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The USFDA has accepted for filing Astellas Pharma’s supplemental new drug application (sNDA) for Tarceva (erlotinib) tablets for a genetically distinct form of advanced lung cancer.
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Erlotinib
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)
quinazolin-4-amine
17 jan 2013
The USFDA has accepted for filing Astellas Pharma’s supplemental new drug application (sNDA) for Tarceva (erlotinib) tablets for a genetically distinct form of advanced lung cancer.
Astellas is seeking approval to use Tarceva as the first-line therapy to treat patients with EGFR activating mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).
The sNDA, which was granted priority review status, included data from EURTAC trial, a randomized, controlled Phase 3 study designed to assess the use of Tarceva compared to platinum-based chemotherapy in NSCLC patients with EGFR activating mutations.
Astellas Pharma Global Development medical oncology head, vice president Stephen Eck said the FDA granted an expedited six-month review of the application.
“We are proud of Tarceva’s already approved indications for the maintenance and relapsed advanced NSCLC settings,” Eck added.
“If approved, people with a genetically distinct form of lung cancer could have a potential new personalized medicine for use as a first-line treatment.”
The cobas EGFR Mutation Test, developed by Roche Molecular Diagnostics, is a companion diagnostic for which a pre-market approval application was also submitted to the regulatory body.
Erlotinib hydrochloride (trade name Tarceva) is a drug used to treat non-small celllung cancer, pancreatic cancer and several other types of cancer. It is a reversibletyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR). It is marketed in the United States by Genentech and OSI Pharmaceuticals and elsewhere by Roche
Erlotinib is an EGFR inhibitor. The drug follows Iressa (gefitinib), which was the first drug of this type. Erlotinib specifically targets the epidermal growth factor receptor (EGFR)tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor.[1] For the signal to be transmitted, two EGFR molecules need to come together to form a homodimer. These then use the molecule of ATP to trans-phosphorylate each other on tyrosine residues, which generates phosphotyrosine residues, recruiting the phosphotyrosine-binding proteins to EGFR to assemble protein complexes that transduce signal cascades to the nucleus or activate other cellular biochemical processes. By inhibiting the ATP, formation of phosphotyrosine residues in EGFR is not possible and the signal cascades are not initiated.
Erlotinib hydrochloride (1), chemically named as N-(3-ethynylphenyl)-6,7-bis-(2-meth- oxyethoxy)-4-qumazolimmine monohydro chloride, is an inhibitor of oncogenic and proto- oncogenic protein tyrosine kinases, e.g. epidermal growth factor receptor (EGFR). Erlotinib is therefore useful in the treatment of proliferative disorders and is currently marketed for the treatment of lung cancer and pancreatic cancer.
(Erlotinib Hydrochloride)
(1)
It has been reported that erlotinib hydrochloride can exist in different polymorphic forms. The manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound which is the active ingredient can exist in more than one polymorphic form. It is essential in pharmaceutical development to ensure that the manufacturing process for the preparation of the active ingredient affords a single polymorph with a consistent level of polymorphic purity. If the manufacturing process produces a product with varying degrees of polymorphic purity and/ or or where the process does not control polymorphic inter-conversion, it could lead to serious problems in dissolution and/ or bioavailability in the finished pharmaceutical composition comprising the active ingredient, Erlotinibhydrochloride is disclosed in patent US 5,747,498 and details of the disclosed method for the preparation of erlotinib hydrochloride are described in Scheme 1.
Scheme 1
4-Chloro-6,7-bis-(2-methoxyed oxy)qiunazoline (2) was reacted with 3-emynylaniline (3) or its hydrochloride salt using various solvents and pyridine as a base to yield erlotinib hydrochloride (1) which was treated widi a biphasic mixture consisting of saturated aqueous NaHC03, chloroform and methanol, to formerlotinib base (4). The base (4) obtained in the organic phase was purified by flash chromatography to afford purified erlotinib base. The purified base was further treated with hydrochloric acid in the presence of diethyl ether and chloroform to yield erlotinib hydrochloride. This isolation of purified erlotinib base required the use of a lengthy workup process including column chromatography and required the chlorinated solvent, chloroform, which is not particularly suitable £01 commercial production of pharmaceuticals. Furthermore, the p irification by column chromatography is neither economical nor feasible at industrial scale. In addition, substantially pure erlotinib could not be obtained. Two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), were characterized by XRPD in patent application, WO 01/34574. Erlotinib hydrochloride can be obtained in form A or in a mixture of polymorph A and B, by refluxing 3-ethynylaniline and 4-chloro-6,7-bis-(2-methoxyemoxy)-qitiiiazoline in a mixture of toluene and acetonitrile. This afforded polymorph A or a mixture of polymorph A and B. It was also disclosed that the formation of polymorph A was favoixred by reducing the amounts of acetonitrile with respect to toluene. Furthermore, erlotinibhydrochloride polymorph A can be converted into polymorph B by refluxing the polymorph A with alcohol/water. Consequently, in the disclosed methods, there was always contamination of form A with form B and vice-versa. In addition, the products of the reaction are not chemically pure and difficult to purify thereafter. Consequently, these methods are not suitable for preparation of commercial quantities of pure polymorph A.
