPSCCCTKP TDGNCTCIPI351PSSWAFAKYL WEWASVRFSW LSLLVPFVQW FVGLSPTVWL SAIWMMWYWG401PSLYSIVSPF IPLLPIFFCL WVYI

RTS,S/AS01 (RTS,S)

RTS,S/AS01, Mosquirix

Cas 149121-47-1

203-400-Antigen CS (Plasmodium falciparum strain NF54 reduced), 203-L-methionine-204-L-methionine-205-L-alanine-206-L-proline-207-L-aspartic acid-210-L-alanine-211-L-asparagine-313-L-asparagine-329-L-glutamic acid-330-L-glutamine-333-L-lysine-336-L-lysine-339-L-isoleucine-373-L-glutamic acid-396-L-arginine-397-L-proline-398-L-valine-399-L-threonine-400-L-asparagine-, (400→1′)-protein with antigen (hepatitis B virus subtype adw small surface reduced) (9CI) 

Other Names

  • Malaria vaccine RTS,S
  • Mosquirix
  • RTS,S

Protein Sequence

Sequence Length: 424

An external file that holds a picture, illustration, etc. Object name is khvi-16-03-1669415-g002.jpg

Figure 2.

Graphical depiction of circumsporozoite (CSP) and RTS,S structures. CSP comprises an N-terminal region containing a signal peptide sequence and Region I that binds heparin sulfate proteoglycans and has embedded within it a conserved five amino acid (KLKQP) proteolytic cleavage site sequence; a central region containing four-amino acid (NANP/NVDP) repeats; and a C-terminal region containing Region II [a thrombospondin (TSP)-like domain] and a canonical glycosylphosphatidylinositol (GPI) anchor addition sequence. The region of the CSP included in the RTS,S vaccine includes the last 18 NANP repeats and C-terminus exclusive of the GPI anchor addition sequence. Hepatitis B virus surface antigen (HBsAg) monomers self-assemble into virus-like particles and approximately 25% of the HBsAg monomers in RTS,S are genetically fused to the truncated CSP and serve as protein carriers. The CSP fragment in RTS,S contains three known T-cell epitopes: a highly variable CD4 + T-cell epitope before the TSP-like domain (TH2R), a highly variable CD8 + T-cell epitope within the TSP-like domain (TH3R), and a conserved “universal” CD4 + T cell epitope (CS.T3) at the C-terminus. (Figure courtesy of a recent publication16 and open access,
PATENTWO 2009080715

https://patents.google.com/patent/WO2009080715A2/tr

XAMPLES

Example 1Recipe for component for a single pediatric dose of RTS, S malaria vaccine (2 vial formulation)Component AmountRTS,S 25μgNaCl 2.25mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 125μgWater for Injection Make volume to 250 μLThe above is prepared by adding RTS, S antigen to a mix of Water for Injection, NaCl 150OmM, phosphate buffer (NaZK2) 50OmM (pH 6.8 when diluted x 50) and an aqueous solution of monothioglycerol at 10%. Finally pH is adjusted to 7.0 ± 0.1.This may be provided as a vial together with a separate vial of adjuvant, for example a liposomal formulation of MPL and QS21Component Amount l,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 500 μgCholesterol 125 μgMPL 25 μgQS21 25 μgNaCl 2.25mg Phosphate buffer (NaZK2) 1 OmMWater for Injection Make volume to250 μLFor administration the adjuvant formulation is added to the component formulation, for example using a syringe, and then shaken. Then the dose is administered in the usual way. The pH of the final liquid formulation is about 6.6 +/- 0.1.Example IAA final pediatric liquid formulation (1 vial) according to the invention may be prepared according to the following recipe.Component AmountRTS,S 25μgNaCl 4.5mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 125μg1 ,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 500 μgCholesterol 125 μgMPL 25 μgQS21 25 μgWater for Injection Make volume to500 μLThe pH of the above liquid formulation is either adjusted to 7.0 +/- 0.1 (which is favorable for antigen stability, but not favorable at all for the MPL stability), or to 6.1 +/- 0.1 (which is favorable for MPL stability, but not favorable at all for RT S, S stability). Therefore this formulation is intended for rapid use after preparation.The above is prepared by adding RTS, S antigen to a mix of Water for Injection, NaCl 150OmM, phosphate buffer (NaZK2) 50OmM (pH 6.8 when diluted x 50) and an aqueous solution of monothioglycerol at 10%. Then a premix of liposomes containing MPL with QS21 is added, and finally pH is adjusted. Example IBA final adult dose (1 vial formulation) for the RTS, S according to the invention may be prepared as follows:Component AmountRTS,S 50μgNaCl 4.5mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 250μg1 ,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 1000 μgCholesterol 250 μgMPL 50 μgQS21 50 μgWater for Injection Make volume to500 μLExample 1CExample 1C may prepared by putting Example 1, IA or IB in an amber vial, for example flushed with nitrogen before filing.

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WHO recommends groundbreaking malaria vaccine for children at risk

Historic RTS,S/AS01 recommendation can reinvigorate the fight against malaria6 October 2021https://www.who.int/news/item/06-10-2021-who-recommends-groundbreaking-malaria-vaccine-for-children-at-risk

The World Health Organization (WHO) is recommending widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children in sub-Saharan Africa and in other regions with moderate to high P. falciparum malaria transmission. The recommendation is based on results from an ongoing pilot programme in Ghana, Kenya and Malawi that has reached more than 800 000 children since 2019.

“This is a historic moment. The long-awaited malaria vaccine for children is a breakthrough for science, child health and malaria control,” said WHO Director-General Dr Tedros Adhanom Ghebreyesus. “Using this vaccine on top of existing  tools to prevent malaria could save tens of thousands of young lives each year.”

Malaria remains a primary cause of childhood illness and death in sub-Saharan Africa. More than 260 000 African children under the age of five die from malaria annually.

In recent years, WHO and its partners have been reporting a stagnation in progress against the deadly disease.

“For centuries, malaria has stalked sub-Saharan Africa, causing immense personal suffering,” said Dr Matshidiso Moeti, WHO Regional Director for Africa. “We have long hoped for an effective malaria vaccine and now for the first time ever, we have such a vaccine recommended for widespread use. Today’s recommendation offers a glimmer of hope for the continent which shoulders the heaviest burden of the disease and we expect many more African children to be protected from malaria and grow into healthy adults.”

WHO recommendation for the RTS,S malaria vaccine

Based on the advice of two WHO global advisory bodies, one for immunization and the other for malaria, the Organization recommends that:

WHO recommends that in the context of comprehensive malaria control the RTS,S/AS01 malaria vaccine be used for the prevention of P. falciparum malaria in children living in regions with moderate to high transmission as defined by WHO.  RTS,S/AS01 malaria vaccine should be provided in a schedule of 4 doses in children from 5 months of age for the reduction of malaria disease and burden.

Summary of key findings of the malaria vaccine pilots

Key findings of the pilots informed the recommendation based on data and insights generated from two years of vaccination in child health clinics in the three pilot countries, implemented under the leadership of the Ministries of Health of Ghana, Kenya and Malawi. Findings include:

  • Feasible to deliver: Vaccine introduction is feasible, improves health and saves lives, with good and equitable coverage of RTS,S seen through routine immunization systems. This occurred even in the context of the COVID-19 pandemic.
  • Reaching the unreached: RTS,S increases equity in access to malaria prevention.
    • Data from the pilot programme showed that more than two-thirds of children in the 3 countries who are not sleeping under a bednet are benefitting from the RTS,S vaccine.
    • Layering the tools results in over 90% of children benefitting from at least one preventive intervention (insecticide treated bednets or the malaria vaccine).
  • Strong safety profile: To date, more than 2.3 million doses of the vaccine have been administered in 3 African countries – the vaccine has a favorable safety profile.
  • No negative impact on uptake of bednets, other childhood vaccinations, or health seeking behavior for febrile illness. In areas where the vaccine has been introduced, there has been no decrease in the use of insecticide-treated nets, uptake of other childhood vaccinations or health seeking behavior for febrile illness.
  • High impact in real-life childhood vaccination settings: Significant reduction (30%) in deadly severe malaria, even when introduced in areas where insecticide-treated nets are widely used and there is good access to diagnosis and treatment.
  • Highly cost-effective: Modelling estimates that the vaccine is cost effective in areas of moderate to high malaria transmission.

Next steps for the WHO-recommended malaria vaccine will include funding decisions from the global health community for broader rollout, and country decision-making on whether to adopt the vaccine as part of national malaria control strategies.

Financial support

Financing for the pilot programme has been mobilized through an unprecedented collaboration among three key global health funding bodies: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

Note to editors:

  • The malaria vaccine, RTS,S, acts against P. falciparum, the most deadly malaria parasite globally, and the most prevalent in Africa.
  • The Malaria Vaccine Implementation Programme is generating evidence and experience on the feasibility, impact and safety of the RTS,S malaria vaccine in real-life, routine settings in selected areas of Ghana, Kenya and Malawi.
  • Pilot malaria vaccine introductions are led by the Ministries of Health of Ghana, Kenya and Malawi.
  • The pilot programme will continue in the 3 pilot countries to understand the added value of the 4th vaccine dose, and to measure longer-term impact on child deaths.
  • The Malaria Vaccine Implementation Programme is coordinated by WHO and supported by in-country and international partners, including PATH, UNICEF and GSK, which is donating up to 10 million doses of the vaccine for the pilot.
  • The RTS,S malaria vaccine is the result of 30 years of research and development by GSK and through a partnership with PATH, with support from a network of African research centres.
  • The Bill & Melinda Gates Foundation provided catalytic funding for late-stage development of RTS,S between 2001 and 2015.

RTS,S/AS01 (trade name Mosquirix) is a recombinant protein-based malaria vaccine. In October 2021, the vaccine was endorsed by the World Health Organization (WHO) for “broad use” in children, making it the first malaria vaccine candidate, and first vaccine to address parasitic infection, to receive this recommendation.[3][4][5]

The RTS,S vaccine was conceived of and created in the late 1980s by scientists working at SmithKline Beecham Biologicals (now GlaxoSmithKline (GSK) Vaccines) laboratories in Belgium.[6] The vaccine was further developed through a collaboration between GSK and the Walter Reed Army Institute of Research in the U.S. state of Maryland[7] and has been funded in part by the PATH Malaria Vaccine Initiative and the Bill and Melinda Gates Foundation. Its efficacy ranges from 26 to 50% in infants and young children.

Approved for use by the European Medicines Agency (EMA) in July 2015,[1] it is the world’s first licensed malaria vaccine and also the first vaccine licensed for use against a human parasitic disease of any kind.[8] On 23 October 2015, WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee (MPAC) jointly recommended a pilot implementation of the vaccine in Africa.[9] This pilot project for vaccination was launched on 23 April 2019 in Malawi, on 30 April 2019 in Ghana, and on 13 September 2019 in Kenya.[10][11]

Background

Main article: Malaria vaccine

Potential malaria vaccines have been an intense area of research since the 1960s.[12] SPf66 was tested extensively in endemic areas in the 1990s, but clinical trials showed it to be insufficiently effective.[13] Other vaccine candidates, targeting the blood-stage of the malaria parasite’s life cycle, have also been insufficient on their own.[14] Among several potential vaccines under development that target the pre-erythrocytic stage of the disease, RTS,S has shown the most promising results so far.[15]

Approval history

The EMA approved the RTS,S vaccine in July 2015, with a recommendation that it be used in Africa for babies at risk of getting malaria. RTS,S was the world’s first malaria vaccine to get approval for this use.[16][8] Preliminary research suggests that delayed fractional dosing could increase the vaccine’s efficacy up to 86%.[17][18]

On 17 November 2016, WHO announced that the RTS,S vaccine would be rolled out in pilot projects in three countries in sub-Saharan Africa. The pilot program, coordinated by WHO, will assess the extent to which the vaccine’s protective effect shown in advanced clinical trials can be replicated in real-life settings. Specifically, the programme will evaluate the feasibility of delivering the required four doses of the vaccine; the impact of the vaccine on lives saved; and the safety of the vaccine in the context of routine use.[19]

Vaccinations by the ministries of health of Malawi, Ghana, and Kenya began in April and September 2019 and target 360,000 children per year in areas where vaccination would have the highest impact. The results are planned to be used by the World Health Organization to advise about a possible future deployment of the vaccine.[10][11][20] In 2021 it was reported that the vaccine together with other anti-malaria medication when given at the most vulnerable season could reduce deaths and illness from the disease by 70%.[21][22]

Funding

RTS,S has been funded, most recently, by the non-profit PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline with funding from the Bill and Melinda Gates Foundation.[23] The RTS,S-based vaccine formulation had previously been demonstrated to be safe, well tolerated, immunogenic, and to potentially confer partial efficacy in both malaria-naive and malaria-experienced adults as well as children.[24]

Components and mechanism

 

The RTS,S vaccine is based on a protein construct first developed by GlaxoSmithKline in 1986. It was named RTS because it was engineered using genes from the repeat (‘R’) and T-cell epitope (‘T’) of the pre-erythrocytic circumsporozoite protein (CSP) of the Plasmodium falciparum malaria parasite together with a viral surface antigen (‘S’) of the hepatitis B virus (HBsAg).[7] This protein was then mixed with additional HBsAg to improve purification, hence the extra “S”.[7] Together, these two protein components assemble into soluble virus-like particles similar to the outer shell of a hepatitis B virus.[25]

A chemical adjuvant (AS01, specifically AS01E) was added to increase the immune system response.[26] Infection is prevented by inducing humoral and cellular immunity, with high antibody titers, that block the parasite from infecting the liver.[27]

The T-cell epitope of CSP is O-fucosylated in Plasmodium falciparum[28][29] and Plasmodium vivax,[30] while the RTS,S vaccine produced in yeast is not.

References

  1. Jump up to:a b “Mosquirix H-W-2300”European Medicines Agency (EMA). Retrieved 4 March 2021.
  2. ^ “RTS,S Malaria Vaccine: 2019 Partnership Award Honoree”YouTube. Global Health Technologies Coalition. Retrieved 6 October 2021.
  3. ^ Davies L (6 October 2021). “WHO endorses use of world’s first malaria vaccine in Africa”The Guardian. Retrieved 6 October2021.
  4. ^ Drysdale C, Kelleher K. “WHO recommends groundbreaking malaria vaccine for children at risk” (Press release). Geneva: World Health Organization. Retrieved 6 October 2021.
  5. ^ Mandavilli A (6 October 2021). “A ‘Historical Event’: First Malaria Vaccine Approved by W.H.O.” New York Times. Retrieved 6 October 2021.
  6. ^ “HYBRID PROTEIN BETWEEN CS FROM PLASMODIUM AND HBsAG”.
  7. Jump up to:a b c Heppner DG, Kester KE, Ockenhouse CF, Tornieporth N, Ofori O, Lyon JA, et al. (March 2005). “Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research”Vaccine23 (17–18): 2243–50. doi:10.1016/j.vaccine.2005.01.142PMID 15755604Archived from the original on 23 July 2018.
  8. Jump up to:a b Walsh F (24 July 2015). “Malaria vaccine gets ‘green light'”BBC NewsArchived from the original on 21 July 2020. Retrieved 25 July 2015.
  9. ^ Stewart S (23 October 2015). “Pilot implementation of first malaria vaccine recommended by WHO advisory groups” (Press release). Geneva: World Health OrganizationArchived from the original on 19 September 2021.
  10. Jump up to:a b Alonso P (19 June 2019). “Letter to partners – June 2019”(Press release). Wuxi: World Health Organization. Retrieved 22 October 2019.
  11. Jump up to:a b “Malaria vaccine launched in Kenya: Kenya joins Ghana and Malawi to roll out landmark vaccine in pilot introduction” (Press release). Homa Bay: World Health Organization. 13 September 2019. Retrieved 22 October 2019.
  12. ^ Hill AV (October 2011). “Vaccines against malaria”Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences366 (1579): 2806–14. doi:10.1098/rstb.2011.0091PMC 3146776PMID 21893544.
  13. ^ Graves P, Gelband H (April 2006). Graves PM (ed.). “Vaccines for preventing malaria (SPf66)”The Cochrane Database of Systematic Reviews (2): CD005966. doi:10.1002/14651858.CD005966PMC 6532709PMID 16625647.
  14. ^ Graves P, Gelband H (October 2006). Graves PM (ed.). “Vaccines for preventing malaria (blood-stage)”The Cochrane Database of Systematic Reviews (4): CD006199. doi:10.1002/14651858.CD006199PMC 6532641PMID 17054281.
  15. ^ Graves P, Gelband H (October 2006). Graves PM (ed.). “Vaccines for preventing malaria (pre-erythrocytic)”The Cochrane Database of Systematic Reviews (4): CD006198. doi:10.1002/14651858.CD006198PMC 6532586PMID 17054280.
  16. ^ “First malaria vaccine receives positive scientific opinion from EMA”European Medicines Agency. 24 July 2015. Retrieved 24 July 2015.
  17. ^ Birkett A (16 September 2016). “A vaccine for malaria elimination?”PATH.
  18. ^ Regules JA, Cicatelli SB, Bennett JW, Paolino KM, Twomey PS, Moon JE, et al. (September 2016). “Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study”The Journal of Infectious Diseases214 (5): 762–71. doi:10.1093/infdis/jiw237PMID 27296848.
  19. ^ “Malaria: The malaria vaccine implementation programme (MVIP)”.
  20. ^ “WHO | MVIP countries: Ghana, Kenya and Malawi”.
  21. ^ Chandramohan D, Zongo I, Sagara I, Cairns M, Yerbanga RS, Diarra M, et al. (September 2021). “Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention”The New England Journal of Medicine385 (11): 1005–1017. doi:10.1056/NEJMoa2026330PMID 34432975.
  22. ^ Roxby P (26 August 2021). “Trial suggests malaria sickness could be cut by 70%”BBC NewsArchived from the original on 3 October 2021. Retrieved 26 August 2021.
  23. ^ Stein R (18 October 2011). “Experimental malaria vaccine protects many children, study shows”Washington Post.
  24. ^ Regules JA, Cummings JF, Ockenhouse CF (May 2011). “The RTS,S vaccine candidate for malaria”Expert Review of Vaccines10 (5): 589–99. doi:10.1586/erv.11.57PMID 21604980S2CID 20443829.
  25. ^ Rutgers T, Gordon D, Gathoye AM, Hollingdale M, Hockmeyer W, Rosenberg M, De Wilde M (September 1988). “Hepatitis B Surface Antigen as Carrier Matrix for the Repetitive Epitope of the Circumsporozoite Protein of Plasmodium Falciparum”Nature Biotechnology6 (9): 1065–1070. doi:10.1038/nbt0988-1065S2CID 39880644.
  26. ^ RTS,S Clinical Trials Partnership (July 2015). “Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial”Lancet386 (9988): 31–45. doi:10.1016/S0140-6736(15)60721-8PMC 5626001PMID 25913272.
  27. ^ Foquet L, Hermsen CC, van Gemert GJ, Van Braeckel E, Weening KE, Sauerwein R, et al. (January 2014). “Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection”The Journal of Clinical Investigation124 (1): 140–4. doi:10.1172/JCI70349PMC 3871238PMID 24292709.
  28. ^ Swearingen KE, Lindner SE, Shi L, Shears MJ, Harupa A, Hopp CS, et al. (April 2016). “Interrogating the Plasmodium Sporozoite Surface: Identification of Surface-Exposed Proteins and Demonstration of Glycosylation on CSP and TRAP by Mass Spectrometry-Based Proteomics”PLOS Pathogens12 (4): e1005606. doi:10.1371/journal.ppat.1005606PMC 4851412PMID 27128092.
  29. ^ Lopaticki S, Yang AS, John A, Scott NE, Lingford JP, O’Neill MT, et al. (September 2017). “Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts”Nature Communications8 (1): 561. Bibcode:2017NatCo…8..561Ldoi:10.1038/s41467-017-00571-yPMC 5601480PMID 28916755.
  30. ^ Swearingen KE, Lindner SE, Flannery EL, Vaughan AM, Morrison RD, Patrapuvich R, et al. (July 2017). “Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites”PLOS Neglected Tropical Diseases11 (7): e0005791. doi:10.1371/journal.pntd.0005791PMC 5552340PMID 28759593.

Further reading

  • Wilby KJ, Lau TT, Gilchrist SE, Ensom MH (March 2012). “Mosquirix (RTS,S): a novel vaccine for the prevention of Plasmodium falciparum malaria”. The Annals of Pharmacotherapy46 (3): 384–93. doi:10.1345/aph.1Q634PMID 22408046.
  • Asante KP, Abdulla S, Agnandji S, Lyimo J, Vekemans J, Soulanoudjingar S, et al. (October 2011). “Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial”. The Lancet. Infectious Diseases11 (10): 741–9. doi:10.1016/S1473-3099(11)70100-1PMID 21782519.

External links

Vaccine description
TargetP. falciparum; to a lesser extent Hepatitis B
Vaccine typeProtein subunit
Clinical data
Trade namesMosquirix
Routes of
administration
intramuscular injection (0.5 mL)[1]
Legal status
Legal statusIn general: ℞ (Prescription only)

A poster advertising trials of the RTS,S vaccine[2]

malaria vaccine is a vaccine that is used to prevent malaria. The only approved vaccine as of 2021, is RTS,S, known by the brand name Mosquirix.[1] It requires four injections.[1]

Research continues with other malaria vaccines. The most effective malaria vaccine is R21/Matrix-M, with a 77% efficacy rate shown in initial trials, and significantly higher antibody levels than with the RTS,S vaccine.[2] It is the first vaccine that meets the World Health Organization‘s (WHO) goal of a malaria vaccine with at least 75% efficacy.[3][2]

Approved vaccines

RTS,S

Main article: RTS,S

RTS,S (developed by PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline (GSK) with support from the Bill and Melinda Gates Foundation) is the most recently developed recombinant vaccine. It consists of the P. falciparum circumsporozoite protein (CSP) from the pre-erythrocytic stage. The CSP antigen causes the production of antibodies capable of preventing the invasion of hepatocytes and additionally elicits a cellular response enabling the destruction of infected hepatocytes. The CSP vaccine presented problems in the trial stage, due to its poor immunogenicity. RTS,S attempted to avoid these by fusing the protein with a surface antigen from hepatitis B, hence creating a more potent and immunogenic vaccine. When tested in trials an emulsion of oil in water and the added adjuvants of monophosphoryl A and QS21 (SBAS2), the vaccine gave protective immunity to 7 out of 8 volunteers when challenged with P. falciparum.[4]

RTS,S/AS01 (commercial name Mosquirix),[5] was engineered using genes from the outer protein of P. falciparum malaria parasite and a portion of a hepatitis B virus plus a chemical adjuvant to boost the immune response. Infection is prevented by inducing high antibody titers that block the parasite from infecting the liver.[6] In November 2012, a Phase III trial of RTS,S found that it provided modest protection against both clinical and severe malaria in young infants.[7]

As of October 2013, preliminary results of a Phase III clinical trial indicated that RTS,S/AS01 reduced the number of cases among young children by almost 50 percent and among infants by around 25 percent. The study ended in 2014. The effects of a booster dose were positive, even though overall efficacy seems to wane with time. After four years reductions were 36 percent for children who received three shots and a booster dose. Missing the booster dose reduced the efficacy against severe malaria to a negligible effect. The vaccine was shown to be less effective for infants. Three doses of vaccine plus a booster reduced the risk of clinical episodes by 26 percent over three years, but offered no significant protection against severe malaria.[8]

In a bid to accommodate a larger group and guarantee a sustained availability for the general public, GSK applied for a marketing license with the European Medicines Agency (EMA) in July 2014.[9] GSK treated the project as a non-profit initiative, with most funding coming from the Gates Foundation, a major contributor to malaria eradication.[10]

On 24 July 2015, Mosquirix received a positive opinion from the European Medicines Agency (EMA) on the proposal for the vaccine to be used to vaccinate children aged 6 weeks to 17 months outside the European Union.[11][12][1] A pilot project for vaccination was launched on 23 April 2019, in Malawi, on 30 April 2019, in Ghana, and on 13 September 2019, in Kenya.[13][14]

In October 2021, the vaccine was endorsed by the World Health Organization for “broad use” in children, making it the first malaria vaccine to receive this recommendation.[15][16][17]

Agents under development

A completely effective vaccine is not available for malaria, although several vaccines are under development. Multiple vaccine candidates targeting the blood-stage of the parasite’s life cycle have been insufficient on their own.[18] Several potential vaccines targeting the pre-erythrocytic stage are being developed, with RTS,S the only approved option so far.[19][7]

R21/Matrix-M

The most effective malaria vaccine is R21/Matrix-M, with 77% efficacy shown in initial trials. It is the first vaccine that meets the World Health Organization’s goal of a malaria vaccine with at least 75% efficacy.[3] It was developed through a collaboration involving the University of Oxford, the Kenya Medical Research Institute, the London School of Hygiene & Tropical MedicineNovavax, the Serum Institute of India, and the Institut de Recherche en Sciences de la Santé in NanoroBurkina Faso. The R21 vaccine uses a circumsporozoite protein (CSP) antigen, at a higher proportion than the RTS,S vaccine. It includes the Matrix-M adjuvant that is also utilized in the Novavax COVID-19 vaccine.[20]

A Phase II trial was reported in April 2021, with a vaccine efficacy of 77% and antibody levels significantly higher than with the RTS,S vaccine. A Phase III trial is planned with 4,800 children across four African countries. If the vaccine is approved, over 200 million doses can be manufactured annually by the Serum Institute of India.[2]

Nanoparticle enhancement of RTS,S

In 2015, researchers used a repetitive antigen display technology to engineer a nanoparticle that displayed malaria specific B cell and T cell epitopes. The particle exhibited icosahedral symmetry and carried on its surface up to 60 copies of the RTS,S protein. The researchers claimed that the density of the protein was much higher than the 14% of the GSK vaccine.[21][22]

PfSPZ vaccine

Main article: PfSPZ Vaccine

The PfSPZ vaccine is a candidate malaria vaccine developed by Sanaria using radiation-attenuated sporozoites to elicit an immune response. Clinical trials have been promising, with trials taking place in Africa, Europe, and the US protecting over 80% of volunteers.[23] It has been subject to some criticism regarding the ultimate feasibility of large-scale production and delivery in Africa, since it must be stored in liquid nitrogen.

The PfSPZ vaccine candidate was granted fast track designation by the U.S. Food and Drug Administration in September 2016.[24]

In April 2019, a phase 3 trial in Bioko was announced, scheduled to start in early 2020.[25]

saRNA vaccine against PMIF

A patent was published in February 2021 for a Self-amplifying RNA (saRNA) vaccine that targets the protein PMIF, which is produced by the plasmodium parasite to inhibit the body’s T-cell response. The vaccine has been tested in mice and is described as, “probably the highest level of protection that has been seen in a mouse model” according to Richard Bucala, co-inventor of the vaccine. There are plans for phase one tests in humans later in 2021.[26]

Other developments

  • SPf66 is a synthetic peptide based vaccine developed by Manuel Elkin Patarroyo team in Colombia, and was tested extensively in endemic areas in the 1990s. Clinical trials showed it to be insufficiently effective, with 28% efficacy in South America and minimal or no efficacy in Africa.[27]
  • The CSP (Circum-Sporozoite Protein) was a vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporozoite protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed.[citation needed]
  • The NYVAC-Pf7 multi-stage vaccine attempted to use different technology, incorporating seven P.falciparum antigenic genes. These came from a variety of stages during the life cycle. CSP and sporozoite surface protein 2 (called PfSSP2) were derived from the sporozoite phase. The liver stage antigen 1 (LSA1), three from the erythrocytic stage (merozoite surface protein 1, serine repeat antigen and AMA-1) and one sexual stage antigen (the 25-kDa Pfs25) were included. This was first investigated using Rhesus monkeys and produced encouraging results: 4 out of the 7 antigens produced specific antibody responses (CSP, PfSSP2, MSP1 and PFs25). Later trials in humans, despite demonstrating cellular immune responses in over 90% of the subjects, had very poor antibody responses. Despite this following administration of the vaccine some candidates had complete protection when challenged with P.falciparum. This result has warranted ongoing trials.[citation needed]
  • In 1995 a field trial involving [NANP]19-5.1 proved to be very successful. Out of 194 children vaccinated none developed symptomatic malaria in the 12-week follow up period and only 8 failed to have higher levels of antibody present. The vaccine consists of the schizont export protein (5.1) and 19 repeats of the sporozoite surface protein [NANP]. Limitations of the technology exist as it contains only 20% peptide and has low levels of immunogenicity. It also does not contain any immunodominant T-cell epitopes.[28]
  • A chemical compound undergoing trials for treatment of tuberculosis and cancer—the JmJc inhibitor ML324 and the antitubercular clinical candidate SQ109—is potentially a new line of drugs to treat malaria and kill the parasite in its infectious stage. More tests still need to be carried out before the compounds would be approved as a viable treatment.[29]

Considerations

The task of developing a preventive vaccine for malaria is a complex process. There are a number of considerations to be made concerning what strategy a potential vaccine should adopt.