A process for the preparation of erlotinib hydrochloride, polymorph E by condensation reaction of 3-emynylaiiiline and 4-chloro-6,7-bis-(2-memoxyethoxy)quii azoline in ( , , )- trifiuorotoluene and HC1 was disclosed in U.S. Patent application 2004/0162300. Polymorph E was characterized by XRPD, IR and melting point. However, (α,α,α)- trifluorotoluene is a highly flammable and dangerous solvent for the environment and is not suitable for commercial production. A process for the preparation of erlotinib hydrochloride, polymorph A by reaction of erlotinib base widi aqueous or gaseous HC1 was disclosed in US 2009/0131665. In this method, toluene, a mixture of toluene and methanol, TBME, ethyl acetate, 1-butanol or MIBK were used as a solvent. However, when DCM, diethyl ether, isopropyl acetate, was used as a solvent, polymorph B was formed. In practice, it has been found that the disclosed methods are inconsistent and afford polymorphic mixtures. In particular, example 1 of US 2009/131665 was repeated and erlotinib hydrochloride was obtained with only 97% purity. In addition, XRPD analysis showed d at the example afforded form B or mixtures of forms A and B. Furthermore, several crystallizations of erlotinib hydrochloride, obtained from repetition of the example, using various solvents and their combinations would not yield a product pure enough to comply with ICH guidelines.
A process for the preparation of a hydrate of erlotinib hydrochloride comprising crystallization of erlotinib hydrochloride using water as solvent, preferably in the absence of organic solvent was disclosed in US 20080167327. This patent also disclosed the process to prepare hemihydrate polymorph form I as well as form II.
A process for the preparation of erlotinib hydrochloride, polymorph M, N and P by reaction of erlotinib base and aqueous or gaseous HC1 dissolved in organic solvents was disclosed in WO 2008/102369.
A process for the preparation of erlotinib hydrochloride by condensation reaction of 4- chloro~6,7-bis-(2-me oxyemoxy)-quinazoline and 3-ethynylaniline in isopropyl alcohol as a solvent and pyridine as a base was disclosed in Molecules Journal (Vol, 11, 286, 2006) but no details on the polymorph were disclosed.
A method for the preparation of erlotinib hydrochloride polymorph A comprising passing hydrochloride gas onto solid erlotinib base containing residual amounts of isopropanol was disclosed in WO 2010/040212. However, in practice it was found that the process did not afford chemically or polymorphically pure product. Repetition of example 1 (page 8) of WO 2010/040212 to prepare erlotinibhydrochloride, by reaction of erlotinib base and gaseous HQ in IPA as a solvent, afforded a mixture of polymorph A and polymorph B (as checked by XRPD).
A process for the preparation of acid salts of erlotinib by reaction of 4-chloro-6,7-bis-(2- memoxyemoxy)-quinazoline and 3-emynykniline or an acid salt of 3-emynylaniline under acidic conditions to form the corresponding erlotinib salt was disclosed in US 2010/0094004. In order to complete the reaction, several hours (6 hours) of reflux was required and hence it is not a cost effective process. In addition, in practice it was found that the process did not afford chemically or polymorplxLcally pure product. A process £oi the preparation of erlotinib base, polymorph Gl, G2 and G3 was disclosed in WO 2009/002538 and WO 2010/05924.
Scheme 2
A method for the preparation of eiiotinib hydrochloride was disclosed in US 2009/0306377. The method, illustrated in Scheme 2, involves treating 6,7-dimethoxy- 4(3H)-quinazolone (5) with hydrobiOmic acid or pyridine-hydrochloric acid to afford 6,7- dihydroxy-4(3H)-quinazolone (6), which was diacetylated with acetic anhydride to afford diester (7), which was treated with oxalyl chloride/DMF to afford 4-chloro-6,7- ctiacetoxyquinazoline (8). Compound (8) was condensed with 3-e ynylaniline to afford JV- (3-ethynylphenyl)-6,7-dihydfoxy-4-quinazolinamine hydrochloride (9), which was converted into the diol N-(3-emynylphenyl)-6,7-dmyckOxy-4-quinazolinamine (10) by treatment with aqueous ammonia/methanol. The diol (10) was treated with 2-iodo-ethylmethyl ether to yield compound (4) which on treatment with HC1 afforded erlotinib hydrochloride (1). However, this preparation of erlotinib hydrochloride is a long synthetic route and gives low yields and requires very toxic reagents like pyridine, HBi and controlled reagents like acetic anhydride. Hence, it is not suitable for large scale production. Object of the invention
The priot art processes described above for the preparation of erlotinib and its salts have major disadvantages with respect to the formation and removal of process related chemical and polymorphic impurities; poor commercial viability due to die use of hazardous reactants; expensive, time consuming separation methods such as column chromatography and/ or low yields and purity of final and intermediate products.
As the commercial production of erlotinib hydrochloride is of great importance, for the treatment of cancer, and in view of the above disadvantages associated with the prior art there is a real need for alternative and improved processes for the preparation of erlotinib hydrochloride which do not involve multiple steps and further eliminates the need for cumbersome purification techniques, particularly for the removal of the chemical and polymorphic impurities. The alternative processes must be economical and high yielding and provide erlotinib and its salts with a high degree of chemical and polymorphic purity.
U.S. Patent No. 5,747,498 disclosed 4-(substituted phenylamino) quinazoline derivatives, processes for their preparation, pharmaceutical compositions in which they are present and method of use thereof. These compounds are Tyrosine Kinase Inhibitors and are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. Among them, erlotinib hydrochloride, chemically N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride is a selective inhibitor of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and is useful for the treatment of proliferative disorders, such as cancers, particularly non small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, head cancer or neck cancer.
Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
Erlotinib hydrochloride can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
The U.S. Patent No. 5,747,498 (herein after referred to as the ‘498 patent) makes no reference to the existence of specific polymorphic forms of erlotinibhydrochloride. In this patent, it is disclosed that the compound is isolated according to conventional techniques; more precisely, according to the embodiments exemplified, crude erlotinib hydrochloride residue (obtained by reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline with 3-ethynylaniline or its hydrochloride salt in a solvent such as a d-Cβ-alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, pyridine or other aprotic solvents, preferably isopropanol) is basified with saturated aqueous NaHCO3 in the presence of methanol and chloroform followed by flash chromatography on silica using 30% acetone in hexane to afford erlotinib free base, which is further treated with hydrochloric acid in the presence of diethyl ether and chloroform to give erlotinib hydrochloride (melting point: 228° – 2300C).
PCT Patent Publication No. WO 99/55683 disclosed erlotinib mesylate anhydrate and hydrate polymorphic forms, their method of preparation and pharmaceutical compositions containing thereof.
PCT Patent Publication No. WO 01/34574 A1 (herein after referred to as the ‘574 patent publication) described two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), characterized by powder X-ray diffraction (p-XRD) pattern. The publication further taught that the synthetic procedure described and exemplified in the ‘498 patent produces the erlotinib hydrochloride as a mixture of the polymorphs A and B.
TARCEVA (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA contains erlotinib as the hydrochloride salt that has the following structural formula:
 |
Erlotinib hydrochloride has the molecular formula C22H23N3O4•HCl and a molecular weight of 429.90. The molecule has a pKa of 5.42 at 25oC. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.
Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2.
wo 2012028861
wo2007060691
Shenzhen Neptunus Bioengineering submits first ever application for conducting Phase 2 trials in the US for Traditional Chinese Medicine ( Polydatin Injection) in the class of innovative drugs
polydatin
Resveratrol 3-beta-mono-D-glucoside
trans-piceid
3,5,4′-trihydroxystilbene-3-O-β-D-glucopyranoside
Shenzhen Neptunus Bioengineering submits first ever application for conducting Phase 2 trials in the US for Traditional Chinese Medicine ( Polydatin Injection) in the class of innovative drugs
Piceid is a stilbenoid glucoside and is a major resveratrol derivative in grape juices.[1] It can be found in the bark of Picea sitchensis.[2] It can also be isolated from Polygonum cuspidatum,[3] the Japanese knotweed (syn. Fallopia japonica).