Parasite diversity

P. falciparum has demonstrated the capability, through the development of multiple drug-resistant parasites, for evolutionary change. The Plasmodium species has a very high rate of replication, much higher than that actually needed to ensure transmission in the parasite’s life cycle. This enables pharmaceutical treatments that are effective at reducing the reproduction rate, but not halting it, to exert a high selection pressure, thus favoring the development of resistance. The process of evolutionary change is one of the key considerations necessary when considering potential vaccine candidates. The development of resistance could cause a significant reduction in efficacy of any potential vaccine thus rendering useless a carefully developed and effective treatment.[30]

Choosing to address the symptom or the source

The parasite induces two main response types from the human immune system. These are anti-parasitic immunity and anti-toxic immunity.

  • “Anti-parasitic immunity” addresses the source; it consists of an antibody response (humoral immunity) and a cell-mediated immune response. Ideally a vaccine would enable the development of anti-plasmodial antibodies in addition to generating an elevated cell-mediated response. Potential antigens against which a vaccine could be targeted will be discussed in greater depth later. Antibodies are part of the specific immune response. They exert their effect by activating the complement cascade, stimulating phagocytic cells into endocytosis through adhesion to an external surface of the antigenic substances, thus ‘marking’ it as offensive. Humoral or cell-mediated immunity consists of many interlinking mechanisms that essentially aim to prevent infection entering the body (through external barriers or hostile internal environments) and then kill any micro-organisms or foreign particles that succeed in penetration. The cell-mediated component consists of many white blood cells (such as monocytesneutrophilsmacrophageslymphocytesbasophilsmast cellsnatural killer cells, and eosinophils) that target foreign bodies by a variety of different mechanisms. In the case of malaria both systems would be targeted to attempt to increase the potential response generated, thus ensuring the maximum chance of preventing disease.[citation needed]
  • “Anti-toxic immunity” addresses the symptoms; it refers to the suppression of the immune response associated with the production of factors that either induce symptoms or reduce the effect that any toxic by-products (of micro-organism presence) have on the development of disease. For example, it has been shown that Tumor necrosis factor-alpha has a central role in generating the symptoms experienced in severe P. falciparum malaria. Thus a therapeutic vaccine could target the production of TNF-a, preventing respiratory distress and cerebral symptoms. This approach has serious limitations as it would not reduce the parasitic load; rather it only reduces the associated pathology. As a result, there are substantial difficulties in evaluating efficacy in human trials.

Taking this information into consideration an ideal vaccine candidate would attempt to generate a more substantial cell-mediated and antibody response on parasite presentation. This would have the benefit of increasing the rate of parasite clearance, thus reducing the experienced symptoms and providing a level of consistent future immunity against the parasite.

Potential targets

See also: PfSPZ Vaccine

Parasite stageTarget
SporozoiteHepatocyte invasion; direct anti-sporozite
HepatozoiteDirect anti-hepatozoite.
Asexual erythrocyticAnti-host erythrocyte, antibodies blocking invasion; anti receptor ligand, anti-soluble toxin
GametocytesAnti-gametocyte. Anti-host erythrocyte, antibodies blocking fertilisation, antibodies blocking egress from the mosquito midgut.

By their very nature, protozoa are more complex organisms than bacteria and viruses, with more complicated structures and life cycles. This presents problems in vaccine development but also increases the number of potential targets for a vaccine. These have been summarised into the life cycle stage and the antibodies that could potentially elicit an immune response.

The epidemiology of malaria varies enormously across the globe, and has led to the belief that it may be necessary to adopt very different vaccine development strategies to target the different populations. A Type 1 vaccine is suggested for those exposed mostly to P. falciparum malaria in sub-Saharan Africa, with the primary objective to reduce the number of severe malaria cases and deaths in infants and children exposed to high transmission rates. The Type 2 vaccine could be thought of as a ‘travellers’ vaccine’, aiming to prevent all cases of clinical symptoms in individuals with no previous exposure. This is another major public health problem, with malaria presenting as one of the most substantial threats to travellers’ health. Problems with the available pharmaceutical therapies include costs, availability, adverse effects and contraindications, inconvenience and compliance, many of which would be reduced or eliminated entirely if an effective (greater than 85–90%) vaccine was developed.[citation needed]

The life cycle of the malaria parasite is particularly complex, presenting initial developmental problems. Despite the huge number of vaccines available, there are none that target parasitic infections. The distinct developmental stages involved in the life cycle present numerous opportunities for targeting antigens, thus potentially eliciting an immune response. Theoretically, each developmental stage could have a vaccine developed specifically to target the parasite. Moreover, any vaccine produced would ideally have the ability to be of therapeutic value as well as preventing further transmission and is likely to consist of a combination of antigens from different phases of the parasite’s development. More than 30 of these antigens are being researched[when?] by teams all over the world in the hope of identifying a combination that can elicit immunity in the inoculated individual. Some of the approaches involve surface expression of the antigen, inhibitory effects of specific antibodies on the life cycle and the protective effects through immunization or passive transfer of antibodies between an immune and a non-immune host. The majority of research into malarial vaccines has focused on the Plasmodium falciparum strain due to the high mortality caused by the parasite and the ease of a carrying out in vitro/in vivo studies. The earliest vaccines attempted to use the parasitic circumsporozoite protein (CSP). This is the most dominant surface antigen of the initial pre-erythrocytic phase. However, problems were encountered due to low efficacy, reactogenicity and low immunogenicity.[citation needed]

  • The initial stage in the life cycle, following inoculation, is a relatively short “pre-erythrocytic” or “hepatic” phase. A vaccine at this stage must have the ability to protect against sporozoites invading and possibly inhibiting the development of parasites in the hepatocytes (through inducing cytotoxic T-lymphocytes that can destroy the infected liver cells). However, if any sporozoites evaded the immune system they would then have the potential to be symptomatic and cause the clinical disease.
  • The second phase of the life cycle is the “erythrocytic” or blood phase. A vaccine here could prevent merozoite multiplication or the invasion of red blood cells. This approach is complicated by the lack of MHC molecule expression on the surface of erythrocytes. Instead, malarial antigens are expressed, and it is this towards which the antibodies could potentially be directed. Another approach would be to attempt to block the process of erythrocyte adherence to blood vessel walls. It is thought that this process is accountable for much of the clinical syndrome associated with malarial infection; therefore a vaccine given during this stage would be therapeutic and hence administered during clinical episodes to prevent further deterioration.
  • The last phase of the life cycle that has the potential to be targeted by a vaccine is the “sexual stage”. This would not give any protective benefits to the individual inoculated but would prevent further transmission of the parasite by preventing the gametocytes from producing multiple sporozoites in the gut wall of the mosquito. It therefore would be used as part of a policy directed at eliminating the parasite from areas of low prevalence or to prevent the development and spread of vaccine-resistant parasites. This type of transmission-blocking vaccine is potentially very important. The evolution of resistance in the malaria parasite occurs very quickly, potentially making any vaccine redundant within a few generations. This approach to the prevention of spread is therefore essential.
  • Another approach is to target the protein kinases, which are present during the entire lifecycle of the malaria parasite. Research is underway on this, yet production of an actual vaccine targeting these protein kinases may still take a long time.[31]
  • Report of a vaccine candidate capable to neutralize all tested strains of Plasmodium falciparum, the most deadly form of the parasite causing malaria, was published in Nature Communications by a team of scientists from the University of Oxford in 2011.[32] The viral vector vaccine, targeting a full-length P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) was found to induce an antibody response in an animal model. The results of this new vaccine confirmed the utility of a key discovery reported from scientists at the Wellcome Trust Sanger Institute, published in Nature.[33] The earlier publication reported P. falciparum relies on a red blood cell surface receptor, known as ‘basigin’, to invade the cells by binding a protein PfRH5 to the receptor.[33] Unlike other antigens of the malaria parasite which are often genetically diverse, the PfRH5 antigen appears to have little genetic diversity. It was found to induce very low antibody response in people naturally exposed to the parasite.[32] The high susceptibility of PfRH5 to the cross-strain neutralizing vaccine-induced antibody demonstrated a significant promise for preventing malaria in the long and often difficult road of vaccine development. According to Professor Adrian Hill, a Wellcome Trust Senior Investigator at the University of Oxford, the next step would be the safety tests of this vaccine. At the time (2011) it was projected that if these proved successful, the clinical trials in patients could begin within two to three years.[34]
  • PfEMP1, one of the proteins known as variant surface antigens (VSAs) produced by Plasmodium falciparum, was found to be a key target of the immune system’s response against the parasite. Studies of blood samples from 296 mostly Kenyan children by researchers of Burnet Institute and their cooperators showed that antibodies against PfEMP1 provide protective immunity, while antibodies developed against other surface antigens do not. Their results demonstrated that PfEMP1 could be a target to develop an effective vaccine which will reduce risk of developing malaria.[35][36]
  • Plasmodium vivax is the common malaria species found in India, Southeast Asia and South America. It is able to stay dormant in the liver and reemerge years later to elicit new infections. Two key proteins involved in the invasion of the red blood cells (RBC) by P. vivax are potential targets for drug or vaccine development. When the Duffy binding protein (DBP) of P. vivax binds the Duffy antigen (DARC) on the surface of RBC, process for the parasite to enter the RBC is initiated. Structures of the core region of DARC and the receptor binding pocket of DBP have been mapped by scientists at the Washington University in St. Louis. The researchers found that the binding is a two-step process which involves two copies of the parasite protein acting together like a pair of tongs which “clamp” two copies of DARC. Antibodies that interfere with the binding, by either targeting the key region of the DARC or the DBP will prevent the infection.[37][38]
  • Antibodies against the Schizont Egress Antigen-1 (PfSEA-1) were found to disable the parasite ability to rupture from the infected red blood cells (RBCs) thus prevent it from continuing with its life cycle. Researchers from Rhode Island Hospital identified Plasmodium falciparum PfSEA-1, a 244 kd malaria antigen expressed in the schizont-infected RBCs. Mice vaccinated with the recombinant PfSEA-1 produced antibodies which interrupted the schizont rupture from the RBCs and decreased the parasite replication. The vaccine protected the mice from lethal challenge of the parasite. Tanzanian and Kenyan children who have antibodies to PfSEA-1 were found to have fewer parasites in their blood stream and milder case of malaria. By blocking the schizont outlet, the PfSEA-1 vaccine may work synergistically with vaccines targeting the other stages of the malaria life cycle such as hepatocyte and RBC invasion.[39][40]

Mix of antigenic components

Increasing the potential immunity generated against Plasmodia can be achieved by attempting to target multiple phases in the life cycle. This is additionally beneficial in reducing the possibility of resistant parasites developing. The use of multiple-parasite antigens can therefore have a synergistic or additive effect.

One of the most successful vaccine candidates in clinical trials[which?][when?] consists of recombinant antigenic proteins to the circumsporozoite protein.[41] (This is discussed in more detail below.)[where?]

Delivery system

 

The selection of an appropriate system is fundamental in all vaccine development, but especially so in the case of malaria. A vaccine targeting several antigens may require delivery to different areas and by different means in order to elicit an effective response. Some adjuvants can direct the vaccine to the specifically targeted cell type—e.g. the use of Hepatitis B virus in the RTS,S vaccine to target infected hepatocytes—but in other cases, particularly when using combined antigenic vaccines, this approach is very complex. Some methods that have been attempted include the use of two vaccines, one directed at generating a blood response and the other a liver-stage response. These two vaccines could then be injected into two different sites, thus enabling the use of a more specific and potentially efficacious delivery system.

To increase, accelerate or modify the development of an immune response to a vaccine candidate it is often necessary to combine the antigenic substance to be delivered with an adjuvant or specialised delivery system. These terms are often used interchangeably in relation to vaccine development; however in most cases a distinction can be made. An adjuvant is typically thought of as a substance used in combination with the antigen to produce a more substantial and robust immune response than that elicited by the antigen alone. This is achieved through three mechanisms: by affecting the antigen delivery and presentation, by inducing the production of immunomodulatory cytokines, and by affecting the antigen presenting cells (APC). Adjuvants can consist of many different materials, from cell microparticles to other particulated delivery systems (e.g. liposomes).

Adjuvants are crucial in affecting the specificity and isotype of the necessary antibodies. They are thought to be able to potentiate the link between the innate and adaptive immune responses. Due to the diverse nature of substances that can potentially have this effect on the immune system, it is difficult to classify adjuvants into specific groups. In most circumstances they consist of easily identifiable components of micro-organisms that are recognised by the innate immune system cells. The role of delivery systems is primarily to direct the chosen adjuvant and antigen into target cells to attempt to increase the efficacy of the vaccine further, therefore acting synergistically with the adjuvant.

There is increasing concern that the use of very potent adjuvants could precipitate autoimmune responses, making it imperative that the vaccine is focused on the target cells only. Specific delivery systems can reduce this risk by limiting the potential toxicity and systemic distribution of newly developed adjuvants.

Studies into the efficacy of malaria vaccines developed to date[when?] have illustrated that the presence of an adjuvant is key in determining any protection gained against malaria. A large number of natural and synthetic adjuvants have been identified throughout the history of vaccine development. Options identified thus far for use combined with a malaria vaccine include mycobacterial cell walls, liposomes, monophosphoryl lipid A and squalene.

History

Individuals who are exposed to the parasite in endemic countries develop acquired immunity against disease and death. Such immunity does not however prevent malarial infection; immune individuals often harbour asymptomatic parasites in their blood. This does, however, imply that it is possible to create an immune response that protects against the harmful effects of the parasite.

Research shows that if immunoglobulin is taken from immune adults, purified and then given to individuals who have no protective immunity, some protection can be gained.[42]

Irradiated mosquitoes

In 1967, it was reported that a level of immunity to the Plasmodium berghei parasite could be given to mice by exposing them to sporozoites that had been irradiated by x-rays.[43] Subsequent human studies in the 1970s showed that humans could be immunized against Plasmodium vivax and Plasmodium falciparum by exposing them to the bites of significant numbers of irradiated mosquitos.[44]

From 1989 to 1999, eleven volunteers recruited from the United States Public Health ServiceUnited States Army, and United States Navy were immunized against Plasmodium falciparum by the bites of 1001–2927 mosquitoes that had been irradiated with 15,000 rads of gamma rays from a Co-60 or Cs-137 source.[45] This level of radiation is sufficient to attenuate the malaria parasites so that, while they can still enter hepatic cells, they cannot develop into schizonts nor infect red blood cells.[45] Over a span of 42 weeks, 24 of 26 tests on the volunteers showed that they were protected from malaria.[46]

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  35. ^ Parish T (2 August 2012). “Lifting malaria’s deadly veil: Mystery solved in quest for vaccine”. Burnet Institute. Retrieved 14 August2012.
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  37. ^ Mullin E (13 January 2014). “Scientists capture key protein structures that could aid malaria vaccine design”. fiercebiotechresearch.com. Retrieved 16 January 2014.
  38. ^ Batchelor JD, Malpede BM, Omattage NS, DeKoster GT, Henzler-Wildman KA, Tolia NH (January 2014). “Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC”PLOS Pathogens10 (1): e1003869. doi:10.1371/journal.ppat.1003869PMC 3887093PMID 24415938.
  39. ^ Mullin E (27 May 2014). “Antigen Discovery could advance malaria vaccine”. fiercebiotechresearch.com. Retrieved 22 June2014.
  40. ^ Raj DK, Nixon CP, Nixon CE, Dvorin JD, DiPetrillo CG, Pond-Tor S, et al. (May 2014). “Antibodies to PfSEA-1 block parasite egress from RBCs and protect against malaria infection”Science344(6186): 871–7. Bibcode:2014Sci…344..871Rdoi:10.1126/science.1254417PMC 4184151PMID 24855263.
  41. ^ Plassmeyer ML, Reiter K, Shimp RL, Kotova S, Smith PD, Hurt DE, et al. (September 2009). “Structure of the Plasmodium falciparum circumsporozoite protein, a leading malaria vaccine candidate”The Journal of Biological Chemistry284 (39): 26951–63. doi:10.1074/jbc.M109.013706PMC 2785382PMID 19633296.
  42. ^ “Immunoglobulin Therapy & Other Medical Therapies for Antibody Deficiencies”Immune Deficiency Foundation. Retrieved 30 September 2019.
  43. ^ Nussenzweig RS, Vanderberg J, Most H, Orton C (October 1967). “Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei”. Nature216 (5111): 160–2. Bibcode:1967Natur.216..160Ndoi:10.1038/216160a0PMID 6057225S2CID 4283134.
  44. ^ Clyde DF (May 1975). “Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites”. The American Journal of Tropical Medicine and Hygiene24 (3): 397–401. doi:10.4269/ajtmh.1975.24.397PMID 808142.
  45. Jump up to:a b Hoffman SL, Goh LM, Luke TC, Schneider I, Le TP, Doolan DL, et al. (April 2002). “Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites”The Journal of Infectious Diseases185 (8): 1155–64. doi:10.1086/339409PMID 11930326.
  46. ^ Hoffman SL, Goh LM, Luke TC, Schneider I, Le TP, Doolan DL, et al. (April 2002). “Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites”The Journal of Infectious Diseases185 (8): 1155–64. doi:10.1086/339409PMID 11930326.

Further reading

External links

Screened cup of malaria-infected mosquitoes which will infect a volunteer in a clinical trial
Vaccine description
TargetMalaria
Vaccine typeProtein subunit
Clinical data
Trade namesMosquirix
Routes of
administration
Intramuscular[1]
ATC codeNone
Legal status
Legal statusEU: Rx-only [1]
Identifiers
CAS Number149121-47-1
ChemSpidernone

//////////////RTS,S/AS01, Mosquirix, malaria vaccine, gsk, VACCINE, RTS,S, APPROVALS 2021

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Tisotumab vedotin


Pipeline – Tisotumab Vedotin – Seagen
A first-in-human antibody–drug conjugate: Hope for patients with advanced solid tumours? | Immunopaedia

Tisotumab vedotin

チソツマブベドチン (遺伝子組換え)Immunoglobulin G1, anti-(human blood-coagulation factor III) (human monoclonal HuMax-TF heavy chain), disulfide with human monoclonal HuMax-TF κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide 

  • HuMax-TF-ADC
  • Immunoglobulin G1, anti-(human tissue factor) (human monoclonal HuMax-TF heavy chain), disulfide with human monoclonal HuMax-TF κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide

Protein Sequence

Sequence Length: 1324, 448, 448, 214, 214multichain; modified (modifications unspecified)

FormulaC6418H9906N1710O2022S44.(C68H106N11O15)n
EfficacyAntineoplastic
  DiseaseCervical cancer
CommentAntibody-drug conjugateCAS:1418731-10-8
  • HuMax-TF-ADC
  • Tisotumab vedotin
  • Tisotumab vedotin [WHO-DD]
  • UNII-T41737F88A
  • WHO 10148

US FDA APPROVED 2021/9/20 , TIVDAK

25 Great American USA Animated Flags Gifs

FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer………..  https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer

On September 20, 2021, the Food and Drug Administration granted accelerated approval to tisotumab vedotin-tftv (Tivdak, Seagen Inc.), a tissue factor-directed antibody and microtubule inhibitor conjugate, for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Approval was based on innovaTV 204, an open-label, multicenter, single-arm clinical trial (NCT03438396). Efficacy was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Sixty-nine percent of patients had received bevacizumab as part of prior systemic therapy. Patients received tisotumab vedotin-tftv 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The main efficacy outcome measures were confirmed objective response rate (ORR) as assessed by an independent review committee (IRC) using RECIST v1.1 and duration of response (DOR). The ORR was 24% (95% CI: 15.9%, 33.3%) with a median response duration of 8.3 months (95% CI: 4.2, not reached).

The most common adverse reactions (≥25%), including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash. Product labeling includes a boxed warning for ocular toxicity.

The recommended dose is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

View full prescribing information for Tivdak.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

A fully human monoclonal antibody specific for tissue factor conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker.

Tisotumab vedotin, sold under the brand name Tivdak is a human monoclonal antibody used to treat cervical cancer.[1]

Tisotumab vedotin was approved for medical use in the United States in September 2021.[1][2]

Tisotumab vedotin is the international nonproprietary name (INN).[3]

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References

  1. Jump up to:a b c d https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761208s000lbl.pdf
  2. ^ “Seagen and Genmab Announce FDA Accelerated Approval for Tivdak (tisotumab vedotin-tftv) in Previously Treated Recurrent or Metastatic Cervical Cancer”. Seagen. 20 September 2021. Retrieved 20 September 2021 – via Business Wire.
  3. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information30 (1): 159–60. hdl:10665/331046.

External links

Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetTissue factor (TF)
Clinical data
Trade namesTivdak
Other namesTisotumab vedotin-tftv
License dataUS DailyMedTisotumab_vedotin
Pregnancy
category
Contraindicated[1]
Routes of
administration
Intravenous
Drug classAntineoplastic
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number1418731-10-8
UNIIT41737F88A
KEGGD11814

//////////Tisotumab vedotin, チソツマブベドチン (遺伝子組換え) , FDA 2021, APPROVALS 2021, Antineoplastic, CERVICAL CANCER, CANCER, MONOCLONAL ANTIBODY, UNII-T41737F88A, WHO 10148

Avacopan


Avacopan.png
EFD
ChemSpider 2D Image | Avacopan | C33H35F4N3O2
Figure imgf000059_0001

Avacopan

アバコパン

авакопан [Russian] [INN]

أفاكوبان [Arabic] [INN]

阿伐可泮 [Chinese] [INN]

FormulaC33H35F4N3O2
CAS1346623-17-3
Mol weight581.6435

(2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

(2R,3S)-2-(4-Cyclopentylaminophenyl)-l-(2-fluoro-6-methylbenzoyl)piperidine-3- carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

3-​Piperidinecarboxamid​e, 2-​[4-​(cyclopentylamino)​phenyl]​-​1-​(2-​fluoro-​6-​methylbenzoyl)​-​N-​[4-​methyl-​3-​(trifluoromethyl)​phenyl]​-​, (2R,​3S)​-

  • (2R,3S)-2-[4-(Cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]-3-piperidinecarboxamide
  • (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

APPROVED PMDA JAPAN 2021/9/27, Tavneos

File:Animated-Flag-Japan.gif - Simple English Wikipedia, the free  encyclopedia

Anti-inflammatory, Complement C5a receptor antagonist

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis

Avacopan

(2R,3S)-2-[4-(Cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide

C33H35F4N3O2 : 581.64
[1346623-17-3]

CCX 168

Avacopan wasunder investigation in clinical trial NCT02994927 (A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis).

VFMCRP announces approval for TAVNEOS® (avacopan) for the treatment of ANCA-associated vasculitis in Japan

  • First orally administered therapy for the treatment of two types of ANCA-associated vasculitis approved in Japan
  • Partner Kissei to market TAVNEOS® in Japan, with launch expected as soon as possible following National Health Insurance (NHI) price listing

September 27, 2021 02:02 AM Eastern Daylight Time

ST. GALLEN, Switzerland–(BUSINESS WIRE)–Vifor Fresenius Medical Care Renal Pharma (VFMCRP) today announced that Japan’s Ministry of Health and Labor Welfare (MHLW) has granted its partner, Kissei Pharmaceutical Co., Ltd., marketing authorization approval for TAVNEOS® for the treatment of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two main types of ANCA-associated vasculitis, a rare and severe autoimmune renal disease with high unmet medical need.

“We are delighted that TAVNEOS® has been approved in Japan, the first market worldwide, and congratulate our partner Kissei for this significant milestone”

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“We are delighted that TAVNEOS® has been approved in Japan, the first market worldwide, and congratulate our partner Kissei for this significant milestone,” said Abbas Hussain, CEO of Vifor Pharma Group. “ANCA-associated vasculitis is officially designated an intractable disease in Japan, indicating a rare disease without any effective treatment but for which long-term treatment is required. There is significant unmet medical need of over 10,000 patients in Japan, and we believe in the potential of TAVNEOS® for treating it. We are confident that Kissei will fully focus on bringing this breakthrough treatment to this patient population, helping them lead better, healthier lives.”

The approval is based on the marketing authorization application filing by Kissei which was supported by positive clinical data from the pivotal phase-III trial ADVOCATE in a total of 331 patients with MPA and GPA in 18 countries and regions, including Japan. TAVNEOS® demonstrated superiority over standard of care at week 52 based on Birmingham Vasculitis Activity Score (BVAS).

VFMCRP holds the rights to commercialize TAVNEOS® outside the U.S.. In June 2017, VFMCRP granted Kissei the exclusive right to develop and commercialize TAVNEOS® in Japan. Kissei expects to begin to market TAVNEOS® as soon as possible following NHI price listing. Outside Japan, TAVNEOS is currently in regulatory review with various agencies, including the U.S. Food and Drug Administration and the European Medicines Agency.

About Vifor Pharma Group

Vifor Pharma Group is a global pharmaceuticals company. It aims to become the global leader in iron deficiency, nephrology and cardio-renal therapies. The company is a partner of choice for pharmaceuticals and innovative patient-focused solutions. Vifor Pharma Group strives to help patients around the world with severe and chronic diseases lead better, healthier lives. The company develops, manufactures and markets pharmaceutical products for precision patient care. Vifor Pharma Group holds a leading position in all its core business activities and consists of the following companies: Vifor Pharma and Vifor Fresenius Medical Care Renal Pharma (a joint company with Fresenius Medical Care). Vifor Pharma Group is headquartered in Switzerland, and listed on the Swiss Stock Exchange (SIX Swiss Exchange, VIFN, ISIN: CH0364749348).

For more information, please visit viforpharma.com.

About Kissei Pharmaceutical Co., Ltd.

Kissei Pharmaceutical Co., Ltd. is a Japanese pharmaceutical company with approximately 70 years of history. Based on its management philosophy, “contributing to society through high-quality, innovative pharmaceutical products” and “serving society through our employees”, Kissei is concentrating on providing innovative pharmaceuticals to patients worldwide as a strongly R&D-oriented corporation. Kissei is engaged in R&D and licensing activities in the field of nephrology/dialysis, urology, and unmet medical needs in other disease areas. Kissei has an established collaboration with VFMCRP for sucroferric oxyhydroxide which Kissei fully developed in Japan as P-TOL® (known as Velphoro® in Europe/US) for the treatment of hyperphosphatemia. Since the launch in 2015, the market share of P-TOL® has been steadily expanding in Japan. For more information about Kissei Pharmaceutical, please visit www.kissei.co.jp.

About ChemoCentryx Inc.

ChemoCentryx is a biopharmaceutical company developing new medications for inflammatory and autoimmune diseases and cancer. ChemoCentryx targets the chemokine and chemoattractant systems to discover, develop and commercialize orally-administered therapies. Besides ChemoCentryx’s lead drug candidate, avacopan, ChemoCentryx also has early stage drug candidates that target chemoattractant receptors in other inflammatory and autoimmunediseases and in cancer.

About ANCA-associated vasculitis

ANCA-associated vasculitis is a systemic disease in which over-activation of the complement pathway further activates neutrophils, leading to inflammation and destruction of small blood vessels. This results in organ damage and failure, with the kidney as the major target, and is fatal if not treated. Currently, treatment for ANCA-associated vasculitis consists of courses of non-specific immuno-suppressants (cyclophosphamide or rituximab), combined with the administration of daily glucocorticoids (steroids) for prolonged periods of time, which can be associated with significant clinical risk including death from infection.

About TAVNEOS® (avacopan)

Avacopan is an orally-administered small molecule that is a selective inhibitor of the complement C5a receptor C5aR1. By precisely blocking the receptor (the C5aR) for the pro-inflammatory complement system fragment, C5a on destructive inflammatory cells such as blood neutrophils, avacopan arrests the ability of those cells to do damage in response to C5a activation, which is known to be the driver of inflammation. Moreover, avacopan’s selective inhibition of only the C5aR1 leaves the beneficial C5a l pathway through the C5L2 receptor functioning normally.

ChemoCentryx is also developing avacopan for the treatment of patients with C3 Glomerulopathy (C3G) and hidradenitis suppurativa (HS). The U.S. Food and Drug Administration has granted avacopan orphan-drug designation for ANCA-associated vasculitis, C3G and atypical hemolytic uremic syndrome. The European Commission has granted orphan medicinal product designation for avacopan for the treatment of two forms of ANCA vasculitis: microscopic polyangiitis and granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), as well as for C3G. In October 2020, European Medicines Agency (EMA) accepted to review the Marketing Authorization Application (MAA) for avacopan for the treatment of patients with ANCA-associated vasculitis (granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)).

On May 6, 2021 the U.S. Food & Drug Administration’s (FDA’s) Arthritis Advisory Committee narrowly voted in support of avacopan, a C5a receptor inhibitor, for the treatment of adult patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. Although the panelists were excited about the possibility of a steroid-sparing therapy, some raised questions about whether results from the single phase 3 trial could adequately inform the risk/benefit assessment.1 The FDA will weigh the panel’s recommendation as it considers possible approval.

Treatment Needs for ANCA-Associated Vasculitis

ANCA-associated vasculitis is a rare, severe and sometimes fatal form of vasculitis characterized by inflammation of small vessels, often including those in the kidney. One factor that distinguishes it from other forms of vasculitis is the dom­inant role of neutrophils in its pathogenesis. From work in both animal and mouse models, we know activation of the alternative complement pathway plays a role in the disease pathogenesis, triggering attraction and activation of neutrophils in a complex feedback loop.1-3

Morbidity and mortality from ANCA-associated vasculitis has improved in recent decades, partly due to the introduction of new treatment regimens. The FDA approved rituximab for ANCA-associated vasculitis in 2011, and, in 2018, its label was extended to include maintenance therapy. Most patients with newly diagnosed ANCA-associated vasculitis are now started on a tapering dose of glucocorticoids, paired either with cyclo­phosphamide or rituximab, with a later follow-up maintenance dose of rituximab at around six months.

High doses of glucocorticoids are often used for remission induction, and they may also be employed as part of maintenance therapy, flare management and relapsing disease. This is a concern for practitioners, who hope to reduce the toxicity that results from glucocorticoid use, especially when given at high doses for prolonged periods.

Avacopan is the first drug to be specifically developed for a vasculitis indication. Other vasculitis therapies—such as tocilizumab for giant cell arteritis or rituximab for ANCA-associated vasculitis—were first approved for other diseases. Avacopan is an oral C5a receptor antagonist that selectively blocks the effects of C5a, thus dampening neutrophil attraction and activation. It does not have FDA approval for other indications, but has orphan drug status for ANCA-associated vasculitis (specifically for microscopic polyangiitis and granulomatosis with polyangiitis) and for C3 glomerulopathy, a rare kidney disease.

Arthritis Advisory Panel Meeting

The FDA generally requires evidence from at least two adequate and well-controlled phase 3 trials to establish effectiveness of a drug. However, it exercises regulatory flexibility in certain circumstances, such as for some rare diseases. In this case, it may consider the results of a well-designed single study if the evidence is statistically persuasive and clinically meaningful.4

Study design is a challenge for any manufacturer attempting to develop a product to potentially decrease steroid use because the FDA does not accept steroid sparing as an assessable outcome for clinical trials. For example, in the GiACTA trial, the phase 3 trial used as evidence for approval of tocilizumab for patients with giant cell arteritis, the biotechnology company Genentech wanted to give tocilizumab and demonstrate patients could then be safely taken off glucocorticoids. But the FDA required a more complicated multi-arm design.5

Other issues come up because of the way gluco­corticoids have been used historically. Although they have been used for vasculitis since before drug licensing was introduced, glucocorticoids are not themselves licensed for ANCA-associated vasculitis, which brings up certain regulatory barriers in study design. Additionally, the efficacy of glucocorticoids in vasculitis to control disease activity or prevent relapse has never been officially quantified in a placebo-controlled trial.

ADVOCATE Design

For avacopan, ChemoCentryx based its application on a single phase 3 trial and two phase 2 trials.1-3 In pre-meeting documents and during the meeting itself, the company drew comparisons to the RAVE trial, used to establish the non-inferiority of rituximab to standard cyclophosphamide therapy in patients with ANCA-associated vasculitis.6 In this case, a single phase 3 trial (with supporting phase 2 data) was used as evidence for approval of rituximab.

The phase 3 trial of avacopan, ADVOCATE, used a similar, double-blind, double-dummy design.1 ADVOCATE included 331 patients with either new or relapsing ANCA-associated vasculitis. Half the participants received 30 mg of avacopan twice a day orally, as well as a prednisone placebo, out to the study’s end at 12 months. The other half received oral prednisone (tapered to 0 mg at five months) plus an avacopan placebo.

Additionally, patients received immunosuppressive treatment, either cyclo­phosphamide (35%) or rituximab (65%), at the discretion of the prescribing physician. Patients who had received cyclophosphamide also received follow-up azathio­prine at week 15. But after initial treatment, no patients received maintenance rituximab, as would now be common practice.

Prior to enrollment, many participants were already receiving glucocorticoids as part of their treatment, to help get their disease under control. Thus, open-label prednisone treatment continued to be tapered for the early part of the trial in both groups up to the end of week 4. This had to be tapered to 20 mg or less of prednisone daily before beginning the trial, in both treatment groups.

As reported by the investigators, at week 26, the avacopan group was non-inferior to the prednisone group in terms of sustained remission. At the study’s conclusion at week 52, 66% of patients in the avacopan group were in sustained remission, as were 55% of those in the prednisone group. Thus, in terms of remission, avacopan was superior to gluco­corticoids at week 52 (P=0.007).

The researchers also provided encouraging secondary endpoints related to a number of other parameters, including reduced glucocorticoid-related toxicities, fewer relapses, better quality of life measures and improvements in kidney functioning (e.g., glomerular filtration rate changes).

David R.W. Jayne, MD, a professor of clinical auto­immunity at the University of Cambridge and director of the Vasculitis and Lupus Service at Addenbrooke’s Hospital, Cambridge, England, was one of the ADVOCATE investigators and says that in the context of previous vasculitis trials, which have only rarely displayed positive effects from interventions, the ADVOCATE results are impressive.

“We’ve never seen quality-of-life benefits or [glomerular filtration rate] recovery benefits in other vasculitis trials, but we saw them consistently in this one,” says Dr. Jayne.

………………………………………………………………………………………………………………………….

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……………………………………………………………………………………………………………………………

PATENT

Example 1: Preparation of Free Base Crystalline Form of Compound 1

      Crude Compound 1 was prepared essentially as described in WO 2016/053890.
      A free base crystalline form of Compound 1 was prepared by dissolving 18 g of crude Compound 1 in 50 mL acetone with heating at 40° C. (a concentration of about ˜0.36 g/mL). The warm solution was passed through a 10 μm polyethylene filter. The solution was then loaded into rotary evaporator at 30° C. bath temperature and 180 rpm rotational speed. The solid collected was dried further in a 45° C. oven for 1 hour. The XRPD data of the crystalline form is shown in Error! Reference source not found., and the table of peaks measured are listed in Table 1, below.

Example 2: Preparing an Amorphous Form of Compound 1

      Method 1
      Crude Compound 1 was prepared essentially as described in WO 2016/053890.
      Crude Compound 1 (15 grams) was dissolved into 40 mL of acetone at 40° C. temperature. The solution was spray dried using a Buchi B290 Spray Dryer, equipped with a peristaltic pump. The spray drying process was completed by using target inlet temperature of 80° C., target spray rate of 5 mL/min, and process gas flow rate of 20.60 CFM. The spray dried powder collected in the sample collection chamber was the amorphous form of Compound 1 as assessed by XRFD, shown in Error! Reference source not found.
      Method 2 An amorphous form of Compound 1 was prepared by dissolving 1 g of the free base crystalline form of Compound 1 in 9 mL of acetone without any heating (a concentration of about ˜0.11 g/mL). The solution was passed through a 10 μm polyethylene filter by gravity. The solution was then loaded into rotary evaporator at 45° C. bath temperature and 220 rpm rotational speed. The solid collected was dried further in a 45° C. oven for 30 hour. The XRPD data of the starting material (in crystalline form) and the amorphous form produced from Method 2 are shown in Error! Reference source not found.A & FIG. 3B. The DSC data of the starting material (in crystalline form) and the amorphous form produced from Method 2 are shown in Error! Reference source not found. Experimental details related to DSC data collection are described in Example 3.

PATENT

WO 2021163329 

https://patents.google.com/patent/WO2021163329A1/en

PATENT

https://patents.google.com/patent/US20170283446A1/en

PATENT

Example 1: A Besylate Salt of Compound 1 (Form I)

      
 (MOL) (CDX)
      A 3-L round bottom flask equipped with a magnetic stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 250 g, 430 mmol) and MeCN (1.84 L, 8 vol). The resulting mixture was stirred and heated to 75° C. (internal temperature) for 30 min to form a clear solution, and filtered through polyethylene frit filter and rinsed with MeCN (230 mL). To this solution at 60° C. was slowly added a pre-filtered solution of benzenesulfonic acid hydrate (77.9 g, 442 mmol (based on monohydrate), 1.03 eq) in MeCN (276 mL, 3 vol) over 10 min and rinsed with MeCN (92 mL) (internal temperature dropped to 55° C.). The resulting solution was cooled to 50° C., seeded with besylate crystals of Compound 1 (˜100 mg) and slowly cooled to 45° C. over 1 h. The resulting mixture was slowly cooled to RT and stirred for 42 h. The solid was collected by filtration, washed with MeCN (230 mL×2), air-dried and then dried in an oven under vacuum at 50° C. overnight (48 h) to afford N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzenaminium benzenesulfonate as off-white crystals, with a recovery yield of 266.5 g (84%). 1H NMR (400 MHz, DMSO-d 6) (RT) δ 10.44 (s, 1H), 7.90-7.83 (m, 1H), 7.65-6.95 (m, 14H), 6.42-6.34 (m, 1H), 6.05-5.00 (br, 1H), 3.85-3.70 (m, 1H), 3.22-3.00 (m, 3H), 2.38-2.28 (m, 4H), 2.20-1.40 (m, 15H); (65° C.) δ 10.22 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.68-6.70 (m, 15H), 6.44-6.35 (m, 1H), 3.72-3.65 (m, 1H), 3.25-2.98 (m, 3H), 2.40-2.28 (m, 4H), 2.22-1.40 (m, 15H). MS: (ES) m/z calculated for C 333643[M+H] 582.3, found 582.2. A plot of the XRPD is shown in FIG. 1, and Table 1, below, summarizes significant peaks observed in the XRPD plot. HPLC (both achiral analytical and chiral): >99%. Elemental Analysis consistent with formula of C 3941435S, KF: 0.66%.

PATENT

 WO 2011163640

https://patents.google.com/patent/WO2011163640A1

Figure imgf000028_0002

Example 11[0147] The following are representative compounds prepared and evaluated using methods similar to the examples herein. Characterization data is provided for the compounds below. Biological evaluation is shown in Figure 1 for these compounds and others prepared as described herein.(2R,3S)-2-(4-Cyclopentylaminophenyl)-l-(2-fluoro-6-methylbenzoyl)piperidine-3- carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide

Figure imgf000059_0001

[0148] 1H NMR (400 MHz, TFA-d) δ 7.91 (d, J= 8.6 Hz, 1 H), 7.84 (d, J= 8.6 Hz, 1 H), 7.58-6.82 (m, 8 H), 6.75 (t, J= 8.6 Hz, 1 H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m, 4H), 1.82-.169 (m, 7H)

PATENTUS 20110275639https://patents.google.com/patent/US20110275639PATENT
https://patents.google.com/patent/US20160090357A1/en

  • [0097]This example illustrates the preparation of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide by the method provided more generally in FIG. 1 (Scheme 1) using the reagents provided below:
  • [0098]Step 1:
  • [0099]An oven-dried 12 L, 3-necked flask equipped with a mechanical stirrer, condenser, and thermometer was charged with acrolein diethyl acetal (1127 g, 8.666 mole, 1.05 equiv.) and warmed up to 40° C. A mixture of solid ethyl 3-(4-nitrophenyl)-3-oxo-propanoate (1956 g, 8.253 mole) and (R)-(−)-2-phenylglycinol (>99.5% e.e., 1187 g, 8.666 mole, 1.05 equiv.) was added in portions over 40 min. to maintain a stirrable mixture at an internal temperature of approximately 40° C. After all solids were added, the mixture was stirred at 40° C. for 10 minutes. 4M HCl in dioxane (206.2 mL, 0.825 mole, 10 mol. %) was subsequently added through the condenser within 2 minutes and the internal temperature was increased to 70 OC. The reaction was stirred for 22 h whereupon LC-MS showed consumption of starting materials and enamine intermediate. The heating was turned off and ethanol (6.6 L) was added. The solution was then seeded with 4 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate and stirred at room temperature for 18 h. The solid was subsequently filtered off and 0.1 L of ethanol was used to rinse the flask and equipment onto the filter. The isolated solid was then washed three times on the filter with ethanol (250 mL each) and dried under vacuum to generate 1253 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate as a bright yellow solid (38% yield, 98.5% HPLC wt/wt purity, 0.15 wt % of EtOH).
  • [0100]Step 2:
  • [0101]260 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate (0.659 mol), 0.66 L of ethanol, and 56 g of palladium catalyst (10% Pd/C, Degussa type E101 NE/W, 50% wet, 21.5 wt. % of powder, 4.0 mol % Pd) were placed in a 2.2 L Parr bottle and purged with nitrogen. The bottle was mounted on a Parr shaker apparatus and hydrogen was added at a rate to keep the external temperature of the bottle below 30° C. After 4 hours, the consumption of hydrogen slowed down. The bottle was then shaken under 50 psi of hydrogen for 2 hours. 94 mL of glacial acetic acid (1.65 mol, 2.5 equiv.) was subsequently added to the bottle and the bottle was purged three times with hydrogen at 50 psi. The bottle was then shaken under 35-55 psi of hydrogen for 48 hours, keeping the temperature below 30° C. The bottle was removed from the apparatus and 55 mL of 12M HCl aq. was added (0.659 mol, 1 equiv.) followed by 87 mL of cyclopentanone (0.989 mol, 1.5 equiv.). The bottle was purged three times with hydrogen at 50 psi and then shaken under 50 psi of hydrogen for 16-20 hours. The mixture was removed from the apparatus and filtered through a fritted funnel containing celite (80 g) and then washed three times with 0.125 L of ethanol. 54.1 g of anhydrous sodium acetate (0.659 mol, 1 equiv.) was added and the mixture was concentrated in vacuo at 40-55° C. to remove 0.9 L of the volatile components. 2.0 L of acetonitrile was added and 2.0 L of volatile components were removed in vacuo. The crude material was diluted with 1.0 L of acetonitrile and mechanically stirred at r.t. for 30 minutes. The mixture was filtered through Celite (40 g) and the cake was washed with 0.28 L of acetonitrile. The combined filtrates gave a solution of the crude amine acetate (Solution A, e.e. =78%). Solutions A of two independent runs were combined for further processing.
  • [0102]In a 12-L 3-neck flask equipped with a mechanical stirrer, internal thermometer, and reflux condenser (−)-O,O′-di-p-toluoyl-L-tartaric acid (1.019 kg, 2.64 mol, 2 equiv.) was dissolved in 5.8 L of acetonitrile. The mixture was heated to 60° C. with stirring, followed by a quick addition of 1 L of Solution A. The resultant solution was seeded with 4 g of the crystalline ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) and stirred at 60° C. for 15 minutes. After 15 minutes at 60 OC the seed bed has formed. The remaining amount of Solution A was added over a period of 2.5 hours, maintaining an internal temperature at 60° C. When the addition was complete, the heat source was turned off and the mixture was stirred for 17 hours, reaching a final temperature of 22.5° C. The suspension was filtered and the solids were washed with 0.50 L of acetonitrile to rinse the equipment and transfer all solids onto the filter. The resultant wet solids were washed on the funnel with 3.0 L of acetonitrile and dried in a vacuum oven at 45° C. for 48 hours to provide 1.005 kg of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) as an off-white solid (70% yield, contains 1 wt. % of acetonitrile). The enantiomeric ratio of the product was 99.4:0.6.
  • [0103]Step 3:
  • [0104]In a 5 L 3-necked flask equipped with a mechanical stirrer and an addition funnel, solid anhydrous potassium carbonate (K2CO3, 226 g, 1.64 mol, 4.1 equiv.) was dissolved in H2O (0.82 L) and cooled to ambient temperature. MTBE (0.82 L) was added, followed by solid ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) (436 g, 0.400 mol). The mixture was vigorously stirred at r.t. for 1 hour, then 2-fluoro-6-methylbenzoyl chloride (72.5 g, 0.420 mmol, 1.05 equiv.) in MTBE (0.14 L) was added dropwise over 1 hour. The product started precipitating from the reaction before addition of the acid chloride was completed. The reaction was vigorously stirred at r.t. for 30 minutes and monitored by LC-MS for the disappearance of starting material. The mixture was subsequently transferred to a 5 L evaporation flask using 0.3 L of MTBE to rinse the equipment and remove all solids. The mixture was concentrated in vacuo to remove the MTBE, then 0.3 L of heptane was added and the mixture was evaporated again to leave only the product suspended in aqueous solution. The flask was removed from the rotavap and water (0.82 L) and heptane (0.82 L) were added. The suspension was vigorously stirred for 16 hours using a mechanical stirrer. The contents were then filtered and the solid was washed with water (2×0.42 L) and heptane (0.42 L). The solid was dried in a vacuum oven at 45° C. to provide 172 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate as an off-white powder (95% yield).
  • [0105]Step 4:
  • [0106]A 0.5 L 3-necked round-bottom flask was dried overnight in an oven at 200° C. and then cooled under a stream of nitrogen. The flask was equipped with a magnetic stir bar, nitrogen inlet, and a thermometer. The flask was charged with 30.2 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate (66.7 mmol), 11.5 mL of 4-methyl-5-trifluoromethylaniline (80 mmol, 1.2 equiv.) and 141 mL of dry toluene under an atmosphere of nitrogen. Nitrogen was bubbled through the resultant solution for 10 minutes and then the solution was warmed to 30° C. The oil bath was removed and 100 mL of a 2 M solution of AlMein toluene (Aldrich, 200 mmol, 3 equiv.) was cannulated into the reaction mixture at a rate maintaining the reaction temperature between 35-40° C., a process that took approximately 45 minutes. The temperature of the reaction mixture was then increased to 55° C. over a period of 1 hour and the reaction mixture was stirred at 55° C. for 8 hours, whereupon all of the starting ester was consumed (monitored by LC-MS). The reaction was subsequently cooled overnight to ambient temperature and the solution was then cannulated into a mechanically stirred 1 L flask containing a solution of 67.8 g of sodium potassium tartrate tetrahydrate (240 mmol, 3.6 equiv.) in 237 mL of water, pre-cooled to 10 OC in an ice bath. The addition process took approximately 30 minutes, during which the reaction mixture self-heated to 57° C. The empty reaction flask was subsequently rinsed with 20 mL of dry toluene and the solution was combined with the quench mixture. The mixture was then cooled to r.t. with stirring, 91 mL of ethyl acetate was added, and the mixture was stirred an additional 15 minutes. The mixture was subsequently filtered through a pad of Celite and the filtrate was allowed to separate into two layers. The organic layer was then separated and washed with a solution of 5.7 g of sodium potassium tartrate tetrahydrate (20 mmol) in 120 mL of water and then with two 120 mL portions of water. The wet organic solution was concentrated in vacuo to a weight of ˜150 g and a solvent exchange with ethanol was performed maintaining a total volume of 0.2-0.3 L, until <1 mol. % toluene with respect to ethanol was observed by 1H NMR. The solution was then evaporated at elevated temperature to a weight of 223 g and heated to reflux. Mechanical stirring was initiated and 41 mL of water was added. The resulting solution was seeded with (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide crystals at 60 OC and then slowly cooled to r.t. over 2 hours. The slurry was subsequently stirred for 18 hours and the solids were filtered off. The solids were then washed with two 30 mL portions of 7:3 ethanol/water and dried in a vacuum oven for 24 hours at 50 OC to afford 31.0 g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide as off-white crystals (80% yield). Analytical data: HPLC purity: 99.59%; >99.8% d.e. and e.e. by HPLC; ICP-OES Pd: <1 ppm; Al: δ ppm; residual toluene by headspace GC-MS: 15 ppm; microash<0.1%; K—F 0.1%. 1H NMR (400 MHz, TFA-d) δ 7.91 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.58-6.82 (m, 8H), 6.75 (t, J=8.6 Hz, 1H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m, 4H), 1.82-1.69 (m, 7H), MS: (ES) m/z 582 (M+H+).

PATENT

WO2019236820

The present disclosure is directed to, inter alia, methods of treating ANCA-associated vasculitis (AAV) in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of avacopan, having the structure shown below:

References

  1. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitisN Engl J Med. 2021 Feb 18;384(7):599–609.
  2. Merkel PA, Niles J, Jimenez R, et al. Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitisACR Open Rheumatol. 2020;2(11):662–671.
  3. Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitisJ Am Soc Nephrol. 2017 Sep;28(9):2756–2767.
  4. U.S. Department of Health and Human Services. Food and Drug Administration. Demonstrative substantial evidence of effectiveness for human drug and biological products: Guidance for industry. 2019.
  5. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritisN Engl J Med. 2017 Jul 27;377(4):317–328.
  6. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitisN Engl J Med. 2010 Jul 15;363(3):221–232.
  7. Warrington KJ. Avacopan—time to replace glucocorticoids? N Engl J Med. 2021 Feb 18;384(7):664–665.

////////////Avacopan, アバコパン , JAPAN 2021, APPROVALS 2021, CCX 168, авакопан , أفاكوبان , 阿伐可泮 , 

CC1=C(C(=CC=C1)F)C(=O)N2CCCC(C2C3=CC=C(C=C3)NC4CCCC4)C(=O)NC5=CC(=C(C=C5)C)C(F)(F)F

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BIAPENEM


Biapenem.png
ChemSpider 2D Image | Biapenem | C15H18N4O4S
Biapenem.png

Biapenem

RPX7009

  • Molecular FormulaC15H18N4O4S
  • Average mass350.393 Da

Biapenern

CL 186-815LJ

C10,627LJ

C10627LJC 10627

omegacin

YR5U3L9ZH1

(4R,5S,6S)-3-((6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

[4R-[4a,5b,6b(R*)]]-6-[[2-Carboxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5 H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt

120410-24-4[RN]

5H-Pyrazolo[1,2-a][1,2,4]triazol-4-ium, 6-[[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-, inner salt [ACD/Index Name]

6-[[(4R,5S,6S)-2-Carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt

7074

(4R,5S,6S)-3-(6,7-Dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-ylsulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

TL8000539UNII:YR5U3L9ZH1UNII-YR5U3L9ZH1биапенем

بيابينام比

阿培南

 

INDIA CDSCO APPROVED 25 SEPT 2021, BDR PHARMA,  File:Animated-Flag-India.gif - Wikipedia
https://www.cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCTApprovals/BDR.pdfhttps://medicaldialogues.in/news/industry/pharma/bdr-pharma-gets-dcgi-nod-for-generic-antibiotic-drug-biapenem-82384

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Biapenem (INN) is a carbapenem antibiotic. It has in vitro activity against anaerobes.[1] 1-β-methyl-carbapenem antibiotic. Approved in Japan in 2001.

PATENT

EP 168707

EP 289801

JP 02088578

ZA 9100014

EP 533149

CN 1995040

IN 2006DE01555

CN 101121716

IN 2008CH00177

CN 101805359

CN 101851206

CN 101935321

CN 111875622

WO 2018074916

WO 2016059622

US 20150328323

WO 2015151081

WO 2015155753

WO 2015151078

US 20150284416

WO 2015151080

US 20150038726

WO 2014104488

IN 2013MU00181

WO 2014111957

CN 103570750

WO 2014097221

IN 2012CH01371

WO 2013150550

PAPERS

 Journal of Organic Chemistry (1992), 57(15), 4243-9.

Heterocycles (1993), 36(8), 1729-34.

Journal of Antibiotics (1993), 46(12), 1866-82.

e-EROS Encyclopedia of Reagents for Organic Synthesis (2008), 1-3.

Bioorganic & medicinal chemistry letters (2009), 19(17), 5162-5.

 IP.com Journal (2014), 14(12A), 1-3

IP.com Journal (2014), 14(10A), 1-2.

Bioorganic & medicinal chemistry (2013), 21(18), 5841-50.

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PATENT

https://patents.google.com/patent/WO2014097221A1/esBiapenem is chemically known as 6-[[2(4R,5S,6S)-carboxy-6-[(lR)- hydroxy ethyl] -4-methyl-7-oxo- 1 -azabicyclo [3.2.0]hept-2-en-3 -yljthio] 6,7-dihydro-5H- pyrazolo[l,2-a][l,2,4]triazol-4-ium inner salt, and is represented by Formula 1. It is indicated for the treatment of bacterial infection and sepsis.