Resveratrol can be produced from piceid fermented by Aspergillus oryzae.[3] This latter species produces a piceid-b-D-glucosidase.[4]
Trans-piceid is the glucoside formed with trans-resveratrol, while cis-piceid is formed with cis-resveratrol.
Trans-resveratrol-3-O-glucuronide is one of the two metabolites of trans-piceid in rat.[5]
Resveratrol glucoside from transgenic alfalfa has been used for the prevention of aberrant crypt foci in mice.[6]
- Romero-Pérez, A. I.; Ibern-Gómez, M.; Lamuela-Raventós, R. M.; De La Torre-Boronat, M. C. (1999). “Piceid, the Major Resveratrol Derivative in Grape Juices”. Journal of Agricultural and Food Chemistry 47 (4): 1533–1536. doi:10.1021/jf981024g.PMID 10564012. edit
- Aritomi, M.; Donnelly, D. M. X. (1976). “Stilbene glucosides in the bark of Picea sitchensis”. Phytochemistry 15 (12): 2006. doi:10.1016/S0031-9422(00)88881-0. edit
- Wang, H.; Liu, L.; Guo, Y. -X.; Dong, Y. -S.; Zhang, D. -J.; Xiu, Z. -L. (2007). “Biotransformation of piceid in Polygonum cuspidatum to resveratrol by Aspergillus oryzae”. Applied Microbiology and Biotechnology 75 (4): 763–768. doi:10.1007/s00253-007-0874-3. PMID 17333175. edit
- Purification and characterization of piceid-b-D-glucosidase from Aspergillus oryzae. Chunzhi Zhang, Dai Li, Hongshan Yu, Bo Zhang and Fengxie Jin, Process Biochemistry, 2007, 42, pages 83–88, doi:10.1016/j.procbio.2006.07.019
- Zhou, M.; Chen, X.; Zhong, D. (2007). “Simultaneous determination of trans-resveratrol-3-O-glucoside and its two metabolites in rat plasma using liquid chromatography with ultraviolet detection”. Journal of Chromatography B 854: 219.doi:10.1016/j.jchromb.2007.04.025. edit
- RKineman, B. D.; Brummer, E. C.; Paiva, N. L.; Birt, D. F. (2010). “Resveratrol from Transgenic Alfalfa for Prevention of Aberrant Crypt Foci in Mice”. Nutrition and Cancer 62(3): 351–361. doi:10.1080/01635580903407213. PMID 20358473
Novartis gets European approval for first Meningitis B vaccine
Bexero is a vaccine indicated for the treatment of the meningococal gp B disease
Novartis has received approval from the European Commission for the first vaccine to protect children against Meningitis B.
Bexsero (4CMenB) will be used in Europe to prevent meningococcal B meningitis (MenB), one of the most common and deadly forms of the disease in babies and infants under five years of age.
There is currently no approved vaccine offering protection against this particular type of meningitis.
Novartis has committed to making the Bexsero available as soon as possible, the firm said in a statement on Tuesday.
Meningitis UK is today urging the government to introduce the vaccine into the UK, which has one of the highest incidence rates for MenB in the world.
Meningitis UK Founder Steve Dayman said; “The Government must introduce the Meningitis B vaccine into the immunisation schedule as soon as possible – it will save thousands of lives and spare families so much suffering.
“Any delay means lives will be lost.”
The Joint Committee on Vaccination and Immunisation (JCVI), which advises the government, plans to meet in June 2013 to discuss the vaccine.
MenB is caused by bacteria, leading to inflammation of the lining around the brain and spinal cord. It can kill within 24 hours.
In December 2010, Novartis submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for bexsero based on positive results from Phase III trials.
In November 2012, the Committee for Medicinal Products for Human Use (CHMP) of EMA adopted a positive opinion for approval of the MAA.
Novartis plans to submit marketing applications in Asia, Latin America and North America.
Meningococcal is a life threatening disease which can lead to death within 24 to 48 hours of the first symptoms. The disease manifests in the form of bacterial meningitis, which leads to an infection of the membrane around the brain and spine and a bloodstream infection called sepsis.
The bacteria which causes meningococcal disease is called meningococcus and is divided into five main groups, called serogroups, namely A, B, C, W135 and Y. MenB is the most common type of bacteria causing meningococcal disease.