Figure imgf000002_0001

Formula 1U.S. Patent No. 4,866,171, in Example 6, discloses the purification of biapenem using chromatography and/or lyophilization techniques. This patent also describes a process for the conversion of amorphous biapenem into a crystalline form by dissolving the amorphous biapenem in water while heating, followed by cooling, then washing the obtained crystals with a 50% aqueous ethanol solution.U.S. Patent No. 5,241,073 describes a process for the purification of biapenem involving column chromatography and crystallization with ethanol.U.S. Patent No. 5,286,856 describes a process for the crystallization of biapenem from an aqueous solution, comprising maintaining the temperature of the aqueous solution from eutectic temperature (-10°C to -2°C) to a temperature lower than 0°C, followed by lyophilization.The Journal of Organic Chemistry, 63(23):8145-8149 (1998) describes the purification of biapenem involving resin chromatography.The present invention provides an alternate process for the purification of biapenem that avoids making use of tedious techniques like chromatography and lyophilization. At the same time, it results in a high yield and high purity of the final product. Advantageously, the crystalline biapenem of this invention can be directly isolated from the reaction mixture. Further, the process of the present invention involves fewer steps, is easily scalable, and industrially advantageous.EXAMPLESExample 1 : Purification of BiapenemBiapenem (12 g) was added into water (300 mL) at 65°C, stirred for 5 minutes, and cooled to 30°C within 10 minutes. Enoantichromos carbon (0.6 g) was added to the reaction mixture and stirred for 10 minutes to 15 minutes at 25°C to 30°C. The reaction mixture was filtered through a hyflo bed and washed with water (36 mL). The filtrate obtained was passed through a 0.45 micron filter, and its pH was adjusted to 5.5 using 5% aqueous sodium hydroxide solution at 10°C to 15°C. Acetone (336 mL) was added to the reaction mixture at 5°C to 10°C. The resultant slurry was stirred for 3 hours at 5°C to 10°C, filtered, and the obtained solid was washed with acetone (60 mL). The solid was dried under reduced pressure (720 mmHg) at 30°C to 35°C to obtain the title product as white crystals.Yield: 84%HPLC Purity: 99.87% Example 2: Purification of BiapenemBiapenem (18 g) was added into water (450 mL) at 65°C, stirred for 5 minutes, and cooled to 30°C within 10 minutes. Enoantichromos carbon (0.9 g) was added to the reaction mixture and stirred for 30 minutes at 25°C to 30°C. The reaction mixture was filtered through a hyflo bed and washed with water (54 mL). The filtrate obtained was passed through a 0.45 micron filter and its pH was adjusted to 4.9 using 5% aqueous sodium hydroxide solution at 10°C to 15°C. Acetone (504 mL) was added to the reaction mixture at 10°C to 15°C. The resultant slurry was stirred for 3 hours at 5°C to 10°C, filtered, and the obtained solid was washed with acetone (90 mL). The solid was dried under reduced pressure (720 mmHg) at 35°C to 40°C to obtain the title product as white crystals.Yield: 81.77%HPLC Purity: 99.80% 
PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013150550

The present invention relates to an improved process for the preparation of carbapenem antibiotic; more particularly relates to the preparation of Ertapenem monosodium salt of formula (I) having purity greater than 98.5% and having pharmaceutically acceptable level of residual solvent and palladium content.

The US patents namely US 5,478,820 and US 5,856,321 disclose various processes for preparing Ertapenem and its sodium salt. Example 12 of US 5,478,820 discloses a process in which the Ertapenem was isolated using column purification followed by freeze-drying technique. According to Example-4 of this patent disodium salt of Ertapenem was prepared by dissolving crude product in water using NaHCO3, followed by purification using column chromatography and subsequent lyophilization.

US 6,504,027 provides a process for preparing Ertapenem in crystalline form which comprises deprotecting and extracting a polar organic solution containing a crude mono-protected Ertapenem of formula

wherein P represents protecting group and X represents charge balancing group like sodium

with C4.10 alcohol in the presence of ion-pairing reagent followed by adjusting the pH of the aqueous layer to 5.5 and crystallizing using methanol and 1-propanol to produce a crystalline compound; this patent process involves operations like

multiple extractions which is cumbersome in plant and said operation affects the overall yield.

US 7,145,002 provides a process for producing Ertapenem or its sodium salt and/or its solvate in crystalline form. This patent states (refer para 3, lines 31-41) that contact of Ertapenem sodium with water and alcoholic solvents results in the formation of crystalline solvates. The processes reported in examples- 1 & 2 provide crystalline Ertapenem monosodium which is isolated from a mixture of methanol, 1-propanol and water followed by washing with aqueous isopropyl alcohol which results in the formation of crystalline solvate of Ertapenem sodium. Applicant found the Ertapenem monosodium obtained according to this process contain higher amount of residual solvent and palladium content.

US 7,022,841 provide a process for reducing the levels of organic solvents in Ertapenem to pharmaceutically acceptable levels. This patent discloses (Refer para 1, lines 52-60) that Ertapenem sodium obtained from water/alcohol mixture according to US 7, 145,002 becomes amorphous when water content of the solid is reduced and further the organic solvent present in the solid is not readily removed. In view of this drawback, this patent provides a process wherein the water content of Ertapenem sodium is maintained between 13-25% during the washing and drying process. This patent further discloses that (Refer para 9, lines 6-14) the washing of Ertapenem sodium can be carried out using anhydrous solvents which results in the formation of amorphous solid, which is then dried using hydrated nitrogen by increasing the water content of the solid. Due to the hygroscopic and unstable nature of Ertapenem sodium when in contact with water, the above processes result in more degradation of Ertapenem. The patent further discloses in example 5 that the degradation of Ertapenem sodium is more when it takes more time for drying.

Further this patent requires repetitive washing and control of moisture content to get the desired results.

For isolation of Ertapenem sodium from the reaction mass, all the above discussed prior art patents utilize methanol and 1-propanol as crystallization solvent. The filtration of Ertapenem sodium formed by using these solvents or their mixture takes longer time duration and subsequent drying for the removal of residual solvent also takes several hours due to occlusion of solvent into Ertapenem sodium. During these operations the Ertapenem sodium degrades an results in the formation of many impurities such as several dimers, methanolysis impurity etc., and hence the reported processes is not suitable to manufacture Ertapenem sodium on commercial scale with purity greater than 98.5% and with pharmaceutically acceptable level of residual solvent content.

Methanolysis impurity Dimer-I

Dimer-II

Further the applicant found that Ertapenem monosodium isolated by following the process reported in prior art was having palladium content above the pharmaceutically acceptable level. Hence the process reported in prior art is not suitable on manufacturing scale where maintaining stringent technological condition is cumbersome and involves higher operating cost.

Thus all the reported processes suffer in terms of one or more of the following facts:

 Filtration time of Ertapenem sodium takes several hours.

 Drying time takes several hours due to occlusion of solvent and nature of the solid.

 Stringent technological condition is required for maintenance of moisture content during washing & drying operation.

■ Palladium content is found to be higher (greater than 25 ppm) which is not acceptable for pharmaceutical products.

■ The isolated Ertapenem sodium is having higher amount of residual solvents.

■ The purity is reduced over to several hours of filtration & drying.

With our continued research for developing a process for the preparation of Ertapenem monosodium of formula (I) to overcome the above mentioned drawbacks, we surprisingly found that when esters of organic acid were used as solvents in place of 1-propanol, the solid obtained was easily filterable with less cycle time. Further the washing with hydrocarbon solvents containing 0-75% alcoholic solvent followed by drying results in Ertapenem having residual solvent content well below the pharmaceutically acceptable levels. The use of thiourea, thiosemicarbazide or their N-substituted derivatives in the presence of organic solvents during isolation brings down the palladium content to pharmaceutically acceptable level.

The Ertapenem or its sodium salt can be prepared according the processes provi

(I)

P’ and P” represent carboxylic protecting groups and X is H or Na

Scheme-1

The present invention is illustrated with the following examples, which should not be construed to limit the scope of the invention.

Example- I

Preparation of Ertapenem monosodium of formula (I)

Step-I:

To a stirred solution of p-nitrobenzyl (4R,5S,6S)-3-(diphenyloxy)phosphoryloxy-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (compound II) (100 g) and (2S,4S)-2-[[(3-carboxyphenyl) amino]carbonyl]-4-mercapto-l-(4-nitrobenzyl)pyrrolidinecarboxylate (compound III) (75 g) in N,N-dimethylformamide was added Ν,Ν-diisopropylethylamine at -30 to -40° C and stirred. The reaction mass, after completion of the reaction, was quenched with a mixture of phosphate buffer solution-ethyl acetate and the pH was adjusted to 5 – 6 with phosphoric acid. The organic layer was separated, washed with water and subjected to carbon treatment. To the organic layer containing the compound of formula (IV) (wherein P’ and P” refers to p-nitrobenzyl), a solution of sodium 2-ethylhexanoate (42 g in 500 mL methanol) was added and taken to next step as such. (If required the compound of formula (IV) is isolated either as sodium salt or as free acid by following the process reported in prior art and taken further)

Step-II:

To the Step-I organic layer containing the compound of formula (IV) (wherein P’ and P” refers to p-nitrobenzyl & X is Na), 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8- 10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered to remove palladium on carbon. To the filtrate, thiourea (5 g) and tetrahydrofuran were added and stirred. The aqueous layer was separated and treated with carbon and neutral alumina at 10-15° C while degassing and filtered. The filtrate was added to methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol (200 ml) and dried under vacuum. Yield: 46 g; Purity by HPLC: 98.93%; Palladium content: 1.8 ppm by ICP MS

The HPLC purity of Ertapenem monosodium was checked using the following parameters

Column : Zorbax Eclipse plus C8, (50 mm x 4.6 mm), 1.8μ).

Mobile phase : Ammoniam acetate buffer: Acetonitile: water

Detector : UV at 250 nm

Flow rate : 0.5 mL/min

Run time : 45 min.

Example- II

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8-10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and 2-methyltetrahydrofuran and the layers separated. The aqueous layer was treated with carbon & neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with cyclohexane (200 ml) and

dried under vacuum. Yield: 44 g; Purity by HPLC: 98.84%; Palladium content: 0.93 ppm by ICP MS

The term ICP MS method refers to the inductively coupled plasma mass spectrometry. The following parameter was used to determine the content of palladium.

The carbapenem was digested in a closed vessel system in presence of reagents Nitric acid, Hydrogen peroxide and Hydrochloric acid by using Microwave reaction system with microwave radiation power 1200 Watts. The digested sample was introduced into inductively coupled plasma mass spectrometer by help of Peltier cooled spray chamber. The sample aerosol is getting atomized then ionized in the argon plasma. The ionized Palladium was estimated by using Quadrupole mass detector. The sample was quantified against NIST traceable reference standards at mass number ! 05.

Example- III

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and tetrahydrofuran and the layers separated. The aqueous layer was separated and treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of toluene: ethanol (200 ml) and dried under vacuum. Yield: 42 g; Purity by HPLC: 99.03%

Example- IV

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction was filtered and the filtrate was treated with thiosemicarbazide and tetrahydrofuran and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C followed by the addition of ethyl acetate and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol (200 ml) and dried under vacuum. Yield: 41 g; Purity by HPLC: 99.13%; Palladium content: 1.71 ppm by ICP MS

Example- V

Preparation of Ertapenem monosodium of formula (I)

To the Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and subjected to hydrogenation using palladium on carbon at 8-10° C with 9-10 kg hydrogen pressure. The reaction mass, after completion of reaction, was filtered and the filtrate was treated with thiourea and 2-methyltetrahydrofuran and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5 – 6 using aqueous acetic acid. To the mass, a mixture of ethyl acetate containing 10% methyl acetate was added and stirred. The solid obtained was

filtered, washed with cyclohexane:ethanol and dried under vacuum. Yield: 40.5 g; Purity by HPLC: 98.77%; Palladium content: 1.43 ppm by ICP MS

Example-VI

(V ) (V I )

The diprotected Meropenem of formula (V) (where P and P’ were p-nitrobenzyl) was dissolved in tetrahydrofuran and 3-(N-morpholino)propanesulfonic acid buffer and hydrogenated using palladium on carbon at 9-10 kg hydrogen pressure. The mass was filtered and the filtrate was washed with ethyl acetate. The aqueous layer was treated with thiourea and 2-methyltetrahydrofuran. The aqueous layer was separated, treated with carbon and degassed. The carbon was filtered off and acetone was added to the filtrate to crystallize Meropenem trihydrate of formula (VI). The product was filtered and washed with aq. acetone and dried under vacuum to get Meropenem trihydrate. Purity: 99.8%; Pd content: 0.08 ppm

Reference example-I:

Preparation of Ertapenem monosodium of formula (I)

To Step-I organic layer as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered. The filtrate was treated with thiourea and tetrahydrofuran and the layers separated. The aqueous layer was treated with carbon and neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass ethyl acetate was added and stirred. The solid obtained was filtered, washed with ethanol (5 * 100 ml) and dried under vacuum. Yield: 31 g; Purity by HPLC: 96.76%

Reference example-II:

Preparation of Ertapenem monosodium of formula (I)

To the Step-I reaction mass , as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction was filtered and the layers separated. The aqueous layer was treated with carbon and neutral alumina at 10-15° C and filtered. The filtrate was mixed with methanol at -20° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass, ethyl acetate was added and stirred. The solid obtained was filtered, washed with a mixture of cyclohexane: ethanol and dried under vacuum. Yield: 43 g; Purity by HPLC: 98.6%; Palladium content: 35.8 ppm by ICP MS.

Reference example-HI:

Preparation of Ertapenem monosodium of formula (I)

To the Step-I reaction mass as provided in Example-I, 3-(N-morpholino)propanesulfonic acid solution was added and hydrogenated at 9-10 kg pressure using palladium on carbon at 8-10° C. The reaction mass, after completion of reaction, was filtered and the layers separated. The aqueous layer was treated with carbon, neutral alumina at 10-15° C and filtered. The filtrate was mixed with 1-propanol at -5° C and the pH was adjusted to 5.5-5.7 using aqueous acetic acid. To the mass methanol and 1-propanol were added and stirred. The solid obtained was filtered, washed with ethanol and dried under nitrogen atmosphere in vacuum. Yield: 25 g; Purity by HPLC: 97 %.: palladium content: 38.2 ppm

The following tables illustrate the advantages of the present invention over prior art process:

Table-I: Comparison of present process with prior art process

The crystallization and washing method disclosed in US 7,022,841 was followed.

The above table indicates that the use of ethyl acetate as crystallization solvent results with improved yield and high purity with less filtration and drying time thereby increasing the productivity significantly on manufacturing scale. Further the use of thiourea or thiosemicarbazide as reagents in the present process results in the pharmaceutically acceptable level of palladium content.

Table-II: Comparison of solvents for washing Ertapenem monosodium

The above table indicates that the use of hydrocarbon solvents containing 0-75% of alcoholic solvent helps in washing to remove the residual solvent content in shorter duration and with single run wash. On the other hands the use of ethanol alone results in Ertapenem monosodium having less yield and purity requiring repetitive washing.

Table-IH: Effect of different reagent in reduction of palladium content

Reagent : thiourea, thiosemicarbazide or its N-substituted derivatives

Advantages of the process of the present invention:

> The use of ester of an organic acid for the crystallization of Ertapenem sodium results in fast filtration and reduced cycle time, thereby increasing the productivity.

> Washing of Ertapenem sodium with hydrocarbon solvent optionally containing alcohol results in improved physical nature of Ertapenem sodium resulting in reduced washing and drying time thereby avoid the degradation of Ertapenem and providing Ertapenem sodium with purity greater than 98.5% by HPLC.

Use of thiourea, thiosemicarbazide or their N-substituted derivatives in the process results in Ertapenem sodium having pharmaceutically acceptable level of palladium content.

PATENT

https://patents.google.com/patent/WO2002057266A1/enEXAMPLE

Figure imgf000013_0001

PNB = p-nitrobenzyl

Figure imgf000013_0002

Ia’A hydrogenator is charged with 63 g of 10% Pd on carbon catalyst (dry weight) in 1.8 L of water. The vessel is placed under hydrogen then vented and placed under nitrogen. Sodium hydroxide (68 g, 50%) is charged adjusting the pH to about 7.5 with carbon dioxide.The enol phosphate (170 g) and the thiol (86 g) are dissolved in 1.3L of N- ethylpyrrolidinone (NEP). The mixture is cooled to below -40°C and 1,1,3,3- tetramethylguanidine (109 g) is added. After 3 hours, the reaction mixture is quenched into the hydrogenator at below 15°C adjusting the pH to about 8 with carbon dioxide. The vessel is placed under hydrogen. When the reaction is complete, the hydrogen is vented and the reaction mixture is treated with activated carbon and filtered. The filtrate is extracted with iso-amyl alcohol containing diphenylphosphoric acid (240 g) and 50% NaOH (44 g). The resulting aqueous solution is further extracted with iso-amyl alcohol to give an aqueous solution containing at least 90 mg/mL of the product. Both extractions are performed using two CINC centrifugal separators set in series for countercurrent extraction. The pH is adjusted to 5.5 with acetic acid. The product is crystallized by adding equal volumes of methanol and 1- propanol at below -5°C and isolated by filtration. The solid is washed with a mixture of 2-propanol and water (85: 15 v/v) then dried to yield a compound of formula la’.While certain preferred embodiments of the invention have been described herein in detail, numerous alternative embodiments are contemplated as falling within the scope of the appended claims. Consequently the invention is not to be limited thereby.

Patent Citations

Publication numberPriority datePublication dateAssigneeTitleUS4866171A1987-04-111989-09-12Lederle (Japan), Ltd.(1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)]thio-6-[R-1-hydroxyethyl]-1-methyl-carbapenum-3-carboxylateUS5241073A1990-10-121993-08-31Lederle (Japan)Process for preparing (1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo [1,2-a][1,2,4]triazolium-6-yl)]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate and starting materials thereofUS5286856A1991-09-201994-02-15Takeda Chemical Industries, Ltd.Production of crystalline penemWO2002057266A1 *2001-01-162002-07-25Merck & Co., Inc.Improved process for carbapenem synthesisWO2009047604A1 *2007-10-082009-04-16Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of carbapenem antibioticCN102268025A *2011-07-152011-12-07海南美兰史克制药有限公司一种比阿培南化合物及其制法

References

  1. ^ Aldridge KE, Morice N, Schiro DD (April 1994). “In vitro activity of biapenem (L-627), a new carbapenem, against anaerobes”Antimicrob. Agents Chemother38 (4): 889–93. doi:10.1128/aac.38.4.889PMC 284564PMID 8031067.

External links

 
Clinical data
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IV
ATC codeJ01DH05 (WHO)
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Legal statusIn general: ℞ (Prescription only)
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CAS Number120410-24-4 
PubChem CID71339
ChemSpider64442 
UNIIYR5U3L9ZH1
ChEBICHEBI:3089 
ChEMBLChEMBL285347 
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FormulaC15H18N4O4S
Molar mass350.39 g·mol−1
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ClinicalTrials.gov

CTID TitlePhaseStatusDate
NCT04552444Clinical Efficacy of Combination Therapy Based on High-dose Biapenem in CRKP Infections Recruiting2020-09-17
NCT01772836Safety Study of Intravenous Biapenem (RPX2003) and RPX7009 Given Alone and in CombinationPhase 1Completed2013-07-11
NCT01702649Safety, Tolerability, Pharmacokinetics of Intravenous RPX2003 (Biapenem) in Healthy Adult SubjectsPhase 1Completed2012-12-03

NIPH Clinical Trials Search of Japan

CTID TitlePhaseStatusDate
UMIN000017219Feasibility and efficacy of the de-escalation therapy by Biapenem for postoperative bacterial pneumonia.NoneRecruiting2015-04-22
UMIN000003964Clinical evaluation of Biapenem 0.3g, three times daily dosing in eldery patients with pneumonia (moderate and severe infection)Not applicableComplete: follow-up complete2010-07-29

/////////BIAPENEM, TL8000539, UNII:YR5U3L9ZH1, UNII-YR5U3L9ZH1, биапенем, بيابينام ,比阿培南 , Biapenern, CL 186-815, CL 186815, L 627, LJC 10627, Omegacin, Antibacterial, Antibiotics, Lactams, Carbapenems, ind 2021, india 2021, approvals 2021

CC1C2C(C(=O)N2C(=C1SC3CN4C=NC=[N+]4C3)C(=O)[O-])C(C)O

https://clinicaltrials.gov/search/intervention=Biapenem

updated

Biapenem is chemically known as 6-[[2(4R,5S,6S)-carboxy-6-[(lR)-hydroxy ethyl] -4-methyl-7-oxo- 1 -azabicyclo [3.2.0]hept-2-en-3-yljthio] 6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt, and is represented by Formula 1. It is indicated for the treatment of bacterial infection and sepsis.

Formula 1

U.S. Patent No. 4,866,171, in Example 6, discloses the purification of biapenem using chromatography and/or lyophilization techniques. This patent also describes a process for the conversion of amorphous biapenem into a crystalline form by dissolving the amorphous biapenem in water while heating, followed by cooling, then washing the obtained crystals with a 50% aqueous ethanol solution.

U.S. Patent No. 5,241,073 describes a process for the purification of biapenem involving column chromatography and crystallization with ethanol.

U.S. Patent No. 5,286,856 describes a process for the crystallization of biapenem from an aqueous solution, comprising maintaining the temperature of the aqueous solution from eutectic temperature (-10°C to -2°C) to a temperature lower than 0°C, followed by lyophilization.

The Journal of Organic Chemistry, 63(23):8145-8149 (1998) describes the purification of biapenem involving resin chromatography.

The present invention provides an alternate process for the purification of biapenem that avoids making use of tedious techniques like chromatography and lyophilization. At the same time, it results in a high yield and high purity of the final product. Advantageously, the crystalline biapenem of this invention can be directly isolated from the reaction mixture. Further, the process of the present invention involves fewer steps, is easily scalable, and industrially advantageous.

EXAMPLES

Example 1 : Purification of Biapenem

Biapenem (12 g) was added into water (300 mL) at 65°C, stirred for 5 minutes, and cooled to 30°C within 10 minutes. Enoantichromos carbon (0.6 g) was added to the reaction mixture and stirred for 10 minutes to 15 minutes at 25°C to 30°C. The reaction mixture was filtered through a hyflo bed and washed with water (36 mL). The filtrate obtained was passed through a 0.45 micron filter, and its pH was adjusted to 5.5 using 5% aqueous sodium hydroxide solution at 10°C to 15°C. Acetone (336 mL) was added to the reaction mixture at 5°C to 10°C. The resultant slurry was stirred for 3 hours at 5°C to 10°C, filtered, and the obtained solid was washed with acetone (60 mL). The solid was dried under reduced pressure (720 mmHg) at 30°C to 35°C to obtain the title product as white crystals.

Yield: 84%

HPLC Purity: 99.87%

Example 2: Purification of Biapenem

Biapenem (18 g) was added into water (450 mL) at 65°C, stirred for 5 minutes, and cooled to 30°C within 10 minutes. Enoantichromos carbon (0.9 g) was added to the reaction mixture and stirred for 30 minutes at 25°C to 30°C. The reaction mixture was filtered through a hyflo bed and washed with water (54 mL). The filtrate obtained was passed through a 0.45 micron filter and its pH was adjusted to 4.9 using 5% aqueous sodium hydroxide solution at 10°C to 15°C. Acetone (504 mL) was added to the reaction mixture at 10°C to 15°C. The resultant slurry was stirred for 3 hours at 5°C to 10°C, filtered, and the obtained solid was washed with acetone (90 mL). The solid was dried under reduced pressure (720 mmHg) at 35°C to 40°C to obtain the title product as white crystals.

Yield: 81.77%

HPLC Purity: 99.80%

PATENT

Background of the Invention Biapenem is a synthetic broad-spectrum carbapenem antibiotic which suppresses bacterial growth by inhibiting the enzymes responsible for bacterial cell wall synthesis, and shows broad-spectrum antibacterial activity both against gram-positive bacteria and gram-negative bacteria. Biapenem is chemically known as (4R,5S,6S)-3-(6,7-dihydro-5H-pyrazolo[l,2-a][ 1,2,4] triazol-8-ium-6-ylsulfanyl)-6-( 1 -hydroxyethyl)-4-methyl-7-oxo-1 -azabicyclo [3.2.0]hept-2-ene-2-carboxylate and marketed in Japan as OMEGACIN®.Various methods are reported in the prior art for the preparation of Biapenem of formula (I) which includes the condensation of compound of formula (II) with compound of formula (III) and subsequent deprotection of the protecting group as shown in scheme-1. wherein R1 is hydrogen or hydroxy protecting group such as tert-butyl dimethyl silyl and the like, R2 is hydrogen or carboxyl protecting group such as p-nitrobenzyl, p-methoxy benzyl, allyl and the like, A is an activating group such as P(0)(OR)2, SO2R and the like wherein R is selected from substituted or unsubstituted C1-6 alkyl, aralkyl or aryl to form the compound of formula (II). The X” in compound of formula (III) is halogen selected from Br or CI.Biapenem was first disclosed in US 4,866,171 and the said patent also discloses a process for the preparation of the same. US 5,241,073 disclosed the method for the preparation of compound of formula (III) followed by condensation with compound of general formula (II) using base such as N-ethyldiisopropylamine and subsequent deprotection yields Biapenem which was isolated by column chromatography followed by crystallization from ethanol.EP 0289801 discloses a process for the preparation of crystalline Biapenem wherein Biapenem was dissolved in water and lyophilized to get amorphous compound. The amorphous compound was dissolved in water at 40° C followed by cooling to get crystalline product. This patent further provides the PXRD values of the crystalline Biapenem. The Biapenem obtained according to the process provided in this patent takes longer time for reconstitution and hence not suitable.US 5,286,856 and US 5,424,069 provide a process for the crystallization of Biapenem which utilizes freeze-drying technique and vial lyophillisation method respectively. These patents disclose (refer para 1, lines 10-33 of US’ 856) that the process provided in EP 0289801 results with Biapenem crystals which take relatively longer time for dissolution during use. To overcome the above issues, these patents utilize the freeze-drying and vial lyophillisation methods. The said methods involve freezing of the solution containing Biapenem followed by raising the temperature and repeating the cooling and heating process followed by lyophillisation to get the crystalline product. Lyophillisation and related process are capital intensive techniques and uneconomical in commercial scale operations.All the above said prior arts utilize either the lyophillisation technique or preparing the amorphous material and crystallizing it from water to get crystalline Biapenem.Biapenem is available as powder for injection which needs to be reconstituted with water or saline solution before injection. The process of preparing a solution having an appropriate concentration of an active ingredient for the administration is called “reconstitution”. The reconstitution time (RCT) plays a critical role in injectable powders. Short reconstitution time is preferable for both a member of medical center and patients. If the reconstitution time is too long, it will increase the preparation time thus making it difficult to administrate it to many patients at the same, which will eventually lower the competitiveness of the drug. The problem before the applicants is to find economic and robust process for the preparation of Biapenem with high purity and yield which should dissolve in water in less than 25 seconds (reconstitution time). With our continued intensive and diligent research for developing a process for the preparation of Biapenem having high purity and yield with reconstitution time of less than 25 seconds, we have identified an improved process which is commercially viable and eliminates the issues associated with reconstitution time. The process of this invention is simple and obviates the use of freeze crystallization. Further the present invention fulfils the need for a process for the manufacture of Biapenem which is convenient to operate in commercial scale

Objectives of the inventionThe main objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the crystallization of Biapenem of formula (I) with high purity and good yield.Yet another objective of the present invention is to provide a simple and commercially suitable process for the preparation of Biapenem of formula (I) with reconstitution time less than 25 seconds. The reconstitution time is calculated by the time taken to dissolve 300 mg of Biapenem in 100 ml of water or saline solution.Summary of the inventionAccordingly the primary aspect of the present invention is to provide an improved process for the preparation of Biapenem of formula (I) the said process comprises;(i) obtaining a solution of Biapenem in water containing co-solvent; and(ii) adding anti-solvent in to the solution of step (i) or vice-versa to crystallize Biapenem followed by filtration. Detailed Description In an embodiment of the present invention, the co-solvent used in step (i) is selected from alcoholic solvents consisting of methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol and iso-butanol or mixtures thereof; preferably methanol, ethanol and isopropyl alcohol; more preferably methanol.In another embodiment of the present invention the anti-solvent used in step (ii) is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, butyl acetate, tetrahydrofuran or mixtures thereof; preferably acetone. In yet another embodiment of the present invention, the solution of Biapenem in step (i) can be obtained by (a) dissolving Biapenem in water followed by addition of co-solvent (b) dissolving Biapenem in water containing the co-solvent (c) the aqueous solution containing Biapenem can be obtained directly from the reaction mass followed by addition of co-solvent (d) the aqueous solution of Biapenem containing co-solvent can be obtained directly from the reaction mass. The said solutions, if necessary can be subjected to sterile filtration before the addition of anti-solvent. Thus the present invention provided a process for the preparation of sterile Biapenem having reconstitution time less than 25 seconds, more preferably less than 15 seconds.The prior art lyophillisation process for the preparation of Biapenem requires capital investment and high operating cost due to the involvement of repetitive heating and cooling process which is tedious technology in commercial scale operations. The reported prior art process for the crystallization of Biapenem of formula (I) from water results in the formation of crystalline powder which takes longer time for dissolution in water or saline solution (reconstitution time). Surprisingly, applicant found that the use of co-solvents during the crystallization of Biapenem results with Biapenem having reconstitution time of less than 25 seconds. This constitutes the novelty of the present invention.In this present invention the Biapenem of formula (I) is obtained as crystalline solid with purity above 99.0 % by HPLC with good stability and further can be easily filled in vials.

The following examples are provided by way of illustration only and should not be construed to limit the scope of the invention.

Crystallization of (4R,5S,6S)-3-(6,7-dihvdro-5H-pyrazolo[l,2-al 11,2,41 triazol-8-ium-6-vlsulfanvl)-6-(l-hydroxvethvl)-4-methvl-7-oxo-l-azabicyclo [3.2.01hept-2-ene-2-carboxvlate [Biapenem of formula (1)1:Example -1:To water (4 lit), Biapenem (100 g) was added at 40° C and dissolved to get a clear solution. Activated carbon and EDTA were added to the clear solution and filtered through hi-flow bed, washed with water followed by filtration through micron filters in sterile area. To the filtrate, methanol (600 mL) was added followed by acetone under stirring. To the reaction mass, Biapenem seed material was added and stirred. The crystallized product was filtered, washed with aqueous acetone and dried under vacuum to get crystalline Biapenem.Yield: 85 g Purity by HPLC: 99.5% Reconstitution time (RCT): < 15 seconds

Example -2:To water (4 lit), Biapenem (100 g) was added at 40° C and dissolved to get a clear solution. To the filtrate, isopropyl alcohol (500 ml) was added followed by acetone under stirring. The mass was cooled and stirred. The crystallized product was filtered, washed with aqueous acetone and dried under vacuum to get crystalline Biapenem.Yield: 83 g Purity by HPLC: 99.6% Reconstitution time: < 15 seconds

Example -3;To water (4 lit), Biapenem (100 g) was added at 40° C and dissolved to get a clear solution. The solution was filtered through micron filters. To the filtrate, ethanol (600 ml) was added followed by acetone and stirred. The crystallized product was filtered, washed with aqueous acetone and dried under vacuum to get crystalline Biapenem.Yield: 84 g Purity by HPLC: 99.5% Reconstitution time : < 15 seconds

Example -4:To water (4 lit), Biapenem (100 g) was added at 40° C and dissolved to get a clear solution. The solution was filtered through hi-flow bed, washed with water followed by filtration through micron filters. To the filtrate, methanol (450 ml) was added followed by acetone and stirred. The crystallized product was filtered, washed with aqueous acetone and dried under vacuum to get crystalline Biapenem. Yield: 87 g Purity by HPLC: 99.4% Reconstitution time (RCT): < 15 seconds

Reference example -1:Preparation of Biapenem (Non-Sterile)Step-I: Preparation of p-Nitrobenzyl (4R,5S,6S)-3-(6,7-dihydro-5H-pvrazolofl,2-al[l,2,41triazol-8-ium-6-vlsulfanvn-6-(l-hvdroxvethyl)-4-methvI-7-oxo-l-azabicvclo[3.2.01hept-2-ene-2-carboxylate [Compound of formula (IV)1To a mixture of acetonitrile and DMF, P-Nitrobenzyl (4R,5S,6S)-3-(dipheny loxy)phosphory loxy-6- [(1R)-1 -hydroxyethy 1] -4-methy 1-7-oxo-1 -azabicyclo[3,2,0]hept-2-ene-2-carboxylate (compound of formula II) and 6,7-dihydro-6-mercapto-5H-pyrazolo[l,2-a] [1,2,4] triazole chloride (compound of formula III) were added and cooled to 0-5° C. To this mixture, N-ethyldiisopropyl amine was added and stirred till the completion of the reaction, followed by the addition of dichloromethane to crystallize the p-Nitrobenzyl (4R,5S,6S)-3-(6,7-dihydro-5H-pyrazolo[l,2-a][l,2,4]triazol-8-ium-6-ylsulfanyl)-6-(l -hydroxyethyl)-4-methyl-7-oxo-1 -azabicyclo[3.2.0] hept-2-ene-2-carboxylate which was filtered and dried under nitrogen.

Step-II: Preparation of BiapenemTo a solution of MOPS buffer and THF, p-Nitrobenzyl (4R,5S,6S)-3-(6,7-dihydro-5H-pyrazolo[l,2-a][l,2,4]triazol-8-ium-6-ylsulfanyl)-6-(l-hydroxy ethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (Compound of formula-IV) was added at pH 7-8 and cooled to 5-10° C. The mixture was hydrogenated using palladium on carbon as catalyst. The catalyst was filtered and the filtrate was treated with activated carbon and filtered. The filtrate was extracted with dichloromethane and the layers separated. The aqueous layer was degassed. To the aqueous layer, acetone was added to crystallize Biapenem at 20-25° C. The product was filtered, washed with aqueous acetone and dried under vacuum to get Biapenem (Non-Sterile).

Reference example -2: Crystallization of Biapenem

Example -1 was repeated without the addition of methanol.Yield: 84 g Purity by HPLC: 99.5%Reconstitution time : > 90 secondsThe reconstitution time is calculated by the time taken to dissolve 300 mg of Biapenem in 100 ml of water or saline solution.Table-1: Comparative Data:The comparative data provided in the table-1 clearly indicates that the addition of co-solvent during crystallization provides Biapenem with reconstitution time less than 25 seconds.

Mobocertinib


Mobocertinib - Wikipedia
Mobocertinib.png

Mobocertinib

1847461-43-1

MF C32H39N7O4
MW 585.70

propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate

TAK-788AP32788TAK788UNII-39HBQ4A67LAP-3278839HBQ4A67L

US10227342, Example 10MFCD32669806NSC825519s6813TAK-788;AP32788WHO 11183

NSC-825519example 94 [WO2015195228A1]GTPL10468BDBM368374BCP31045EX-A3392

US FDA APPROVED 9/15/2021, Exkivity, To treat locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutation

Mobocertinib succinate Chemical Structure

Mobocertinib succinate Chemical Structure

CAS No. : 2389149-74-8

Molecular Weight703.78
FormulaC₃₆H₄₅N₇O₈
img

Mobocertinib mesylateCAS# 2389149-85-1 (mesylate)C33H43N7O7S
Molecular Weight: 681.809

CAS #: 2389149-85-1 (mesylate)   1847461-43-1 (free base)   2389149-74-8 (succinate)   2389149-76-0 (HBr)   2389149-79-3 (HCl)   2389149-81-7 (sulfate)   2389149-83-9 (tosylate)   2389149-87-3 (oxalate)   2389149-89-5 (fumarate)

JAPANESE ACCEPTED NAME

Mobocertinib Succinate

Propan-2-yl 2-[4-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxy-5-(prop-2-enamido)anilino]-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate monosuccinate

C32H39N7O4▪C4H6O4 : 703.78
[2389149-74-8]

FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations……. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mobocertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20

On September 15, 2021, the Food and Drug Administration granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals, Inc.) for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Today, the FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to select patients with the above mutations for mobocertinib treatment.

Approval was based on Study 101, an international, non-randomized, open-label, multicohort clinical trial (NCT02716116) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Efficacy was evaluated in 114 patients whose disease had progressed on or after platinum-based chemotherapy. Patients received mobocertinib 160 mg orally daily until disease progression or intolerable toxicity.

The main efficacy outcome measures were overall response rate (ORR) according to RECIST 1.1 as evaluated by blinded independent central review (BICR) and response duration. The ORR was 28% (95% CI: 20%, 37%) with a median response duration of 17.5 months (95% CI: 7.4, 20.3).

The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.

The recommended mobocertinib dose is 160 mg orally once daily until disease progression or unacceptable toxicity.

View full prescribing information for mobocertinib.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), and United Kingdom’s Medicines & Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 6 weeks ahead of the FDA goal date.

This application was granted priority review, breakthrough therapy designation and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.Takeda’s EXKIVITY™ (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC…….. https://www.takeda.com/newsroom/newsreleases/2021/takeda-exkivity-mobocertinib-approved-by-us-fda/September 15, 2021

  • Approval based on Phase 1/2 trial results, which demonstrated clinically meaningful responses with a median duration of response (DoR) of approximately 1.5 years
  • Next-generation sequencing (NGS) companion diagnostic test approved simultaneously to support identification of patients with EGFR Exon20 insertion mutations

OSAKA, Japan, and CAMBRIDGE, Mass. September 15, 2021 – Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) today announced that the U.S. Food and Drug Administration (FDA) has approved EXKIVITY (mobocertinib) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. EXKIVITY, which was granted priority review and received Breakthrough Therapy Designation, Fast Track Designation and Orphan Drug Designation from the FDA, is the first and only approved oral therapy specifically designed to target EGFR Exon20 insertion mutations. This indication is approved under Accelerated Approval based on overall response rate (ORR) and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“The approval of EXKIVITY introduces a new and effective treatment option for patients with EGFR Exon20 insertion+ NSCLC, fulfilling an urgent need for this difficult-to-treat cancer,” said Teresa Bitetti, president, Global Oncology Business Unit, Takeda. “EXKIVITY is the first and only oral therapy specifically designed to target EGFR Exon20 insertions, and we are particularly encouraged by the duration of the responses observed with a median of approximately 1.5 years. This approval milestone reinforces our commitment to meeting the needs of underserved patient populations within the oncology community.”

The FDA simultaneously approved Thermo Fisher Scientific’s Oncomine Dx Target Test as an NGS companion diagnostic for EXKIVITY to identify NSCLC patients with EGFR Exon20 insertions. NGS testing is critical for these patients, as it can enable more accurate diagnoses compared to polymerase chain reaction (PCR) testing, which detects less than 50% of EGFR Exon20 insertions.

“EGFR Exon20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute. “The approval of EXKIVITY (mobocertinib) marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses.”

“Patients with EGFR Exon20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed, but also lacking targeted treatment options that can improve response rates,” said Marcia Horn, executive director, Exon 20 Group at ICAN, International Cancer Advocacy Network. “As a patient advocate working with EGFR Exon20 insertion+ NSCLC patients and their families every day for nearly five years, I am thrilled to witness continued progress in the fight against this devastating disease and am grateful for the patients, families, healthcare professionals and scientists across the globe who contributed to the approval of this promising targeted therapy.”

The FDA approval is based on results from the platinum-pretreated population in the Phase 1/2 trial of EXKIVITY, which consisted of 114 patients with EGFR Exon20 insertion+ NSCLC who received prior platinum-based therapy and were treated at the 160 mg dose. Results were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting from the Phase 1/2 trial and demonstrated a confirmed ORR of 28% per independent review committee (IRC) (35% per investigator) as well as a median DoR of 17.5 months per IRC, a median overall survival (OS) of 24 months and a median progression-free survival (PFS) of 7.3 months per IRC.

The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. The EXKIVITY Prescribing Information includes a boxed warning for QTc prolongation and Torsades de Pointes, and warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.

The FDA review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE), which provides a framework for concurrent submission and review of oncology products among international partners. We look forward to continuing our work with regulatory agencies across the globe to bring mobocertinib to patients.

About EXKIVITY (mobocertinib)

EXKIVITY is a first-in-class, oral tyrosine kinase inhibitor (TKI) specifically designed to selectively target epidermal growth factor receptor (EGFR) Exon20 insertion mutations.

EXKIVITY is approved in the U.S. for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

Results from the Phase 1/2 trial of mobocertinib have also been accepted for review by the Center for Drug Evaluation (CDE) in China for locally advanced or metastatic NSCLC patients with EGFR Exon20 insertion mutations who have been previously treated with at least one prior systemic chemotherapy.

For more information about EXKIVITY, visit http://www.EXKIVITY.com. For the Prescribing Information, including the Boxed Warning, please visit https://takeda.info/Exkivity-Prescribing-Information.

About EGFR Exon20 Insertion+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of the estimated 2.2 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization.1,2 Patients with epidermal growth factor receptor (EGFR) Exon20 insertion+ NSCLC make up approximately 1-2% of patients with NSCLC, and the disease is more common in Asian populations compared to Western populations.3-7 This disease carries a worse prognosis than other EGFR mutations, as EGFR TKIs – which do not specifically target EGFR Exon20 insertions – and chemotherapy provide limited benefit for these patients.

Takeda is committed to continuing research and development to meet the needs of the lung cancer community through the discovery and delivery of transformative medicines.

EXKIVITY IMPORTANT SAFETY INFORMATION

QTc Interval Prolongation and Torsades de PointesEXKIVITY can cause life-threatening heart rate-corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal, and requires monitoring of QTc and electrolytes at baseline and periodically during treatment. Increase monitoring frequency in patients with risk factors for QTc prolongation.  Avoid use of concomitant drugs which are known to prolong the QTc interval and use of strong or moderate CYP3A inhibitors with EXKIVITY, which may further prolong the QTc.  Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity of QTc prolongation.

Interstitial Lung Disease (ILD)/Pneumonitis: Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold EXKIVITY in patients with suspected ILD/pneumonitis and permanently discontinue EXKIVITY if ILD/pneumonitis is confirmed.

Cardiac Toxicity: Monitor cardiac function, including left ventricular ejection fraction, at baseline and during treatment. Withhold, resume at reduced dose or permanently discontinue based on severity.

Diarrhea: Diarrhea may lead to dehydration or electrolyte imbalance, with or without renal impairment. Monitor electrolytes and advise patients to start an antidiarrheal agent at first episode of diarrhea and to increase fluid and electrolyte intake. Withhold, reduce the dose, or permanently discontinue EXKIVITY based on the severity.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception.

Mobocertinib, sold under the brand name Exkivity, is used for the treatment of non-small cell lung cancer.[2][3]

The most common side effects include diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychiafatigue, dry skin, and musculoskeletal pain.[2]

Mobocertinib is a small molecule tyrosine kinase inhibitor. Its molecular target is epidermal growth factor receptor (EGFR) bearing mutations in the exon 20 region.[4][5]

Mobocertinib was approved for medical use in the United States in September 2021.[2][3] It is a first-in-class oral treatment to target EGFR Exon20 insertion mutations.[3]

Medical uses

Mobocertinib is indicated for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.[2]

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PATENT

WO 2019222093

https://patents.google.com/patent/WO2019222093A1

Figure imgf000004_0002

Scheme I

Figure imgf000018_0001
Figure imgf000020_0001
Figure imgf000024_0001

Example 1 Procedure for the preparation of isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate (Compound (A)).

Figure imgf000049_0001

[00351] Step 1 : Preparation of isopropyl 2-chloro-4-(l -methyl- lH-indo 1-3 -yl)pyrimidine-5- carboxylate.

Figure imgf000049_0002

[00352] To a 2 L Radley reactor equipped with a mechanical stirrer, a thermometer, and a refluxing condenser was charged isopropyl 2,4-dichloropyrimidine-5-carboxylate (100 g, 42.5 mmol, 1.00 eq.) andl,2-dimethoxyethane (DME, 1.2 L, 12 vol) at RT. The mixture was cooled to 3 °C, and granular AlCb (65.5 g, 49.1 mmol, 1.15 eq.) was added in 2 portions (IT 3-12 °C, jacket set 0 °C). The white slurry was stirred 15-25 °C for 60 minutes. 1 -Methylindole (59 g, 44.9 mmol, 1.06 eq.) was added in one portion (IT 20-21°C). DME (100 mL) was used to aid 1- Methylindole transfer. The reaction mixture was aged for at 35 °C for 24 h. Samples (1 mL) were removed at 5 h and 24 h for HPLC analysis (TM1195).[00353] At 5 h the reaction had 70 % conversion, while after 24 h the desired conversion was attained (< 98%).[00354] The reaction mixture was cooled to 0 °C to 5 °C and stirred for 1 h. The solids were collected via filtration and washed with DME (100 mL). The solids (AlCb complex) were charged back to reactor followed by 2-MeTHF (1 L, 10 vol), and water (400 mL, 4 vol). The mixture was stirred for 10 minutes. The stirring was stopped to allow the layers to separate.The organic phase was washed with water (200 mL, 2 vol). The combined aqueous phase was re-extracted with 2-MeTHF (100 mL, 1 vol).[00355] During workup a small amount of product title compound started to crystallize.Temperature during workup should be at about 25-40 °C.[00356] The combined organic phase was concentrated under mild vacuum to 300-350 mL (IT 40-61 °C). Heptane (550 mL) was charged while maintaining the internal temperature between 50 °C and 60 °C. The resulting slurry was cooled at 25 °C over 15 minutes, aged for 1 h (19-25 °C) and the resulting solids isolated by filtration.[00357] The product was dried at 50 °C under vacuum for 3 days to yield 108.1 g (77 % yield) of the title compound, in 100% purity (AUC) as a yellow solid.‘H NMR (400 MHz, DMSO-i/e) d ppm 1.24 (d, J= 6.53 Hz, 6 H) 3.92 (s, 3 H) 5.19 (spt, J=6.27 Hz, 1 H) 7.25 – 7.35 (m, 2 H) 7.59 (d, J=8.03 Hz, 1 H) 8.07 (s, 1 H) 8.16 (d, J= 7.53 Hz, 1 H) 8.82 (s, 1 H).[00358] Step 2: Preparation of isopropyl 2-((4-fhioro-2-methoxy-5-nitrophenyl)amino)-4-(l- methyl-lH-indol-3-yl)pyrimidine-5-carboxylate.

Figure imgf000050_0001

[00359] A mixture of the product of step 1 (85.0 g, 258 mmol, 1.0 eq.), 4-fluoro-2-methoxy- 5nitroaniline (57.0 g, 306 mmol, 1.2 eq.) and PTSA monohydrate (13.3 g, 70.0 mmol, 0.27 eq.) in acetonitrile (1.4 L, 16.5 v) was heated to 76-81 °C under nitrogen in a 2 L Radley reactor. IPC at 19 h indicated that the reaction was complete.[00360] The reaction mixture was cooled to 25 °C and water (80 mL) was charged in one portion (IT during charge dropped from 25 °C to 19 °C). The reaction mixture was aged for 1 h at 21 °C and then the resulting solids were isolated by filtration. The product was washed with EtOAc (2 x 150 mL) and dried in high vacuum at 50 °C to 60 °C for 44 h to give 121.5 g of the title compound (98% yield), HPLC purity 100 % a/a; NMR indicated that PTSA was purged.¾ NMR (400 MHz, DMSO-7,) d ppm 1.21 (d, 7=6.02 Hz, 6 H) 3.91 (s, 3 H) 4.02 (s, 3 H) 5.09 (spt, 7=6.27 Hz, 1 H) 7.10 (t, 7=7.53 Hz, 1 H) 7.26 (t, 7=7.58 Hz, 1 H) 7.42 (d, 7=13.05 Hz, 1 H) 7.55 (d, 7=8.53 Hz, 1 H) 7.90 (br d, 7=7.53 Hz, 1 H) 7.98 (s, 1 H) 8.75 (s, 1 H) 8.88 (d, 7=8.03 Hz, 1 H) 9.03 (s, 1 H).[00361] Step 3: Preparation of isopropyl 2-((4-((2-(dimethylamino)ethyl(methyl)amino)-2- methoxy-5-nitrophenyl)amino)-4-(l-methyl-lH-indol-3-yl)pyrimidine-5-carboxylate.

Figure imgf000051_0001

[00362] A 50 L flask was charged 1.500 kg of the product of step 2 (3.1 moles, l.O equiv.), 639.0 g A,A,A-trimethylethylenediamine (6.3 mol, 2 equiv.), and 21 L MeCN. The resulting slurry was mixed for 7 hours at reflux. The reaction was cooled overnight. Water (16.5 L) was added before the solids were isolated. After isolation of the solids, a wash of 2.25 L MeCN in 2.25 L water was conducted to provide the title compound. The solids were dried, under vacuum, at 75 °C. HPLC purity a/a % of the dry solid was 99.3%.¾ NMR (400 MHz, DMSO-7,) d ppm 1.22 (d, 7=6.02 Hz, 6 H) 2.09 – 2.13 (m, 1 H) 2.19 (s, 6 H) 2.49 – 2.52 (m, 1 H) 2.89 (s, 3 H) 3.29 – 3.35 (m, 2 H) 3.89 (s, 3 H) 3.94 (s, 3 H) 5.10 (spt, 7=6.19 Hz, 1 H) 6.86 (s, 1 H) 7.07 (br t, 7=7.53 Hz, 1 H) 7.24 (t, 7=7.28 Hz, 1 H) 7.53 (d, 7=8.53Hz, 1 H) 7.86 – 8.02 (m, 2 H) 8.36 (s, 1 H) 8.69 (s, 1 H) 8.85 (s, 1 H).[00363] Step 4: Preparation of isopropyl 2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)- amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indo 1-3 -yl)pyrimidine-5-carboxy late.

Figure imgf000051_0002

[00364] To a mixture of the product of step 3 (1.501 kg, 2.67 mol, 1.00 eq.) and 10% Pd/C (64 % wet, 125.0 g, 0.01 1 eq.) was added 2-MeTHF (17.7 L) in a 20 L pressure reactor. The mixture was hydrogenated at 6- 10 psi ¾ and at 40 °C until IPC indicated complete conversion (1 1 h, the reaction product 99.0%). The reaction mixture was filtered (Celite), and the pad rinsed with MeTHF (2.5 L total). The filtrate was stored under N2 in a refrigerator until crystallization.[00365] Approximately 74% of 2-MeTHF was evaporated under reduced pressure while maintaining IT 23-34 °C (residual volume in the reactor was approximately 4.8 L). To the mixture was added n-heptane (6 L) over 15 min via dropping funnel. The resulting slurry was aged at room temperature overnight. The next day the solids on the walls were scraped to incorporate them into the slurry and the solids were isolated by filtration. The isolated solids were washed with n-heptane containing 5% MeTFlF (2 x 750 mL), and dried (75 °C, 30 inch Flg) to yield 1287 g (91 % yield) of the title compound as a yellow solid. F1PLC purity: 99.7% pure.[00366] ¾ NMR (400 MHz, DMSO- ) d ppm 1.20 (d, .7=6.02 Hz, 6 H) 2.21 (s, 6 H) 2.37 -2.44 (m, 2 H) 2.68 (s, 3 H) 2.93 (t, .7=6.78 Hz, 2 H) 3.74 (s, 3 H) 3.90 (s, 3 H) 4.60 (s, 2 H) 5.08 (spt, 7=6.19 Hz, 1 H) 6.80 (s, 1 H) 7.08 – 7.15 (m, 1 H) 7.19 – 7.26 (m, 2 H) 7.52 (d, .7=8.03 Hz, 1 H) 7.94 – 8.01 (m, 2 H) 8.56 (s, 1 H) 8.66 (s, 1 H).[00367] Step 5: Preparation of isopropyl 2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxy-5 -(3 -(phenylsulfonyl)propanamido)phenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate.

Figure imgf000052_0001

lnt-5[00368] A mixture of the product of step 4 (1.284 kg, 2.415 mol, 1.0 eq.) and 3- (phenylsulfonyl)propionic acid (0.5528 kg, 2.580 mol, 1.07 eq.) in anhydrous DCM (8.5 L) was cooled to 2 °C, and treated with DIEA (0.310 kg, 2.399 mol, 1.0 eq.). To the reaction mixture was charged over 40 min, 50 % w/w T3P in MeTHF (1.756 kg, 2.759 mol, 1.14 eq.) while maintaining the internal temperature between 0 °C and 8 °C. The mixture was stirred at 0 °C to 5 °C for 15 minutes and then warmed over 30 min to 15 °C then held at 15 °C to 30 °C for 60 min.[00369] The reaction was quenched with water (179 mL). The reaction mixture was stirred at ambient temperature for 30 min then DIEA (439 g) was charged in one portion. The resulting mixture was aged for 15 min, and then treated with 5% aqueous K2CO3 (7.3 L) at 22-25 °C. The organic layer was separated and the aqueous layer back extracted with DCM (6.142 L). The combined organic extract was washed with brine (2 x 5.5 L).[00370] The organic extract was concentrated to 6.5 L, diluted with EtOFl, 200 Proof (14.3 kg), and the mixture concentrated under vacuum (23-25 inch Flg/IT40-60 °C) to a residual volume of 12.8 L.[00371] The residual slurry was treated with EtOFl, 200 Proof (28.8 Kg), and heated to 69 °C to obtain a thin slurry. The reaction mixture was cooled to 15 °C over 2 h, and stored overnight at 15 °C under nitrogen.[00372] The next day, the mixture was cooled to 5 °C, and aged for 30 minutes. The resulting solid was isolated by filtration, washed with EtOFl (2 x 2.16 kg) and dried to give 1.769 kg (100% yield) of the title compound. F1PLC purity 99.85%.‘H NMR (400 MHz, DMSO-i¾ d ppm 1.08 – 1.19 (m, 8 H) 2.15 (s, 6 H) 2.32 (t, J= 5.77 Hz, 2 H) 2.66 – 2.76 (m, 5 H) 2.88 (br t, J= 5.52 Hz, 2 H) 3.48 (qd, J= 7.03, 5.02 Hz, 1 H) 3.60 – 3.69 (m, 2 H) 3.83 (s, 3 H) 3.89 (s, 3 H) 4.40 (t, J=5.02 Hz, 1 H) 5.04 (quin, J=6.27 Hz, 1 H) 7.01 – 7.09 (m, 2 H) 7.22 (t, J= 7.53 Hz, 1 H) 7.52 (d, J= 8.53 Hz, 1 H) 7.67 – 7.82 (m, 4 H) 7.97 (s, 1 H) 7.98 – 8.00 (m, 1 H) 8.14 (s, 1 H) 8.61 – 8.70 (m, 3 H) 10.09 (s, 1 H).[00373] Step 6: Preparation of isopropyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3-yl)pyrimidine-5-carboxylate (Compound (A)).

Figure imgf000053_0001

compound (A)[00374] The product of step 5 (1.600 kg, 2.198 mol, 1.0 equiv.) was dissolved in anhydrous THF (19.5 kg) and was treated at -1 °C to 1 °C with 2M KOSi(CH3)3 in THF (2.72 L, 5.44 mol, 2.47 equiv.). KOSi(CFb)3 was added over 5 minutes, reactor jacket set at -5 °C to 10 °C. 2 M KOSi(CFh)3 solution was prepared by dissolving 871 g of KOSi(CFh)3 technical grade (90%) in 3.056 L of anhydrous TF1F.[00375] The reaction mixture was aged for 60 minutes. Potable water (22 L) was charged to the reaction mixture over 1 10 minutes, while maintaining temperature at 2-7 °C. The resulting suspension was aged at 3-7 °C for 60 minutes; the product was isolated by filtration (the filtration rate during crude product isolation was (1.25 L/min), washed with potable water (2 x 1.6 L) and air dried overnight and then in high vacuum for 12 h at 45 °C to give 1.186 kg of crude title compound (92% yield).‘H NMR (500 MHz, DMSO-i¾ d ppm 1.05 (t, J= 7.09 Hz, 2 H) 1.1 1 (d, J= 6.36 Hz, 6 H) 2.1 1 (s, 6 H) 2.28 (br t, .7=5.38 Hz, 3 H) 2.55 – 2.67 (m, 3 H) 2.69 (s, 3 H) 2.83 (br t, .7=5.38 Hz, 3 H) 3.31 (s, 3 H) 3.36 – 3.51 (m, 2 H) 3.54 – 3.70 (m, 3 H) 3.75 – 3.82 (m, 3 H) 4.33 (t, .7=5.14 Hz, 1 H) 4.99 (dt, 7=12.35, 6.30 Hz, 2 H) 5.75 (s, 1 H) 6.95 – 7.07 (m, 2 H) 7.17 (br t, .7=7.58 Hz, 2 H) 7.48 (d, 7=8.31 Hz, 2 H) 7.62 – 7.71 (m, 3 H) 7.71 – 7.83 (m, 2 H) 7.93 (d, .7=7.83 Hz, 3 H) 8.09 (s, 2 H) 8.53 – 8.67 (m, 3 H) 10.03 (s, 2 H).[00376] Step 7: Preparation of polymorphic Form-I of isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl) (methyl)amino)-2-methoxyphenyl)amino)-4-(l -methyl- lH-indol-3- yl)pyrimidine-5-carboxylate (Free base Compound (A)).[00377] Method 1 : The crude product of step 6 (1.130 kg) was recrystallized by dissolving it in EtOAc (30.1 kg) at 75 °C, polish filtered (1.2 pm in-line filter), followed by concentration of the filtrate to 14 L of residue (IT during concentration is 58-70 °C). The residual slurry was cooled to 0 °C over 70 minutes and then aged at 0-2 °C for 30 minutes. Upon isolation the product was dried to a constant weight to give 1.007 kg (89% recovery) of the title compound as polymorphic Form-I. Purity (HPLC, a/a %, 99.80%).