MenB strains can mutate making it very difficult to diagnose and treat. It has led to several outbreaks across the world. The highest rates of the disease occur in the semi-arid and sub-Saharan Africa region.
Most of the MenB cases occur in healthy patients. A person can carry the bacteria for up to six months. It is easily transmitted through physical contact, coughing and sneezing. Infants and adolescents are the most vulnerable groups of the disease.
Initial symptoms of the disease are flu-like and hence difficult to diagnose. The main symptoms such as neck stiffness and rashes appear at a later stage of the illness. Existing treatments for the disease include hospitalisation and antimicrobial therapy. The disease, however, is difficult to treat due to its rapid rate of progression.
An estimated 20,000 to 80,000 cases of MenB are reported every year. About 5-10% of the people die even after being diagnosed and treated. Those who survive the disease suffer from severe complications such as brain damage, learning disabilities, behavioural problems and hearing loss.
DR ANTHONY MELVIN CRASTO Ph.D
FDA Approves Exjade to Remove Excess Iron in Patients with genetic blood disorder
Exjade (deferasirox) is an iron chelating agent. Exjade tablets for oral suspension contain 125 mg, 250 mg, or 500 mg deferasirox. Deferasirox is designated chemically as 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1yl]-benzoic acid and its structural formula is:
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Deferasirox is a white to slightly yellow powder. Its molecular formula is C21H15N3O4 and its molecular weight is 373.4.
FDA Approves Exjade to Remove Excess Iron in Patients with genetic blood disorder
January 23, 2013 — The U.S. Food and Drug Administration today expanded the approved use of Exjade (deferasirox) to treat patients ages 10 years and older who have chronic iron overload resulting from a genetic blood disorder called non-transfusion-dependent thalassemia (NTDT).
NTDT is a milder form of thalassemia that does not require individuals to get frequent red blood cell transfusions. However, over time, some patients with NTDT are still at risk for iron overload that can lead to damage to vital organs.
The FDA is also authorizing marketing of FerriScan as an imaging companion diagnostic for Exjade. The agency previously cleared FerriScan for measuring liver iron concentration (LIC), but its use in Exjade clinical studies to select patients for therapy, and to manage therapy, defined its role as an imaging companion diagnostic necessary for Exjade’s safe and effective use. FerriScan measures LIC non-invasively using magnetic resonance imaging.
An estimated 1,000 people in the United States have thalassemia, according to the National Heart, Lung, and Blood Institute. Thalassemia conditions can cause the body to make fewer healthy red blood cells and less hemoglobin, a protein that carries oxygen to all parts of the body and returns carbon dioxide to the lungs so it can be exhaled. Some patients with thalassemia require frequent transfusions of red blood cells to maintain an acceptable level of hemoglobin. Iron overload is common in these patients.
Exjade was previously approved for treatment of chronic iron overload due to blood transfusions in patients ages 2 years and older, and this approval extends its use to treat patients with NTDT who show iron overload. Exjade should be used in patients with NTDT who have an LIC of at least 5 milligrams of iron per gram of dry liver tissue weight.
Exjade’s new indication is being approved under the FDA’s accelerated approval program, which provides patients earlier access to promising new drugs intended to treat serious or life-threatening illnesses while the company conducts additional studies to confirm the drug’s clinical benefit. Exjade was approved based on clinical data showing it can reduce LIC to less than 5 mg/g dry weight, a surrogate endpoint that is judged reasonably likely to predict a clinical benefit to patients.
“Using our accelerated approval process, FDA is able to expedite the availability of this drug to patients who need to reduce excess iron,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Exjade is the first drug approved to treat patients with NTDT who show iron overload.”
The safety and effectiveness of Exjade to treat chronic iron overload in patients with NTDT were established in two clinical trials designed to measure the number of patients whose LIC was reduced to less than 5 mg/g dry weight after 52 weeks of treatment. In the first trial, 166 patients were randomly assigned to receive 5 mg/kg of Exjade, 10 mg/kg of Exjade, or a placebo daily. Results showed 15 percent and 27 percent of Exjade-treated patients achieved the target LIC, respectively, compared with 4 percent in placebo-treated patients. The second trial contained 133 patients from the first study who received an additional year of Exjade treatment or switched from placebo to Exjade treatment. Thirty-five percent of the evaluable patients in this extension trial achieved the target LIC.