PATENT

WO 2015195228

https://patents.google.com/patent/WO2015195228A1/en

PATENT

US10227342, Example 10

https://patents.google.com/patent/US10227342

 
 isopropyl 2-((5-acrylamido-4-((2-R13
 (dimethylamino)ethyl)(methyl)amino)-2- 
 methoxyphenyl)amino)-4-(1-methyl-1H- 
 indol-3-yl)pyrimidine-5-carboxylate 
 1H NMR (CDCl3) δ 10.15 (s, 1 H), 9.80 
 (s, 1 H), 8.91 (s, 1 H), 8.70 (br. s., 1 H), 
 7.91 (s, 1 H), 7.48-7.71 (m, 1 H), 7.15- 
 7.37 (m, 3 H), 6.81 (s, 1 H), 6.49 (dd, 
 J = 17.07, 1.88 Hz, 1 H), 6.36 (dd, 
 J = 16.94, 10.04 Hz, 1 H), 5.73 (dd, 
 J = 10.04, 1.88 Hz, 1 H), 5.02 (dt, 
 J = 12.45, 6.26 Hz, 1 H), 4.00 (s, 3 H), 
 3.90 (s, 3 H), 2.86-2.93 (m, 2 H), 2.76 
 (s, 3 H), 2.26-2.31 (m, 8 H), 1.05 (d, 
 J = 6.15 Hz, 6 H) 
 ESI-MS m/z: 586.3 [M + H]+

 

 

 

 

 

 

 

 

 

 

 

 

 

References

  1. Jump up to:a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215310s000lbl.pdf
  2. Jump up to:a b c d e “FDA grants accelerated approval to mobocertinib for metastatic non-sma”U.S. Food and Drug Administration (FDA). 16 September 2021. Retrieved 16 September 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c “Takeda’s Exkivity (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC” (Press release). Takeda Pharmaceutical Company. 15 September 2021. Retrieved 16 September 2021 – via Business Wire.
  4. ^ “TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy for Non-Small Cell Lung Cancer (NSCLC) With EGFR Exon 20 Insertion Mutations”Clinicaltrials.gov. Retrieved 17 February 2021.
  5. ^ Zhang SS, Zhu VW (2021). “Spotlight on Mobocertinib (TAK-788) in NSCLC with EGFR Exon 20 Insertion Mutations”Lung Cancer. Auckland, N.Z. 12: 61–65. doi:10.2147/LCTT.S307321PMC 8286072PMID 34285620.

External links

Clinical data
Trade namesExkivity
Other namesTAK-788
License dataUS DailyMedMobocertinib
Pregnancy
category
Contraindicated[1]
Routes of
administration
By mouth
Drug classAntineoplastic
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number1847461-43-12389149-74-8
PubChem CID118607832
DrugBankDB16390DBSALT003192
ChemSpider84455481
UNII39HBQ4A67L
KEGGD12001D11969
ChEMBLChEMBL4650319
Chemical and physical data
FormulaC32H39N7O4
Molar mass585.709 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////mobocertinib, Exkivity, TAK 788, AP32788, fda 2021, approvals 2021, cancer

CC(C)OC(=O)C1=CN=C(N=C1C2=CN(C3=CC=CC=C32)C)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC

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Vosoritide


PGQEHPNARK YKGANKKGLS KGCFGLKLDR IGSMSGLGC
(Disulfide bridge: 23-39)
ChemSpider 2D Image | vosoritide | C176H290N56O51S3
Vosoritide.png
SVG Image

H-Pro-Gly-Gln-Glu-His-Pro-Asn-Ala-Arg-Lys-Tyr-Lys-Gly-Ala-Asn-Lys-Lys-Gly-Leu-Ser-Lys-Gly-Cys(1)-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys(1)-OH

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
H-PGQEHPNARKYKGANKKGLSKGC(1)FGLKLDRIGSMSGLGC(1)-OH

PEPTIDE1{P.G.Q.E.H.P.N.A.R.K.Y.K.G.A.N.K.K.G.L.S.K.G.C.F.G.L.K.L.D.R.I.G.S.M.S.G.L.G.C}$PEPTIDE1,PEPTIDE1,23:R3-39:R3$$$

L-prolyl-glycyl-L-glutaminyl-L-alpha-glutamyl-L-histidyl-L-prolyl-L-asparagyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysyl-glycyl-L-alanyl-L-asparagyl-L-lysyl-L-lysyl-glycyl-L-leucyl-L-seryl-L-lysyl-glycyl-L-cysteinyl-L-phenylalanyl-glycyl-L-leucyl-L-lysyl-L-leucyl-L-alpha-aspartyl-L-arginyl-L-isoleucyl-glycyl-L-seryl-L-methionyl-L-seryl-glycyl-L-leucyl-glycyl-L-cysteine (23->39)-disulfide

(4R,10S,16S,19S,22S,28S,31S,34S,37S,40S,43S,49S,52R)-52-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-5-amino-5-oxo-2-[[2-[[(2S)-pyrrolidine-2-carbonyl]amino]acetyl]amino]pentanoyl]amino]-4-carboxybutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]pyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]acetyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]hexanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]acetyl]amino]-40-(4-aminobutyl)-49-benzyl-28-[(2S)-butan-2-yl]-31-(3-carbamimidamidopropyl)-34-(carboxymethyl)-16,22-bis(hydroxymethyl)-10,37,43-tris(2-methylpropyl)-19-(2-methylsulfanylethyl)-6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51-hexadecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hexadecazacyclotripentacontane-4-carboxylic acid

Vosoritide

Formula C176H290N56O51S3
CAS 1480724-61-5
Mol weight 4102.7254

1480724-61-5[RN]BMN 111L-Cysteine, L-prolylglycyl-L-glutaminyl-L-α-glutamyl-L-histidyl-L-prolyl-L-asparaginyl-L-alanyl-L-arginyl-L-lysyl-L-tyrosyl-L-lysylglycyl-L-alanyl-L-asparaginyl-L-lysyl-L-lysylglycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-, cyclic (23→39)-disulfideL-prolylglycyl-(human C-type natriuretic peptide-(17-53)-peptide (CNP-37)), cyclic-(23-39)-disulfideUNII:7SE5582Q2Pвосоритид [Russian] [INN]فوسوريتيد [Arabic] [INN]伏索利肽 [Chinese] [INN]

Voxzogo, 2021/8/26 EU APPROVED

Product details
Name Voxzogo
Agency product number EMEA/H/C/005475
Active substance Vosoritide
International non-proprietary name (INN) or common name vosoritide
Therapeutic area (MeSH) Achondroplasia
Anatomical therapeutic chemical (ATC) code M05BX
OrphanOrphan This medicine was designated an orphan medicine. This means that it was developed for use against a rare, life-threatening or chronically debilitating condition or, for economic reasons, it would be unlikely to have been developed without incentives. For more information, see Orphan designation.
Publication details
Marketing-authorisation holder BioMarin International Limited
Date of issue of marketing authorisation valid throughout the European Union 26/08/2021

On 24 January 2013, orphan designation (EU/3/12/1094) was granted by the European Commission to BioMarin Europe Ltd, United Kingdom, for modified recombinant human C-type natriuretic peptide for the treatment of achondroplasia.

The sponsorship was transferred to BioMarin International Limited, Ireland, in February 2019.

This medicine is now known as Vosoritide.

The medicinal product has been authorised in the EU as Voxzogo since 26 August 2021.

PEPTIDE

Treatment of Achondroplasia
modified recombinant human C-type natriuretic peptide (CNP)

Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia.[1]

The most common side effects include injection site reactions (such as swelling, redness, itching or pain), vomiting and decreased blood pressure.[1]

Vosoritide was approved for medical use in the European Union in August 2021.[1][2]

Voxzogo is a medicine for treating achondroplasia in patients aged 2 years and older whose bones are still growing.

Achondroplasia is an inherited disease caused by a mutation (change) in a gene called fibroblast growth-factor receptor 3 (FGFR3). The mutation affects growth of almost all bones in the body including the skull, spine, arms and legs resulting in very short stature with a characteristic appearance.

Achondroplasia is rare, and Voxzogo was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 24 January 2013. Further information on the orphan designation can be found here: ema.europa.eu/medicines/human/orphan-designations/EU3121094.

Voxzogo contains the active substance vosoritide.

Achondroplasia Posters | Fine Art America

Medical uses

Vosoritide is indicated for the treatment of achondroplasia in people two years of age and older whose epiphyses are not closed.[1]

Mechanism of action

AChondrocyte with constitutionally active FGFR3 that down-regulates its development via the MAPK/ERK pathway
B: Vosoritide (BMN 111) blocks this mechanism by binding to the atrial natriuretic peptide receptor B (NPR-B), which subsequently inhibits the MAPK/ERK pathway at the RAF-1 protein.[3]

Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of fibroblast growth factor receptor 3 (FGFR3).[1] FGFR3 is a receptor that normally down-regulates cartilage and bone growth when activated by one of the proteins known as acidic and basic fibroblast growth factor. It does so by inhibiting the development (cell proliferation and differentiation) of chondrocytes, the cells that produce and maintain the cartilaginous matrix which is also necessary for bone growth. Children with achondroplasia have one of several possible FGFR3 mutations resulting in constitutive (permanent) activity of this receptor, resulting in overall reduced chondrocyte activity and thus bone growth.[3]

The protein C-type natriuretic peptide (CNP), naturally found in humans, reduces the effects of over-active FGFR3. Vosoritide is a CNP analogue with the same effect but prolonged half-life,[3] allowing for once-daily administration.[4]

Chemistry

 

Vosoritide is an analogue of CNP. It is a peptide consisting of the amino acids proline and glycine plus the 37 C-terminal amino acids from natural human CNP. The complete peptide sequence isPGQEHPNARKYKGANKKGLS KGCFGLKLDIGSMSGLGC

with a disulfide bridge between positions 23 and 39 (underlined).[5] The drug must be administered by injection as it would be rendered ineffective by the digestive system if taken by mouth.

History

Vosoritide is being developed by BioMarin Pharmaceutical and, being the only available causal treatment for this condition, has orphan drug status in the US as well as the European Union.[1][2][6] As of September 2015, it is in Phase II clinical trials.[7][4]

Society and culture

Controversy

Some people with achondroplasia, as well as parents of children with this condition, have reacted to vosoritide’s study results by saying that dwarfism is not a disease and consequently does not need treatment.[8]

Research

Vosoritide has resulted in increased growth in a clinical trial with 26 children. The ten children receiving the highest dose grew 6.1 centimetres (2.4 in) in six months, compared to 4.0 centimetres (1.6 in) in the six months before the treatment (p=0.01).[9] The body proportions, more specifically the ratio of leg length to upper body length – which is lower in achondroplasia patients than in the average population – was not improved by vosoritide, but not worsened either.[7][10]

As of September 2015, it is not known whether the effect of the drug will last long enough to result in normal body heights,[10] or whether it will reduce the occurrence of achondroplasia associated problems such as ear infections, sleep apnea or hydrocephalus. This, together with the safety of higher doses, is to be determined in further studies.[4]

References

  1. Jump up to:a b c d e f g “Voxzogo EPAR”European Medicines Agency. 23 June 2021. Retrieved 9 September 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. Jump up to:a b “European Commission Approves BioMarin’s Voxzogo (vosoritide) for the Treatment of Children with Achondroplasia from Age 2 Until Growth Plates Close”BioMarin Pharmaceutical Inc. (Press release). 27 August 2021. Retrieved 9 September 2021.
  3. Jump up to:a b c Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, et al. (December 2012). “Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia”American Journal of Human Genetics91 (6): 1108–14. doi:10.1016/j.ajhg.2012.10.014PMC 3516592PMID 23200862.
  4. Jump up to:a b c Clinical trial number NCT02055157 for “A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)” at ClinicalTrials.gov
  5. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN): List 112” (PDF). WHO Drug Information28 (4): 539. 2014.
  6. ^ “Food and Drug Administration Accepts BioMarin’s New Drug Application for Vosoritide to Treat Children with Achondroplasia” (Press release). BioMarin Pharmaceutical. 2 November 2020. Retrieved 9 September 2021 – via PR Newswire.
  7. Jump up to:a b Spreitzer H (6 July 2015). “Neue Wirkstoffe – Vosoritid”. Österreichische Apothekerzeitung (in German) (14/2015): 28.
  8. ^ Pollack A (17 June 2015). “Drug Accelerated Growth in Children With Dwarfism, Pharmaceutical Firm Says”The New York Times.
  9. ^ “BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study”. BioMarin. 17 June 2015.
  10. Jump up to:a b “Vosoritid” (in German). Arznei-News.de. 20 June 2015.

External links

  • “Vosoritide”Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Trade names Voxzogo
Other names BMN-111
Routes of
administration
Subcutaneous injection
ATC code None
Legal status
Legal status EU: Rx-only [1]
Identifiers
CAS Number 1480724-61-5
DrugBank DB11928
ChemSpider 44210446
UNII 7SE5582Q2P
KEGG D11190
Chemical and physical data
Formula C176H290N56O51S3
Molar mass 4102.78 g·mol−1
3D model (JSmol) Interactive image
showSMILES
showInChI

/////////Vosoritide, Voxzogo, PEPTIDE, ボソリチド (遺伝子組換え) , восоритид , فوسوريتيد , 伏索利肽 , APPROVALS 2021, EU 2021, BMN 111, ORPHAN DRUG

CCC(C)C1C(=O)NCC(=O)NC(C(=O)NC(C(=O)NC(C(=O)NCC(=O)NC(C(=O)NCC(=O)NC(CSSCC(C(=O)NC(C(=O)NCC(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCNC(=N)N)CC(=O)O)CC(C)C)CCCCN)CC(C)C)CC2=CC=CC=C2)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CCCCN)NC(=O)C(CC(=O)N)NC(=O)C(C)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CC3=CC=C(C=C3)O)NC(=O)C(CCCCN)NC(=O)C(CCCNC(=N)N)NC(=O)C(C)NC(=O)C(CC(=O)N)NC(=O)C4CCCN4C(=O)C(CC5=CN=CN5)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)N)NC(=O)CNC(=O)C6CCCN6)C(=O)O)CC(C)C)CO)CCSC)CO

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Ferric pyrophosphate citrate


str1
Thumb
Iron(III) pyrophosphate.svg
ChemSpider 2D Image | Iron(3+) diphosphate (4:3) | Fe4O21P6
Ferric pyrophosphate citrate | C18H24Fe4O42P6 - PubChem
Triferic (Ferric Pyrophosphate Citrate Solution, for Addition to Bicarbonate Concentrate): Uses, Dosage, Side Effects, Interactions, Warning
Physicochemical characterization of ferric pyrophosphate citrate | SpringerLink
Ferric Pyrophosphate Citrate - Drugs and Lactation Database (LactMed) - NCBI Bookshelf
Structure of FERRIC PYROPHOSPHATE CITRATE

Ferric pyrophosphate citrate

1802359-96-1

tetrairon(3+) bis((phosphonooxy)phosphonic acid) tris(2-hydroxypropane-1,2,3-tricarboxylate) (hydrogen phosphonooxy)phosphonate

Iron(3+) diphosphate (4:3)

Proper name: ferric pyrophosphate citrate Chemical names: Iron (3+) cation; 2-oxidopropane-1,2,3-tricarboxylate; diphosphate 1,2,3-propanetricarboxylic acid, 2-hydroxy-, iron (3+), diphosphate Molecular formula: [Fe4 3+(C6H5O7)3(P2O7)3] Molecular mass: 1313

Physicochemical properties: TRIFERIC AVNU (ferric pyrophosphate citrate) contains no asymmetric centers. Ferric pyrophosphate citrate is a yellow to green amorphous powder. The drug substance does not melt, or change state, below 300 °C. Thermal decomposition was observed at 263 ± 3ºC. Ferric pyrophosphate citrate is freely soluble in water (>100 g/L). Ferric pyrophosphate citrate is completely insoluble in most organic solvents (MeOH, Acetone, THF, DMF, DMSO). A 5% solution in water exhibits a solution pH of about 6.  … https://pdf.hres.ca/dpd_pm/00060816.PDF

  • Ferric pyrophosphate citrate
  • FPC
  • SFP
  • Tetraferric nonahydrogen citrate pyrophosphate
  • Triferic

Active Moieties

NAMEKINDUNIICASINCHI KEY
Ferric cationionic91O4LML61120074-52-6VTLYFUHAOXGGBS-UHFFFAOYSA-N

CANADA

30 Great Canada Flag Gifs

Summary Basis of Decision – Triferic AVNU – Health Canada

Date SBD issued:2021-07-29

The following information relates to the new drug submission for Triferic AVNU.

Iron (supplied as ferric pyrophosphate citrate)

Drug Identification Number (DIN):

DIN 02515334 – 1.5 mg/mL iron (supplied as ferric pyrophosphate citrate), solution, intravenous administration

Rockwell Medical Inc.

New Drug Submission Control Number: 239850

On April 22, 2021, Health Canada issued a Notice of Compliance to Rockwell Medical Inc. for the drug product Triferic AVNU.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Triferic AVNU is favourable for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.

Triferic AVNU, an iron preparation, was authorized for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.

Triferic AVNU is not authorized for use in pediatric patients (<18 years of age), as its safety and effectiveness have not been established in this population. No overall differences in efficacy or safety were observed in geriatric patients (≥65 years of age) compared to younger patients in clinical trials.

Triferic AVNU is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation, or component of the container.

Triferic AVNU was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Triferic AVNU (1.5 mg/mL iron [supplied as ferric pyrophosphate citrate]) is presented as a solution. In addition to the medicinal ingredient, the solution contains water for injection.

For more information, refer to the ClinicalNon-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Triferic AVNU Product Monograph, approved by Health Canada and available through the Drug Product Database.

Health Canada considers that the benefit-harm-uncertainty profile of Triferic AVNU is favourable for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (CKD-HD). Triferic AVNU is not intended for use in patients receiving peritoneal dialysis and has not been studied in patients receiving home hemodialysis.

Chronic kidney disease (CKD) is a worldwide public health concern. One of the most common comorbidities of CKD-HD patients is anemia, which may be due to low body iron stores (as a result of blood loss during dialysis) and impaired utilization of iron. Consequently, there is an ongoing need to replenish body iron in CKD-HD patients.

Iron deficiency anemia in CKD-HD patients is generally treated using parenteral (intravenous) iron administration used in conjunction with erythropoiesis stimulating agents (ESAs). Intravenous administration is preferred, as oral iron is not well absorbed and gastrointestinal intolerance is common. At the time of authorization of Triferic AVNU, there were four other intravenous iron products marketed in Canada: Dexiron, an iron dextran (≥1,000 mg/dose); Ferrlecit (sodium ferric gluconate; 125 mg/dose); Venofer (iron sucrose; 200 mg/dose); and the more recently approved Monoferric (Iron Isomaltoside 1,000; up to 500 mg/bolus injection and up to 1,500 mg/infusion). Each of these intravenous iron products are indicated for the treatment of iron deficiency anemia and are associated with safety concerns for hypersensitivity reactions. Serious hypersensitivity reactions have been reported, including life threatening and fatal anaphylactic/anaphylactoid reactions.

Triferic AVNU is an iron replacement product delivered via intravenous infusion into the blood lines pre- and post-dialyzer in CKD-HD patients at each hemodialysis treatment. It is a preservative-free sterile solution containing 1.5 mg elemental iron/mL in water for injection.

Triferic AVNU has been shown to be efficacious in maintaining hemoglobin (Hb) during the treatment period in CKD-HD patients. The market authorization was primarily based on the results of two pivotal, randomized, placebo-controlled, single blind, Phase III clinical studies (Studies SFP-4 and SFP-5). Both studies were identical in design and enrolled a combined total of 599 adult patients with CKD-HD who were iron-replete. Patients were randomized to receive either Triferic AVNU added to bicarbonate concentrate with a final concentration of 110 μg of iron/L in dialysate or placebo (standard dialysate) administered 3 to 4 times per week during hemodialysis. All patients were to remain randomized in their treatment group until pre-specified Hb or ferritin criteria were met, indicating the need for a change in anemia management, or until they had completed 48 weeks of treatment. After randomization, patients’ ESA product, doses, or route of administration were not to be changed and oral or intravenous iron administration were not allowed.

The primary efficacy endpoint (mean change in Hb level from baseline to the end-of-treatment period) was met in both pivotal studies. In Study SFP-4, the mean Hb decreased 0.04 g/dL in the Triferic AVNU group compared to 0.39 g/dL in the placebo group. In Study SFP-5, the mean Hb decreased 0.09 g/dL in the Triferic AVNU group compared to 0.45 g/dL in the placebo group. In both studies, the treatment difference in mean hemoglobin change was 0.36 g/dL (p = 0.011) between the Triferic AVNU and the placebo groups. This value was statistically significant for both studies. The treatment difference of 0.35 g/dL was also statistically significant (p = 0.010) for both studies in the analysis using the intent-to-treat population. A high proportion of patients did not complete the planned 48 weeks of study treatment mainly due to protocol-mandated changes in anemia management (ESA dose changes). However, the proportion was similar for both arms and the analysis of Hb change in this subgroup was consistent with that of the primary efficacy analysis. Secondary endpoints which included changes in reticulocyte Hb content, serum ferritin, and pre-dialysis serum iron panel to the end of treatment, were consistent with the primary efficacy results.

The safety of Triferic AVNU was evaluated in seven controlled and uncontrolled Phase II/III studies, which included the two pivotal studies. In total, 1,411 CKD-HD patients were exposed to Triferic AVNU in the clinical program. In the pivotal studies, 78% of patients in the Triferic AVNU group and 75% of patients in the placebo group had at least one treatment-emergent adverse event (TEAE). The most common TEAEs in the Triferic AVNU group (which were higher than the placebo group) were procedural hypotension (21.6%), muscle spasms (9.6%), headache (9.2%), pain in extremity (6.8%), edema peripheral (6.8%) and dyspnoea (5.8%). Serious TEAEs were reported at similar rates for the two groups at 27.7% for the Triferic AVNU group and 27.4% for the placebo group. The most common serious TEAEs occurring in the Triferic AVNU group (which were higher than the placebo group) were cardiac arrest (1.7%), arteriovenous fistula thrombosis (1.7%), and pulmonary edema (1.4%). Few patients discontinued study treatment due to TEAEs (4.5% in the Triferic AVNU group and 2.4% in the placebo group).

In the overall clinical program, there were two cases (0.1%) of hypersensitivity reactions related to treatment out of the 1,411 patients treated with Triferic AVNU. There were no cases of serious hypersensitivity reaction and no cases of anaphylaxis related to Triferic AVNU treatment. A Serious Warnings and Precautions box describing a warning for hypersensitivity reaction has been included in the Product Monograph for Triferic AVNU.

A Risk Management Plan (RMP) for Triferic AVNU was submitted by Rockwell Medical Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. In the RMP, the sponsor included ‘hypersensitivity reactions’ as an important identified risk; ‘systemic/serious infections’ as an important potential risk; and ‘use in pregnant and breastfeeding women’, ‘use in children’ and ‘concomitant use with other intravenous iron product’ as missing information. Labelling for these safety concerns has been included in the Product Monograph and the sponsor has committed to systemically review clinical and post-marketing safety data as part of routine pharmacovigilance activities. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Triferic AVNU Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Triferic AVNU was accepted.

Overall, the therapeutic benefits of Triferic AVNU therapy seen in the pivotal studies are positive and are considered to outweigh the potential risks. Triferic AVNU has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Triferic AVNU Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the ClinicalNon-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

The Chemistry and Manufacturing information submitted for Triferic AVNU has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored protected from light in the aluminum pouch at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

None of the excipients used in the formulation of Triferic AVNU are of human or animal origin. All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

DIN:

02515334

Product Monograph/Veterinary Labelling:

Date: 2021-04-21  Product monograph/Veterinary Labelling (PDF version ~ 175K)

Company:

ROCKWELL MEDICAL INC
30142 S Wixom Rd
Wixom
Michigan
United States  48393

Class: 

Human

Dosage form(s):

Solution

Route(s) of administration:

Intravenous

Number of active ingredient(s):

1

Schedule(s):

Prescription

Biosimilar Biologic Drug:

No

American Hospital Formulary Service (AHFS):See footnote3

20:04.04   IRON PREPARATIONS

Anatomical Therapeutic Chemical (ATC):See footnote4

B03AC  IRON, PARENTERAL PREPARATIONS

Active ingredient group (AIG) number:See footnote5

0108536041

Active ingredient(s)Strength
IRON (FERRIC PYROPHOSPHATE CITRATE)1.5 MG / ML

RXLIST

TRIFERIC®
(ferric pyrophosphate citrate) Solution, for Hemodialysis Use

TRIFERIC®
(ferric pyrophosphate citrate) powder packet for hemodialysis use

DESCRIPTION

Triferic (ferric pyrophosphate citrate) solution, an iron replacement product, is a mixed-ligand iron complex in which iron (III) is bound to pyrophosphate and citrate. It has a molecular formula of Fe4(C6H4O7)3(H2P2O7)2(P2O7) and a relative molecular weight of approximately 1313 daltons. Ferric pyrophosphate citrate has the following structure:

TRIFERIC® (ferric pyrophosphate citrate) solution, for hemodialysis use TRIFERIC® (ferric pyrophosphate citrate) powder packet for hemodialysis use Structural Formula - Illustration

Triferic Solution

Triferic (ferric pyrophosphate citrate) solution–is a clear, slightly yellow-green color sterile solution containing 27.2 mg of elemental iron (III) per 5 mL (5.44 mg iron (III) per mL) filled in a 5 mL or 272 mg of elemental iron (III) per 50 mL (5.44 mg iron (III) per mL) filled in a 50 Ml low density polyethylene (LDPE) ampule. Each Triferic ampule contains iron (7.5-9.0% w/w), citrate (15-22% w/w), pyrophosphate (15-22% w/w), phosphate (< 2% w/w), sodium (18-25% w/w) and sulfate (20-35%). One Triferic 5 mL ampule is added to 2.5 gallons (9.46 L) of bicarbonate concentrate. One Triferic 50 mL ampule is added to 25 gallons (94.6 L) of master bicarbonate mix.

Triferic Powder Packets

Triferic (ferric pyrophosphate citrate) powder is a slightly yellow-green powder, packaged in single use paper, polyethylene and aluminum foil packets, each containing 272.0 mg of elemental iron (III). Each Triferic packet contains iron (7.5-9.0% w/w), citrate (15-22% w/w), pyrophosphate (15-22% w/w), phosphate (< 2% w/w), sodium (18-25% w/w) and sulfate (20- 35%). One Triferic powder packet is added to 25 (94.6 L) gallons of master bicarbonate mix.

Ferric pyrophosphate citrate (FPC), a novel iron-replacement agent, was approved by the US Food and Drug Administration in January 2015 for use in adult patients receiving chronic hemodialysis (HD). This iron product is administered to patients on HD via the dialysate.

Ferric pyrophosphate citrate is a soluble iron replacement product. Free iron presents several side effects as it can catalyze free radical formation and lipid peroxidation as well as the presence of interactions of iron in plasma. The ferric ion is strongly complexed by pyrophosphate and citrate.1 FPC is categorized in Japan as a second class OTC drug.6 This category is given to drugs with ingredients that in rare cases may cause health problems requiring hospitalization or worst.7 It is also FDA approved since 2015.Label

Iron(III) pyrophosphate is an inorganic chemical compound with the formula Fe4(P2O7)3.

Synthesis

Anhydrous iron(III) pyrophosphate can be prepared by heating the mixture of iron(III) metaphosphate and iron(III) phosphate under oxygen with the stoichiometric ratio 1:3. The reactants can be prepared by reacting iron(III) nitrate nonahydrate with phosphoric acid.[2]

It can be also prepared via the following reaction:[3]3 Na4P2O7(aq) + 4 FeCl3(aq) → Fe4(P2O7)3(s) + 12 NaCl(aq)

References

  1. ^ W.M.Haynes. CRC Handbook of Chemistry and Physics (97th edition). New York: CRC Press, 2016. pp 4-68
  2. ^ Elbouaanani, L.K; Malaman, B; Gérardin, R; Ijjaali, M (2002). “Crystal Structure Refinement and Magnetic Properties of Fe4(P2O7)3 Studied by Neutron Diffraction and Mössbauer Techniques”. Journal of Solid State Chemistry. Elsevier BV. 163 (2): 412–420. doi:10.1006/jssc.2001.9415ISSN 0022-4596.
  3. ^ Rossi L, Velikov KP, Philipse AP (May 2014). “Colloidal iron(III) pyrophosphate particles”. Food Chem151: 243–7. doi:10.1016/j.foodchem.2013.11.050PMID 24423528.
  • Gupta A, Amin NB, Besarab A, Vogel SE, Divine GW, Yee J, Anandan JV: Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999 May;55(5):1891-8. doi: 10.1046/j.1523-1755.1999.00436.x. [Article]
  • Naigamwalla DZ, Webb JA, Giger U: Iron deficiency anemia. Can Vet J. 2012 Mar;53(3):250-6. [Article]
  • Fidler MC, Walczyk T, Davidsson L, Zeder C, Sakaguchi N, Juneja LR, Hurrell RF: A micronised, dispersible ferric pyrophosphate with high relative bioavailability in man. Br J Nutr. 2004 Jan;91(1):107-12. [Article]
  • Pratt RD, Swinkels DW, Ikizler TA, Gupta A: Pharmacokinetics of Ferric Pyrophosphate Citrate, a Novel Iron Salt, Administered Intravenously to Healthy Volunteers. J Clin Pharmacol. 2017 Mar;57(3):312-320. doi: 10.1002/jcph.819. Epub 2016 Oct 3. [Article]
  • Underwood E. (1977). Trace elements in human and animal nutrition (4th ed.). Academic press.
  • KEGG [Link]
  • Nippon [Link]
  • FDA Reports [Link]
Names
Other namesFerric pyrophosphate
Identifiers
CAS Number10058-44-3 (anhydrous) 10049-18-0 (nonahydrate) 
3D model (JSmol)Interactive image
ChEBICHEBI:132767
ChemSpider23258
DrugBankDB09147
ECHA InfoCard100.030.160 
EC Number233-190-0
PubChem CID24877
UNIIQK8899250F 1ZJR117WBQ (nonahydrate) 
CompTox Dashboard (EPA)DTXSID6047600 
showInChI
showSMILES
Properties
Chemical formulaFe4(P2O7)3
Molar mass745.224 (anhydrate)
907.348 (nonahydrate)
Appearanceyellow solid (nonahydrate)[1]
Solubility in waterinsoluble
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

CLIP

https://link.springer.com/article/10.1007/s10534-018-0151-1

Iron deficiency is a significant health problem across the world. While many patients benefit from oral iron supplements, some, including those on hemodialysis require intravenous iron therapy to maintain adequate iron levels. Until recently, all iron compounds suitable for parenteral administration were colloidal iron–carbohydrate conjugates that require uptake and processing by macrophages. These compounds are associated with variable risk of anaphylaxis, oxidative stress, and inflammation, depending on their physicochemical characteristics. Ferric pyrophosphate citrate (FPC) is a novel iron compound that was approved for parenteral administration by US Food and Drug Administration in 2015. Here we report the physicochemical characteristics of FPC. FPC is a noncolloidal, highly water soluble, complex iron salt that does not contain a carbohydrate moiety. X-ray absorption spectroscopy data indicate that FPC consists of iron (III) complexed with one pyrophosphate and two citrate molecules in the solid state. This structure is preserved in solution and stable for several months, rendering it suitable for pharmaceutical applications in solid or solution state.

Iron deficiency with or without associated anemia represents a significant health problem worldwide. While many patients can restore iron levels with the use of oral iron supplements, oral supplementation is not suitable in some patients, including those undergoing chronic hemodialysis for chronic kidney disease (CKD) (Fudin et al. 1998; Macdougall et al. 1996; Markowitz et al. 1997). The limitations of oral iron replacement in patients undergoing hemodialysis likely arise from excessive ongoing losses and insufficient absorption, thus intravenous (IV) iron has become the primary route of administration in such patients (Shah et al. 2016). Multiple IV iron formulations are available, including iron dextran, iron sucrose, sodium ferric gluconate, iron carboxymaltose, ferrumoxytol, and iron isomaltoside (Macdougall et al. 1996). All such formulations are iron–carbohydrate macromolecular complexes, and the majority consist of an iron oxide core surrounded by a carbohydrate moiety (Macdougall et al. 1996; Markowitz et al. 1997).

Intravenous iron products have been used extensively for over 30 years for the treatment of iron-deficiency anemia and to maintain iron balance in hemodialysis patients since these patients have obligatory excessive losses. While these agents are generally well tolerated, they have been associated with risk of anaphylaxis (Wang et al. 2015). Compared to oral iron agents, there may be an increased risk of cardiovascular complications and infections in nondialysis patients with CKD (Macdougall et al. 1996). Additionally, higher mortality rates have been reported with use of high-dose IV iron in hemodialysis patients (Bailie et al. 2015).

Iron possesses oxidizing properties that may cause injury to cells and tissues (Koskenkorva-Frank et al. 2013; Vaziri 2013). Iron loading in general is associated with endocrinological, gastrointestinal, infectious, neoplastic, neurodegenerative, obstetric, ophthalmic, orthopedic, pulmonary, and vascular complications. In addition, excessive or misplaced tissue iron also can contribute to aging and mortality (Weinberg 2010). Normally, the body is able to protect tissues from the damaging effects of iron by regulating iron absorption in the intestine and sequestering iron with iron-binding proteins. However, the concentrations of iron introduced into the bloodstream with IV iron therapy can be as much as 100 times more than that absorbed normally through the intestine. Combined with the fact that IV iron is administered over a period of minutes compared to the slow, regulated absorption in the gut, it is possible that the increased iron load may damage cells and tissues.

A novel parenteral iron formulation, ferric pyrophosphate citrate (FPC), potentially offers a more physiologic delivery of iron. Unlike previous forms of IV iron, FPC contains no carbohydrate shell. Soluble ferric pyrophosphate-citrate complexes, generally referred to as soluble ferric pyrophosphate (SFP) were first described in the mid-1800s by Robiquet and Chapman (Chapman 1862; Robiquet 1857). This class of food-grade iron salts has been available for over 100 years as oral iron supplements and for fortification of food. In the late-1990s, Gupta et al. demonstrated that food-grade SFP could be administered to hemodialysis patients via the dialysate (Gupta et al. 1999). However, the commercially available compounds are poorly characterized and not suitable for further development as a parenteral iron supplement. Therefore, a pharmaceutical-grade SFP was developed. This product had a higher solubility than food-grade SFP and was granted a new USAN name—FPC. In 2015 FPC was approved by the US Food and Drug Administration (FDA) for parenteral delivery by hemodialysis to replace iron losses and thereby maintain hemoglobin levels in hemodialysis-dependent patients with CKD (Rockwell Medical Inc 2018). FPC is currently marketed under the trade name Triferic® (Rockwell Medical Inc., Wixom, Michigan, USA). FPC is the first carbohydrate-free, noncolloidal, water-soluble iron salt suitable for parenteral administration.

Infrared spectroscopy

Infrared (IR) spectroscopy was used to determine the main functional groups present in FPC. Figure 1 shows a representative IR spectrum of FPC. Peak assignments and positions for FPC as well as for sodium citrate, sodium pyrophosphate, and ferric sulfate, which were used to confirm the peak assignments, are shown in Table 1.

figure1
Fig. 1
figure4

X-ray spectra of solid and aqueous iron standards and FPC. a XANES spectra of iron (II) and iron (III) standards as well as FPC in the solid and solution phases show that FPC consists exclusively of iron (III) and that the solid-phase structure is maintained in solution. b EXFAS modeling of FPC in the solid phase (top) and in solution (bottom) at Day 1 and Month 4

Chemical composition of ferric pyrophosphate citrate

From: Physicochemical characterization of ferric pyrophosphate citrate

IonPercentage
Iron8
Citrate19
Pyrophosphate18
Phosphate< 1
Sulfate25–28

PATENT

https://patents.google.com/patent/WO2017040937A1/enProperties of Conventional SFP

Figure imgf000010_0001

Another example of SFP is the composition is the chelate composition described in US Patent Nos. 7,816,404 and 8,178,709. The SFP may be a ferric pyrophosphate citrate (FPC) comprising a mixed-ligand iron compound comprising iron chelated with citrate andpyrophosphate, optionally FPC has the following formula: Fe4(C6H407)3(H2P207)2(P207) (relative MW 1313 daltons), e.g., structure (I):

Figure imgf000011_0001

[0036] An exemplary SFP according to the present disclosure is known to have the properties described in Table 3.Table 3 – Properties of SFP according to the present disclosure

Figure imgf000012_0001
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////////////ferric pyrophosphate citrate, Triferic AVNU, , Ferric pyrophosphate citrate, FPC, SFP, Tetraferric nonahydrogen citrate pyrophosphate, Triferic, FDA 2015, APPROVALS 2021, CANADA 2021, hemodialysis-dependent chronic kidney disease 

[Fe+3].[Fe+3].[Fe+3].[Fe+3].OP(O)(=O)OP(O)(O)=O.OP(O)(=O)OP(O)(O)=O.OP([O-])(=O)OP([O-])([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O.OC(CC([O-])=O)(CC([O-])=O)C([O-])=O

Pegvaliase


Pegvaliase compact.png
Pegvaliase.png
File:Pegvaliase.png

Pegvaliase

(2S)-2-amino-6-[6-(2-methoxyethoxy)hexanoylamino]hexanoic acid

CAS 1585984-95-7

  • Molecular FormulaC15H30N2O5
  • Average mass318.409 Da

BMN-165

Palynziq

pegvaliase

pegvaliase-pqpz

L-Lysine, N6-[6-(2-methoxyethoxy)-1-oxohexyl]-

N6-[6-(2-Methoxyethoxy)hexanoyl]-L-lysine 

AUSTRALIA APPROVAL 2021Australian Flag Animated Gifs

PALYNZIQorphan drug

Evaluation commenced: 30 Sep 2020

Registration decision: 6 Jul 2021

Date registered: 14 Jul 2021

Approval time: 166 (175 working days)

pegvaliase

BioMarin Pharmaceutical Australia Pty Ltd

PALYNZIQ (solution for injection, pre-filled syringe) is indicated for the treatment of patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control despite prior management with available treatment options.

Pegvaliase, sold under the brand name Palynziq, is a medication for the treatment of the genetic disease phenylketonuria.[2][3] Chemically, it is a pegylated derivative of the enzyme phenylalanine ammonia-lyase that metabolizes phenylalanine to reduce its blood levels.[4]

It was approved by the Food and Drug Administration for use in the United States in 2018.[2] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[5]

Pegvaliase is a recombinant phenylalanine ammonia lyase (PAL) enzyme derived from Anabaena variabilis that converts phenylalanine to ammonia and trans-cinnamic acid. Both the U.S. Food and Drug Administration and European Medicines Agency approved pegvaliase-pqpz in May 2018 for the treatment of adult patients with phenylketonuria (PKU). Phenylketonuria is a rare autosomal recessive disorder that is characterized by deficiency of the enzyme phenylalanine hydroxylase (PAH) and affects about 1 in 10,000 to 15,000 people in the United States. PAH deficiency and inability to break down an amino acid phenylalanine (Phe) leads to elevated blood phenylalanine concentrations and accumulation of neurotoxic Phe in the brain, causing chronic intellectual, neurodevelopmental and psychiatric disabilities if untreated. Individuals with PKU also need to be under a strictly restricted diet as Phe is present in foods and products with high-intensity sweeteners. The primary goal of lifelong treatment of PKU, as recommended by the American College of Medical Genetics and Genomics (ACMG) guidelines, is to maintain blood Phe concentration in the range of 120 µmol/L to 3690 µmol/L. Pegvaliase-pqpz, or PEGylated pegvaliase, is used as a novel enzyme substitution therapy and is marketed as Palynziq for subcutanoues injection. It is advantageous over currently available management therapies for PKU, such as [DB00360], that are ineffective to many patients due to long-term adherence issues or inadequate Phe-lowering effects. The presence of a PEG moiety in pegvaliase-pqpz allows a reduced immune response and improved pharmacodynamic stability.

References

  1. Jump up to:a b “Palynziq”Therapeutic Goods Administration (TGA). 23 July 2021. Retrieved 5 September 2021.
  2. Jump up to:a b “FDA approves a new treatment for PKU, a rare and serious genetic disease” (Press release). Food and Drug Administration. May 24, 2018.
  3. ^ Mahan KC, Gandhi MA, Anand S (April 2019). “Pegvaliase: a novel treatment option for adults with phenylketonuria”. Current Medical Research and Opinion35 (4): 647–651. doi:10.1080/03007995.2018.1528215PMID 30247930.
  4. ^ “Palynziq”. BioMarin Pharmaceutica.
  5. ^ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.

External links

Clinical data
Pronunciationpeg val’ i ase
Trade namesPalynziq
Other namesPegvaliase-pqpz; PEG-PAL; RAvPAL-PEG
AHFS/Drugs.comMonograph
MedlinePlusa618057
License dataUS DailyMedPegvaliase
Pregnancy
category
AU: D[1]
Routes of
administration
Subcutaneous
ATC codeA16AB19 (WHO)
Legal status
Legal statusAU: S4 (Prescription only) [1]US: ℞-onlyEU: Rx-only
Identifiers
showIUPAC name
CAS Number1585984-95-7
PubChem CID86278362
DrugBankDB12839
ChemSpider58172730
UNIIN6UAH27EUV
KEGGD11077
Chemical and physical data
FormulaC15H30N2O5
Molar mass318.414 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////pegvaliase, PALYNZIQ, AUSTRALIA 2021, APPROVALS 2021, BioMarin, BMN 165, Palynziq, pegvaliase, pegvaliase-pqpz

COCCOCCCCCC(=O)NCCCCC(C(=O)O)N

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Saquinavir


Saquinavir structure.svg
Saquinavir
Saquinavir.png

Saquinavir,

Ro 31 8959, Ro 31-8959, RO 31-8959/000, Ro 318959, RO-31-8959/000, Sch 52852, SCH-52852

(2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-decahydroisoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-[(quinolin-2-yl)formamido]butanediamide

(2S)-N-[(2S,3R)-4-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1-phenylbutan-2-yl]-2-(quinoline-2-carbonylamino)butanediamide

(-)-cis-N-tert-butyldecahydro-2-{(2R,3S)-2-hydroxy-4-phenyl-3-{[N-(2-quinolylcarbonyl)-L-asparaginyl]amino}butyl}-(3S,4aS,8aS)-isoquinoline-3 carboxamide monomethanesulfonate

Product Ingredients

INGREDIENTUNIICASINCHI KEY
Saquinavir mesylateUHB9Z3841A149845-06-7IRHXGOXEBNJUSN-YOXDLBRISA-N

CAS Registry Number: 127779-20-8 
CAS Name: (2S)-N1[(1S,2R)-3-[(3S,4aS,8aS)-3-[[(1,1-Dimethylethyl)amino]carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]butanediamide 
Additional Names: (S)-N-[(aS)-a-[(1R)-2-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro-2(1H)-isoquinolyl]-1-hydroxyethyl]phenethyl]-2-quinaldamido succinamide; N-tert-butyldecahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl](4aS,8aS)-isoquinoline-3(S)-carboxamide 
Manufacturers’ Codes: Ro-31-8959Molecular Formula: C38H50N6O5Molecular Weight: 670.84Percent Composition: C 68.04%, H 7.51%, N 12.53%, O 11.92% 
Literature References: Selective HIV protease inhibitor.Prepn: J. A. Martin, S. Redshaw, EP432695eidem,US5196438 (1991, 1993 both to Hoffmann-LaRoche); K. E. B. Parkes et al.,J. Org. Chem.59, 3656 (1994).In vitro HIV proteinase inhibition: N. A. Roberts et al.,Science248, 358 (1990). Antiviral properties: J. C. Craig et al.,Antiviral Res.16, 295 (1991); S. Galpin et al.,Antiviral Chem. Chemother.5, 43-45 (1994).Clinical evaluation of tolerability and activity: V. S. Kitchen et al.,Lancet345, 952 (1995). Review of pharmacology and clinical experience: S. Kravcik, Expert Opin. Pharmacother.2 303-315 (2001). 
Properties: White crystalline solid. [a]D20 -55.9° (c = 0.5 in methanol). Soly (21°): 0.22 g/100 ml water.Optical Rotation: [a]D20 -55.9° (c = 0.5 in methanol) 
Derivative Type: Methanesulfonate saltCAS Registry Number: 149845-06-7Additional Names: Saquinavir mesylateManufacturers’ Codes: Ro-31-8959/003Trademarks: Fortovase (Roche); Invirase (Roche)Molecular Formula: C38H50N6O5.CH3SO3HMolecular Weight: 766.95Percent Composition: C 61.08%, H 7.10%, N 10.96%, O 16.69%, S 4.18% 
Therap-Cat: Antiviral.Keywords: Antiviral; Peptidomimetics; HIV Protease Inhibitor.

Saquinavir mesylate was first approved by the U.S. Food and Drug Administration (FDA) on Dec 6, 1995, then approved by European Medicine Agency (EMA) on Oct 4, 1996, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Sep 5, 1997. It was developed by Roche, then marketed as Invirase® by Roche in the US and EU and by Chugai in JP.

Saquinavir mesylate is an inhibitor of HIV-1 protease. It is a peptide-like substrate analogue that binds to the protease active site and inhibits the activity of HIV-1 protease that required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in HIV-1 particles. It is indicated for the treatment of HIV-1 infection in combination with ritonavir and other antiretroviral agents in adults (over the age of 16 years).

Invirase® is available as capsule for oral use, containing 200 mg of free Saquinavir. The recommended dose is 1000 mg twice daily in combination with ritonavir 100 mg twice daily for adults.

Human medicines European public assessment report (EPAR): Invirase, saquinavir, HIV Infections, 03/10/1996, 47, Authorised (updated)

EU 08/09/2021

Invirase is an antiviral medicine used to treat adults infected with the human immunodeficiency virus type 1 (HIV 1), a virus that causes acquired immune deficiency syndrome (AIDS). Invirase should only be used in combination with ritonavir (another antiviral medicine) and other antiviral medicines.

Invirase contains the active substance saquinavir.

Product details
NameInvirase
Agency product numberEMEA/H/C/000113
Active substancesaquinavir
International non-proprietary name (INN) or common namesaquinavir
Therapeutic area (MeSH)HIV Infections
Anatomical therapeutic chemical (ATC) codeJ05AE01
Publication details
Marketing-authorisation holderRoche Registration GmbH
Date of issue of marketing authorisation valid throughout the European Union03/10/1996

Invirase can only be obtained with a prescription and treatment should be started by a doctor who has experience in the treatment of HIV infection.

Invirase is available as capsules (200 mg) and tablets (500 mg). For patients already taking HIV medicines, the recommended dose of Invirase is 1,000 mg with 100 mg ritonavir twice daily. For patients who are not taking HIV medicines, Invirase is started at 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment, given in combination with other HIV medicines. After 7 days, the recommended dose of Invirase is 1,000 mg twice daily with ritonavir 100 mg twice daily in combination with other HIV medicines.

For more information about using Invirase, see the package leaflet or contact a doctor or pharmacist.

The active substance in Invirase, saquinavir, is a ‘protease inhibitor’. It blocks protease, an enzyme involved in the reproduction of HIV. When the enzyme is blocked, the virus does not reproduce normally, slowing down the spread of infection. Ritonavir is another protease inhibitor that is used as a ‘booster’. It slows the breakdown of saquinavir, increasing the levels of saquinavir in the blood. This allows effective treatment while avoiding a higher dose of saquinavir. Invirase, taken in combination with other HIV medicines, reduces the viral load (the amount of HIV in the blood) and keeps it at a low level. Invirase does not cure HIV infection or AIDS, but it may hold off the damage to the immune system and the development of infections and diseases associated with AIDS.

Invirase received a marketing authorisation valid throughout the EU on 4 October 1996.

Drug Name:Saquinavir MesylateResearch Code:Ro-31-8959; Sch-52852Trade Name:Invirase®MOA:HIV-1 protease inhibitorIndication:HIV infectionStatus:ApprovedCompany:Roche (Originator) , ChugaiSales:ATC Code:J05AE01

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2004-12-17New dosage formInviraseHIV infectionTabletEq. 500 mg SaquinavirRochePriority
1995-12-06First approvalInviraseHIV infectionCapsuleEq. 200 mg SaquinavirRochePriority

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Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
1996-10-04First approvalInviraseHIV infectionCapsule200 mgRoche 
1996-10-04First approvalInviraseHIV infectionTablet, Film coated500 mgRoche 

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Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2006-09-01New dosage formInviraseHIV infectionTablet500 mgChugai 
1997-09-05First approvalInviraseHIV infectionCapsule200 mgChugai 

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Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2014-03-13Marketing approval因服雷/InviraseHIV infectionTabletEq. 500 mg SaquinavirRoche 
2009-07-01Marketing approval因服雷/InviraseHIV infectionCapsuleEq. 200 mg SaquinavirRoche

Route 1

Reference:1. US5196438A.Route 2

Reference:1. J. Org. Chem199459, 3656-3664.Route 3

Reference:1. WO2006134612A1.

SYN

English: DOI: 10.1021/jo00393a034

DOI: 10.1021/jo00092a026

DOI: 10.1016/S0040-4039(00)77633-7

File:Saquinavir synthesis.png

SYN

In the following, a possible route for the synthesis of Saquinavir is presented. Since Diazomethane is used, the synthesis is not suitable for a scaled up process. Roche has solved this problem with another reaction mechanism. The mechanism for laboratories starts with a ring opening substitution of an epoxid derivative of Phenylalanine with decaisohydroquinoline in dry iso-propanol with nitrogen atmosphere. The intermediate is purified by flash chromatography. In the second step of synthesis, the protection group is removed with gaseous hydrogen and a carbon/palladium catalyst. Furthermore, the new product reacts with N-Benzyloxycarbonyl-Lasparagine(Cbz AsnOH) in the solvents Cbz Asparagine L(Cbz Asn L) and 1- Hydroxybenzotriazolehydrat(HBOT). Afterwards, the protecting group of the former Asparagine is removed with another mixture of gaseous hydrogen and carbon/palladium catalyst. The final intermediate gets stirred in the last step of synthesis together with the solvents Tetrahydrofuran, HBOT and DCC. The mechanism formulated in detail can be found in the Appendix (VIII).7

Kevin E. B. Parkes; David J. Bushnell; et al. Studies toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959. J. Org. Chem. 1994, 59, 3656–3664.

str1

SYN

he synthesis of Ro-31-8959/003 (X) was carried out as follows: Condensation of L-phenylalanine (I) with formaldehyde in concentrated hydrochloric acid gave the tetrahydroisoquinoline (II), which was hydrogenated in 90% acetic acid over rhodium on carbon to yield the decahydroisoquinoline (III) as a mixture of diastereoisomers. Treatment of (III) with benzyl chloroformate in aqueous sodium hydroxide solution gave a mixture of N-protected amino acids which was separated by fractional crystallization of the cyclohexylamine salts to give the (S,S,S)-isomer. Reaction with dicyclohexylcarbodiimide and N-hydroxysuccinimide in dimethoxyethane, followed by treatment of the activated ester with tert-butylamine in dichloromethane and subsequent hydrogenolysis of the benzyloxycarbonyl protecting group gave the decahydroisoquinoline (IV). In the other branch of the synthesis L-phenylalanine was treated with benzyl chloroformate in aqueous sodium hydroxide solution to give the N-protected amino acid. This was converted to the corresponding mixed anhydride with isobutyl chloroformate and N-ethylmorpholine in tetrahydrofuran and immediately reacted with diazomethane in diethyl ether to give the diazomethyl ketone (V). Treatment of (V) with ethereal hydrogen chloride gave the chloromethyl ketone (VI), which on reduction with sodium borohydride in aqueous tetrahydrofuran gave a mixture of diastereoisomeric chlorohydrins. Solvent extraction with boiling n-hexane followed by recrystallization of the less soluble isomer from isopropanol gave pure chlorohydrin (VII), which on treatment with ethanolic potassium hydroxide gave the epoxide (VIII). Condensation of (VIII) with (IV) in ethanol gave the hydroxyethylamine (IX). Hydrogenolysis of (IX) was followed by condensation with N-benzyloxycarbonyl-L-asparagine in tetrahydrofuran in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Hydrogenolysis in ethanol over palladium on charcoal, followed by condensation with quinoline-2-carboxylic acid in tetrahydrofuran in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, gave the free base, Ro-31-8959/000. Treatment with methanesulfonic acid in aqueous ethanol then afforded the mesylate salt (X), Ro-31-8959/003.

SYN

J Org Chem 1994,59(13),3656

Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.

SYN

2) The condensation of N-phthaloyl-L-phenylalaninyl chloride (XVIII) with 1,1,2-tris(trimethylsilyloxy)ethylene (TMS) (XIX) at 90-100 C followed by acidic hydrolysis with HCl gives the acid (XX), which, without isolation, is decarboxylated, yielding 1-hydroxy-3(S)-phthalimido-4-phenyl-2-butanone (XXI). Sequential protection of the OH- group with dihydropyran, reduction of the CO group with NaBH4, mesylation of the resulting OH group with methanesulfonyl chloride and deprotection of the primary OH group gives 2(R)-(methanesulfonyloxy)-4-phenyl-3(S)-phthalimido-1-butanol (XXII). The epoxidation of (XXII) with potassium tert-butoxide yields the epoxide (XXIII), which is condensed with the decahydroisoquinoline (XI) as before, affording the protected condensation product (XXIV). The elimination of the phthalimido group of (XXIV) with methylamine and HCl gives the amino derivative (XIII), already obtained in scheme 16810301a.

SYN

3) The condensation of N-(tert-butoxycarbonyl)-L-phenylalaninal (XXV) with 2-(trimethylsilyl)thiazole (XXVI) by means of tetrabutylammonium fluoride gives the thiazole derivative (XXVII), which is cleaved by reaction with methyl iodide (formation of the thiazolium derivative) and treated with NaBH4 and HgCl2 to afford the protected 3(S)-amino-2(S)-hydroxy-4-phenylbutanal (XXVIII). Finally, this compound is reductocondensed with isoquinoline (XI) by means of sodium cyanoborohydride to yield the protected condensation product (XII), already obtained in scheme 16810301a.

SYN

4) The selective esterification of 3(S)-azido-4-phenylbutane-1,2(S)-diol (XXIX) with 2,4,6-triiosopropylbenzenesulfonyl chloride (XXX) gives the sulfonate ester (XXXI), which by treatment with KOH is converted to the azido epoxide (XXXII). The condensation of (XXXII) with decahydroisoquinoline (XI) affords the azido condensation product (XXXIII), which is finally hydrogenated with H2 over Pd/C to the amino condensation product (XIII), already obtained in scheme 16810301a. 5) The reaction of (XXIX) with SOCl2 and RuCl3 gives the dioxathiole dioxide (XXXIV), which is condensed with decahydroisoquinoline (XI) to afford the azido condensation product (XXXIII), already obtained.

SYN

The intermediate (3R,4S)-4-[N-(tert-butoxycarbonyl)-N-methylamino]-5-phenyl-3-(tert-butyldimethylsilyloxy)pentanoic acid (VII) has been obtained as follows: The condensation of N-(tert-butoxycarbonyl)-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) by means of CDI gives the beta-ketoester (III), which is reduced with NaBH4 to yield (3R,4S)-4-(tert-butoxycarbonylamino)-3-hydroxy-5-phenylpentanoic acid ethyl ester (IV). The protection of the OH group of (IV) with Tbdms-Cl and imidazole in DMF affords the silylated ester (V), which is hydrolyzed with NaOH to provide the corresponding carboxylic acid (VI). Finally, this compound is N-methylated by means of Me-I and NaH in THF to obtain the target intermediate (VII).

SYN

J Label Compd Radiopharm 1998,41(12),1103

[14C]-Saquinavir: The cyclization of [ring-14C]-aniline (I) with crotonic aldehyde (II) by means of HCl and acetic anhydride gives labeled 2-methylquinoline (III), which is brominated with Br2 in acetic acid yielding the tribromo derivative (IV). The hydrolysis of (IV) with hot sulfuric acid afforded labeled quinoline-2-carboxylic acid (V), which is finally condensed with Ro-32-0445 (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC) in THF.

SYN

Pentadeuterated saquinavir: The nitration of hexadeuterobenzene (VII) with HNO3/H2SO4 gives pentadeuteronitrobenzene (VIII), which is hydrogenated with deuterium/Pt in D1-methanol yielding heptadeuteroaniline (IX). The cyclization of (IX) with crotonic aldehyde (II) by means of DCI/D2O and acetic anhydride as before affords hexadeuterated quinoline (X), which is brominated with Br2 as before giving the tribromo derivative (XI). The hydrolysis of (XI) with sulfuric acid as before yields the acid (XII), which is finally condensed with Ro-32-0445 (VI) as before.

SYN

Tetradeuterated saquinavir: The cyclization of heptadeuteroaniline (IX) with crotonic aldehyde (II) by means of HCl and acetic anhydride as before gives the tetradeuteroquinoline (XIII), which is brominated as described yielding the tribromo derivative (XIV). The hydrolysis of (XIV) with sulfuric acid affords tetradeuterated acid (XV), which is finally condensed with Ro-32-0445 (VI) as indicated.

SYN

Tritiated saquinavir: The cyclization of 4-bromoaniline (XVI) with crotonic aldehyde (II) by means of ZnCl2/HCl gives 6-bromo-4-methylquinoline (XVII), which is brominated as before giving tetrabromo derivative (XVIII). The hydrolysis of (XVIII) with sulfuric cid affords 6-bromoquinoline-2-carboxylic acid (XIX), which is condensed with Ro-32-0445 (VI) by means of HOBT and DCC as indicated giving the bromo derivative of saquinavir (XX). Finally, this compound is tritiated with T2 over Pd/C in ethanol.

SYN

5)[15N,13C,2H]-Saquinavir: The nitration of [13C6]-benzene (XXI) with [15N]-nitric acid gives the corresponding nitrobenzene (XXII), which is reduced with Sn/HCl to the aniline (XXIII). The cyclization of (XXIII) with crotonic aldehyde (II) by means of ClD/D2O and acetic ahydride yields the tetradeuterated quinoline (XXIV), which is brominated as before givig the tribromo derivative (XXV). The hydrolysis of (XXV) with sulfuric acid as usual affords the [15N,13C6,2H3]-labeled quinoline-2-carboxylic acid (XXVI), which is finally condensed with Ro-32-0445 (VI) by means of HOBT and CDI as indicated.

Saquinavir (SQV), sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS.[3] Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect.[3] It is taken by mouth.[3]

Common side effects include nausea, vomiting, diarrhea, and feeling tired.[3] More serious side effects include problems with QT prolongationheart blockhigh blood lipids, and liver problems.[3] It appears to be safe in pregnancy.[3] It is in the protease inhibitor class and works by blocking the HIV protease.[3]

Saquinavir was patented in 1988 and first sold in 1995.[4][5]

Medical uses

Saquinavir is used together with other medications to treat or prevent HIV/AIDS.[3] Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect.[3]

Side effects

The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including diarrhoeanausea, loose stools and abdominal discomfort. Invirase is better tolerated than Fortovase.[medical citation needed]

Bioavailability and drug interactions

Saquinavir, in the Invirase formulation, has a low and variable oral bioavailability, when given alone. The Fortovase formulation at the standard dosage delivers approximately eightfold more active drug than Invirase, also at the standard dosage.[6]

In the clinic, it was found that the oral bioavailability of saquinavir in both formulations significantly increases when patients also receive the PI ritonavir. For patients, this has the major benefit that they can take less saquinavir, while maintaining sufficient saquinavir blood plasma levels to efficiently suppress the replication of HIV.[medical citation needed]

The mechanism behind this welcome observation was not directly known, but later it was determined that ritonavir inhibits the cytochrome P450 3A4 isozyme. Normally, this enzyme metabolizes saquinavir to an inactive form, but with the ritonavir inhibiting this enzyme, the saquinavir blood plasma levels increased considerably. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.[medical citation needed]

Unlike other protease inhibitors, the absorption of saquinavir seems to be improved by omeprazole.[7]

Mechanism of action

Saquinavir is a protease inhibitorProteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases.[8]

History

New HIV infections and deaths, before and after the FDA approval of “highly active antiretroviral therapy”,[9] of which saquinavir, ritonavir and indinavir were key as the first three protease inhibitors.Cully, Megan (28 November 2018). “Protease inhibitors give wings to combination therapy”nature. Open Publishing. Retrieved 28 October 2020. As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.}}[9]

Saquinavir was developed by the pharmaceutical company Roche.[10] Saquinavir was the sixth antiretroviral and the first protease inhibitor approved by the US Food and Drug Administration (FDA), leading ritonavir and indinavir by a few months.[11] This new class of antiretrovirals played a critical role in the development of highly active antiretroviral therapy (HAART), which helped significantly lower the risk of death from AIDS-related causes, as seen by a reduction of the annual U.S. HIV-associated death rate, from over 50,000 to about 18,000 over a period of two years.[9][12]

Roche requested and received approval of Invirase via the FDA’s “Accelerated Approval” program—a process designed to speed drugs to market for the treatment of serious diseases—a decision that was controversial, as AIDS activists disagreed over the benefits of thorough testing versus early access to new drugs.[13][better source needed] It was approved again on November 7, 1997, as Fortovase,[14] a soft gel capsule reformulated for improved bioavailability. Roche announced in May 2005 that, given reduced demand, Fortovase would cease being marketed early in 2006, in favor of Invirase boosted with ritonavir,[15] owing to the ability of the latter co-formulated drug to inhibit the enzyme that metabolizes the AIDS drugs.[citation needed]

Society and culture

Economics

As of 2015, it is not available as a generic medication.[16]

Formulations

Two formulations have been marketed:

  • a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;
  • a soft-gel capsule formulation of saquinavir (microemulsion,[17] orally-administered formulation), with trade name Fortovase, which was discontinued worldwide in 2006.[18]

References

  1. ^ “Saquinavir Use During Pregnancy”Drugs.com. 20 March 2018. Retrieved 28 January 2020.
  2. ^ “Invirase- saquinavir mesylate capsule INVIRASE- saquinavir mesylate tablet, film coated”DailyMed. 26 December 2019. Retrieved 28 January 2020.
  3. Jump up to:a b c d e f g h i “Saquinavir”. The American Society of Health-System Pharmacists. Archived from the original on 8 September 2015. Retrieved 5 September 2015.
  4. ^ Minor, Lisa K. (2006). Handbook of Assay Development in Drug Discovery. Hoboken: CRC Press. p. 117. ISBN 9781420015706Archived from the original on 31 March 2016.
  5. ^ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 509. ISBN 9783527607495.
  6. ^ “Fortovase”Drugs.com. 22 March 2019. Retrieved 28 January2020.
  7. ^ Winston A, Back D, Fletcher C, et al. (2006). “Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation with ritonavir in healthy male and female volunteers”. AIDS20 (10): 1401–6. doi:10.1097/01.aids.0000233573.41597.8aPMID 16791014S2CID 44506039.
  8. ^ Raphael Dolin, Henry Masur, Michael S. Saag. “AIDS Therapy“, Churchill Livingstone, (1999), p. 129.
  9. Jump up to:a b c “HIV Surveillance—United States, 1981-2008”Archivedfrom the original on 9 November 2013. Retrieved 8 November 2013.
  10. ^ J. Hilts, Philip (8 December 1995). “MF.D.A. Backs A New Drug To Fight AIDS”New York Times. Retrieved 28 October 2020.
  11. ^ “Antiretroviral Drug Discovery and Development”NIH. 26 November 2018. Retrieved 29 October 2020.
  12. ^ The CDC, in its Morbidity and Mortality Weekly Report, ascribes this to “highly active antiretroviral therapy”, without mention of either of these drugs, see the preceding citation. A further citation is needed to make this accurate connection between this drop and the introduction of the protease inhibitors.
  13. ^ “Drugs! Drugs! Drugs! An Overview of the Approved Anti-HIV Medications”. The Body. Archived from the original on 9 November 2013. Retrieved 20 February 2013.
  14. ^ “Drug Approval Package: Fortovase/Saquinavir NDA 20828”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 28 January 2020.
  15. ^ Withdrawal of Fortovase (PDF) Archived 2006-05-14 at the Wayback Machine
  16. ^ “Generic Invirase Availability”Drugs.com. Retrieved 9 July2020.
  17. ^ Gibaud S, Attivi D (August 2012). “Microemulsions for oral administration and their therapeutic applications” (PDF). Expert Opinion on Drug Delivery9 (8): 937–51. doi:10.1517/17425247.2012.694865PMID 22663249S2CID 28468973.
  18. ^ News-Medical.Net. May 18, 2005 Roche to discontinue the sale and distribution of Fortovase (saquinavir) Archived 2015-02-22 at the Wayback Machine

External links

links

Clinical data
Trade namesInvirase, Fortovase
AHFS/Drugs.comMonograph
MedlinePlusa696001
License dataEU EMAby INNUS DailyMedSaquinavir
Pregnancy
category
AU: B1[1]
ATC codeJ05AE01 (WHO)
Legal status
Legal statusUS: ℞-only
Pharmacokinetic data
Bioavailability~4% (without ritonavir boosting)[2]
Protein binding98%
MetabolismLiver, mainly by CYP3A4
Elimination half-life9–15 hours
Excretionfeces (81%) and urine (3%)
Identifiers
showIUPAC name
CAS Number127779-20-8 
PubChem CID441243
IUPHAR/BPS4813
DrugBankDB01232 
ChemSpider390016 
UNIIL3JE09KZ2F
KEGGD00429 
ChEMBLChEMBL114 
NIAID ChemDB000640
PDB ligandROC (PDBeRCSB PDB)
CompTox Dashboard (EPA)DTXSID6044012 
Chemical and physical data
FormulaC38H50N6O5
Molar mass670.855 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

///////////////saquinavir, Antiviral, Peptidomimetics, HIV Protease Inhibitor,  Ro-31-8959, EU 2021, APPROVALS 2021, Invirase, Ro 31 8959, Ro 31-8959, RO 31-8959/000, Ro 318959, RO-31-8959/000, Sch 52852, SCH-52852

[H][C@@]12CCCC[C@]1([H])CN(C[C@@H](O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC(N)=O)NC(=O)C1=NC3=C(C=CC=C3)C=C1)[C@@H](C2)C(=O)NC(C)(C)C

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Benzonatate


Benzonatate.svg
ChemSpider 2D Image | Benzonatate | C30H53NO11
Thumb
Benzonatate.png
Chemical structure of benzonatate. | Download Scientific Diagram
Structure forluma for Benzonatate

Benzonatate

  • Molecular FormulaC30H53NO11
  • Average mass603.742 Da

104-31-4[RN]2,5,8,11,14,17,20,23,26-Nonaoxaoctacosan-28-yl 4-(butylamino)benzoateбензонататبنزوناتات苯佐那酯ベンゾナテート;KM 652,5,8,11,14,17,20,23,26-nonaoxaoctacosan-28-yl 4-(butylamino)benzoate2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-(butylamino)benzoate

Benzonatate bulk and Benzonatate capsules 100mg, cdsco india 2021, 15.07.2021

For the treatment of refractory coughCAS Registry Number: 104-31-4CAS Name: 4-(Butylamino)benzoic acid 3,6,9,12,15,18,21,24,27-nonaoxaoctacos-1-yl esterAdditional Names: nonaethyleneglycol monomethyl ether p-n-butylaminobenzoate; p-butylaminobenzoic acid w-O-methylnonaethyleneglycol ester; benzononatineTrademarks: Exangit; Tessalon (Forest)Molecular Formula: C30H53NO11Molecular Weight: 603.74Percent Composition: C 59.68%, H 8.85%, N 2.32%, O 29.15%Literature References: Prepn: Matter, US2714608 (1955 to Ciba).Properties: Colorless to faintly yellow oil. Soluble in most organic solvents except aliphatic hydrocarbons.Therap-Cat: Antitussive.Keywords: Antitussive.

Synthesis Reference

Matter, M.; U.S. Patent 2,714,608; August 2, 1955; assigned to Ciba Pharmaceutical Products, Inc.

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RNFormulaChemical NameCAS Index Name
94-32-6C13H19NO2ethyl 4-butylaminobenzoateBenzoic acid, 4-(butylamino)-, ethyl ester
6048-68-6C19H40O10nonaethylene glycol monomethyl ether2,5,8,11,14,17,20,23,26-Nonaoxaoctacosan-28-ol

Benzonatate, sold under the brand name Tessalon among others, is a medication used to try to help with the symptoms of cough and hiccups.[1][2] It is taken by mouth.[1] Use is not recommended in those under the age of ten.[3] Effects generally begin within 20 minutes and last up to eight hours.[1][4]

Side effects include sleepiness, dizziness, headache, upset stomach, skin rash, hallucinations, and allergic reactions.[1] Excessive doses may cause seizuresirregular heartbeat, and death.[3] Chewing or sucking on the capsule can lead to laryngospasmbronchospasm, and circulatory collapse.[1] It is unclear if use in pregnancy or breastfeeding is safe.[5] It works by numbing stretch receptors in the lungs and suppressing the cough reflex in the brain.[1]

Benzonatate was approved for medical use in the United States in 1958.[1] It is available as a generic medication.[3] It is not available in many countries.[6] In 2018, it was the 113th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[7][8]

Medical uses

100mg generic Benzonatate capsules

100mg generic benzonatate capsules

Cough

Benzonatate is a prescription non-opioid alternative for the symptomatic relief of cough.[1][3] It has been shown to improve cough associated with a variety of respiratory conditions including asthmabronchitispneumoniatuberculosispneumothorax, opiate-resistant cough in lung cancer, and emphysema.[1][9][10]

Benzonatate also reduces the consistency and volume of sputum production associated with cough in those with chronic obstructive pulmonary disorder (COPD).[9]

Compared to codeine, benzonatate has been shown to be more effective in reducing the frequency of induced cough in experiments.[1]

Benzonatate does not treat the underlying cause of the cough.[11]

Hiccups

Benzonatate has been shown to have use in the suppression of hiccups.[2]

Intubation

Benzonatate acts as a local anesthetic and the liquid inside the capsule can be applied in the mouth to numb the oropharynx for awake intubation.[1] However, there can be life-threatening adverse effects when the medication is absorbed by the oral mucosa, including choking, hypersensitivity reactions, and circulatory collapse.[1]

Contraindications

Hypersensitivity to benzonatate or any related compounds is a contraindication to its administration.[4]

Side effects

Benzonatate is generally well-tolerated[vague][specify] if the liquid-capsule is swallowed intact.[1] Potential adverse effects to benzonatate include:

  • Constipation, dizziness, fatigue, stuffy nose, nausea, headache are frequently reported.[12]
  • Sedation, a feeling of numbness in the chest, sensation of burning in the eyes, a vague “chilly” sensation, itchiness, and rashes are also possible.[1][4]
  • Ingestion of a small handful of capsules has caused seizures, cardiac arrhythmia, and death in adults.[13]

Hypersensitivity reactions

Benzonatate is structurally related to anesthetic medications of the para-aminobenzoic acid (PABA) class which includes procaine and tetracaine.[4][13] Procaine and tetracaine, previously used heavily in the fields of dentistry and anesthesiology, have fallen out of favor due to allergies associated with their metabolites.[13] Similarly, severe hypersensitivity reactions to benzonatate have been reported and include symptoms of laryngospasmbronchospasm, and cardiovascular collapse.[4][14] These reactions are possibly associated with chewing, sucking, or crushing the capsule in the mouth.[4][13]

Improper use

Benzonatate should be swallowed whole.[4] Crushing or sucking on the liquid-filled capsule, or “softgel,” will cause release of benzonatate from the capsule and can produce a temporary local anesthesia of the oral mucosa.[4] Rapid development of numbness of the tongue and choking can occur.[4][13] In severe cases, excessive absorption can lead to laryngospasmbronchospasmseizures, and circulatory collapse.[4][13] This may be due to a hypersensitivity reaction to benzonatate or a systemic local anesthetic toxicity, both of which have similar symptoms.[13] There is a potential for these adverse effects to occur at a therapeutic dose, that is, a single capsule, if chewed or sucked on in the mouth.[13]

Psychiatric effects

Isolated cases of bizarre behavior, mental confusion, and visual hallucinations have been reported during concurrent use with other prescribed medications.[4] Central nervous system effects associated with other para-aminobenozic acid (PABA) derivative local anesthetics, for example procaine or tetracaine, could occur with benzonatate and should be considered.[1]

Children

Safety and efficacy in children below the age of 10 have not been established.[4] Accidental ingestion resulting in death has been reported in children below the age of 10.[4] Benzonatate may be attractive to children due to its appearance, a round-shaped liquid-filled gelatin capsule, which looks like candy.[14][15] Chewing or sucking of a single capsule can cause death of a small child.[4][15] Signs and symptoms can occur rapidly after ingestion (within 15–20 minutes) and include restlessness, tremors, convulsionscoma, and cardiac arrest.[15] Death has been reported within one hour of ingestion.[12][15]

Pregnancy and breast feeding

In the U.S., benzonatate is classified by the U.S. Food and Drug Administration (FDA) as pregnancy category C.[5] It is not known if benzonatate can cause fetal harm to a pregnant woman or if it can affect reproduction capacity.[4][5] Animal reproductive studies have not yet been conducted with benzonatate to evaluate its teratogenicity.[4] Benzonatate should only be given to a pregnant woman if it is clearly needed.[4][5]

It is not known whether benzonatate is excreted in human milk.[4][5] It is recommended to exercise caution when benzonatate is given to a nursing woman.[4][5]

Overdose

Benzonatate is chemically similar to other local anesthetics such as tetracaine and procaine, and shares their pharmacology and toxicology.[13]

Benzonatate overdose is characterized by symptoms of restlessness, tremors, seizures, abnormal heart rhythms (cardiac arrhythmia), cerebral edema, absent breathing (apnea), fast heart beat (tachycardia), and in severe cases, coma and death.[1][4][16][11] Symptoms develop rapidly, typically within 1 hour of ingestion.[4][11] Treatment focuses on removal of gastric contents and on managing symptoms of sedation, convulsions, apnea, and cardiac arrhythmia.[4]

Despite a long history of safe and appropriate usage, the safety margin of benzonatate is reportedly narrow.[13] Toxicity above the therapeutic dose is relatively low and ingestion of a small handful of pills can cause symptoms of overdose.[13][11] Children are at an increased risk for toxicity, which have occurred with administration of only one or two capsules.[15][16][11]

Due to increasing usage of benzonatate and rapid onset of symptoms, there are accumulating cases of benzonatate overdose deaths, especially in children.[11]

Pharmacology

Benzonatate is chemically similar to other local anesthetics such as tetracaine and procaine, and shares their pharmacology.[13]

Mechanism of action

Similar to other local anesthetics, benzonatate is a potent voltage-gated sodium channel inhibitor.[13] After absorption and circulation to the respiratory tract, benzonatate acts as a local anesthetic, decreasing the sensitivity of vagal afferent fibers and stretch receptors in the bronchialveoli, and pleura in the lower airway and lung.[1][2] This dampens their activity and reduces the cough reflex.[1][4] Benzonatate also has central antitussive activity on the cough center in central nervous system at the level of the medulla.[1][9] However, there is minimal inhibition of the respiratory center at a therapeutic dosage.[4]

Pharmacokinetics

The antitussive effect of benzonatate begins within 15 to 20 minutes after oral administration and typically lasts between 3 and 8 hours.[4][9]

Benzonatate is hydrolyzed by plasma butyrylcholinesterase (BChE) to the metabolite 4-(butylamino)benzoic acid (BABA) as well as polyethylene glycol monomethyl esters.[13] Like many other local anesthetic esters, the hydrolysis of the parent compound is rapid.[13] There are concerns that those with pseudocholinesterase deficiencies may have an increased sensitivity to benzonatate as this hydrolysis is impaired, leading to increased levels of circulating medication.[13]

Chemical structure

Benzonatate is a butylamine, structurally related to other polyglycol ester local anesthetics such as procaine and tetracaine.[13] The molecular weight of benzonatate is 603.7 g/mol.[4] However, the reference standard for benzonatate is a mixture of n-ethoxy compounds, differing in the abundance of 7-9 repeating units, with an average molecular weight of 612.23 g/mol.[13] There is also evidence that the compound is not uniform between manufacturers.[13]

Society and culture

Benzonatate was first made available in the U.S. in 1958 as a prescription medication for the treatment of cough in individuals over the age of 10.[15][16] There are a variety of prescription opioid-based cough relievers, such as hydrocodone and codeine, but have unwanted side effects and potential of abuse and diversion.[13] However, benzonatate is currently the only prescription non-opioid antitussive and its usage has been rapidly increasing.[13][11] The exact reasons of this increase are unclear.[11]

Economics

In the United States between 2004 and 2009, prescriptions increased 50% from 3.1 million to 4.7 million, the market share of benzonatate among antitussives increased from 6.3% to 13%, and the estimated number of children under the age of 10 years receiving benzonatate increased from 10,000 to 19,000.[13][11] Throughout this same period, greater than 90% of prescriptions were given to those 18 or older.[11] The majority of prescriptions were given by general, family, internal, and osteopathic physicians with pediatricians account for about 3% of prescribed benzonatate.[11]

In 2018, it was the 113th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[7][8]

Brand names

Tessalon is a brand name version of benzonatate manufactured by Pfizer, Inc.[13][11] It is available as perles or capsules.[17] Zonatuss was a brand name manufactured by Atley Pharmaceuticals, Inc. and Vertical Pharmaceuticals, Inc.[18][19]

References

  1. Jump up to:a b c d e f g h i j k l m n o p q r s “Benzonatate Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 23 March 2019.
  2. Jump up to:a b c Becker, DE (2010). “Nausea, vomiting, and hiccups: a review of mechanisms and treatment”Anesthesia Progress57 (4): 150–6, quiz 157. doi:10.2344/0003-3006-57.4.150PMC 3006663PMID 21174569.
  3. Jump up to:a b c d “Drugs for cough”. The Medical Letter on Drugs and Therapeutics60 (1562): 206–208. 17 December 2018. PMID 30625123.
  4. Jump up to:a b c d e f g h i j k l m n o p q r s t u v w x y z “Tessalon – benzonatate capsule”DailyMed. 20 November 2019. Retrieved 21 April 2020.
  5. Jump up to:a b c d e f “Benzonatate Use During Pregnancy”Drugs.com. 10 October 2019. Retrieved 20 February 2020.
  6. ^ Walsh, T. Declan; Caraceni, Augusto T.; Fainsinger, Robin; Foley, Kathleen M.; Glare, Paul; Goh, Cynthia; Lloyd-Williams, Mari; Olarte, Juan Nunez; Radbruch, Lukas (2008). Palliative Medicine E-Book. Elsevier Health Sciences. p. 751. ISBN 9781437721942.
  7. Jump up to:a b “The Top 300 of 2021”ClinCalc. Retrieved 18 February2021.
  8. Jump up to:a b “Benzonatate – Drug Usage Statistics”ClinCalc. Retrieved 18 February 2021.
  9. Jump up to:a b c d Homsi, J.; Walsh, D.; Nelson, K. A. (November 2001). “Important drugs for cough in advanced cancer”. Supportive Care in Cancer9 (8): 565–574. doi:10.1007/s005200100252ISSN 0941-4355PMID 11762966S2CID 25881426.
  10. ^ Estfan, Bassam; LeGrand, Susan (November 2004). “Management of cough in advanced cancer”. The Journal of Supportive Oncology2 (6): 523–527. ISSN 1544-6794PMID 16302303.
  11. Jump up to:a b c d e f g h i j k l McLawhorn, Melinda W.; Goulding, Margie R.; Gill, Rajdeep K.; Michele, Theresa M. (January 2013). “Analysis of benzonatate overdoses among adults and children from 1969-2010 by the United States Food and Drug Administration”. Pharmacotherapy33 (1): 38–43. doi:10.1002/phar.1153ISSN 1875-9114PMID 23307543S2CID 35165660.
  12. Jump up to:a b “Benzonatate (Professional Patient Advice)”Drugs.com. 4 March 2020. Retrieved 21 April 2020.
  13. Jump up to:a b c d e f g h i j k l m n o p q r s t u v w Bishop-Freeman SC, Shonsey EM, Friederich LW, Beuhler MC, Winecker RE (June 2017). “Benzonatate Toxicity: Nothing to Cough At”J Anal Toxicol41 (5): 461–463. doi:10.1093/jat/bkx021PMID 28334901.
  14. Jump up to:a b “Drugs for Cough”The Medical Letter on Drugs and Therapeutics60 (1562): 206–208. 17 December 2018. PMID 30625123.
  15. Jump up to:a b c d e f “FDA Drug Safety Communication: Death resulting from overdose after accidental ingestion of Tessalon (benzonatate) by children under 10 years of age”U.S. Food and Drug Administration (FDA). 28 June 2019. Retrieved 22 April 2020.
  16. Jump up to:a b c “In brief: benzonatate warning”. The Medical Letter on Drugs and Therapeutics53 (1357): 9. 7 February 2011. ISSN 1523-2859PMID 21304443.
  17. ^ “Tessalon- benzonatate capsule”DailyMed. 20 November 2019. Retrieved 25 April 2020.
  18. ^ “Zonatuss (Benzonatate Capsules USP, 150 mg)”DailyMed. 2 June 2010. Retrieved 20 August 2020.
  19. ^ “Zonatuss (Benzonatate Capsules USP, 150 mg)”DailyMed. 31 October 2016. Retrieved 20 August 2020.

External links

Clinical data
Trade namesTessalon, Zonatuss, others
AHFS/Drugs.comMonograph
MedlinePlusa682640
License dataUS DailyMedBenzonatate
Routes of
administration
By mouth
ATC codeR05DB01 (WHO)
Legal status
Legal statusUS: ℞-only
Pharmacokinetic data
Elimination half-life3-8 hours
Identifiers
showIUPAC name
CAS Number32760-16-0 
PubChem CID7699
IUPHAR/BPS7611
DrugBankDB00868 
ChemSpider7413 
UNII5P4DHS6ENR
KEGGD00242 
ChEBICHEBI:3032 
ChEMBLChEMBL1374379 
CompTox Dashboard (EPA)DTXSID9022655 
ECHA InfoCard100.002.904 
Chemical and physical data
FormulaC30H53NO11
Molar mass603.750 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
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