The FDA reviewed data for the FerriScan through the de novo classification process, a regulatory pathway for medical devices that are generally moderate-risk but are not comparable to an already legally marketed device. The FDA’s granting of the de novo request for FerriScan was based largely on data from the Exjade clinical studies that used FerriScan LIC results as the primary outcome measure. Additionally, investigators conducted a 230-patient study that found FerriScan results were as accurate as liver biopsy for measuring LIC.
“The FerriScan device is a non-invasive test that helps physicians to select appropriate patients for Exjade therapy as well as monitor their response to the drug, and discontinue therapy when LIC reaches safe levels,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health.
Exjade is marketed by East Hanover, N.J.-based Novartis. FerriScan is marketed by Resonance Health, based in Australia.
structure
http://www.rxlist.com/exjade-drug.htm
http://en.wikipedia.org/wiki/Deferasirox
http://www.us.exjade.com/index.jsp?usertrack.filter_applied=true&NovaId=4029462066891750194
http://www.novartisoncology.com/index.jsp?lightbox=global-patient
Novo Nordisk has announced that the European Commission has approved its Tresiba and Ryzodeg drugs for the treatment of diabetes in adults.
B29N(epsilon)-omega-carboxypentadecanoyl-gamma-L-glutamyl desB30 human insulin
Novo Nordisk has announced that the European Commission has approved its Tresiba and Ryzodeg drugs fro the treatment of diabetes in adults.
Tresiba (degludec), a long-acting basal insulin analogue, is widely tipped to become a blockbluster drug.
It has already been approved in Japan and is awaiting approval from the US Food and Drug Administration.
The European Commission granted marketing authorisation for Tresiba based on studies in which the drug demonstrated a lower risk of overall nocturnal hypoglycaemia – common in people who treat their diabetes with insulin – compared to insulin glargine.
The treatment, with a duration-of-action beyond 42 hours “is the first basal insulin to offer patients the possibility of adjusting the time of injection, when needed,” Novo Nordisk said in a statement.
Ryzodeg, the brand name for insulin degludec / insulin aspart, can be administered once or twice-daily with the main meals.
In a treat-to-target study, this drug also demonstrated a lower risk of overall and nocturnal hypoglycaemia while successfully achieving equivalent reductions in HbA1c (glycated haemoglobin) when compared to Novo’s NovoMix (biphasic insulin aspart).
Novo Nordisk executive vice president and chief science officer Mads Krogsgaard said; “These marketing authorisations constitute significant milestones for Novo Nordisk and the treatment of diabetes.”
The Danish company expects to launch Tresiba in the UK and Denmark during the first half of 2013 and in other European markets throughout the rest of 2013 and 2014.
Ryzodeg is currently expected to be launched a year later.
“We look forward to making Tresiba and Ryzodeg available to many people with diabetes in Europe,” said Krogsgaard.
Insulin degludec is a ultralong-acting basal insulin analogue being developed by Novo Nordisk under the brand name Tresiba.[1] It is injected subcutaneously three-times a week to help control the blood sugar level of those with diabetes. It has a duration of action that lasts up to 40 hours, unlike the 18 to 26 hours provided by current marketed long-acting insulins such as insulin glargine and insulin detemir.[2][3]
Insulin degludec is a modified insulin that has one single amino acid deleted in comparison to human insulin, and is conjugated to hexadecanedioic acid via gamma-L-glutamyl spacer at the amino acid lysine at position B29.
Insulin degludec is an ultra-long acting insulin that, unlike insulin glargine, is active at a physiologic pH. The addition of hexadecanedioic acid to lysine at the B29 position allows for the formation of multi-hexamers in subcutaneous tissues.[4] This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation.[5]
- CHMP (October 18, 2012), “Summary of opinion 1 (initial authorisation): Tresiba”, Pending EC decisions (EMA), retrieved November 6, 2012
- “Good News for Novo’s Thrice-Weekly Insulin”.DiabetesInControl.com. Retrieved 2010-11-07.
- Schwartzkopff, Frances (2010-06-25). “Novo’s Degludec Insulin as Effective as Lantus With Fewer Doses”.Bloomberg Businessweek. Retrieved 2010-11-07.
- Nasrallah, SN; Reynolds, LR (2012). “Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?”. Clinical medicine insights. Endocrinology and diabetes 5: 31-7. PMID 22879797.
- Robinson, JD; Neumiller, JJ; Campbell, RK (2012 Nov 2). “Can a New Ultra-Long-Acting Insulin Analogue Improve Patient Care? Investigating the Potential Role of Insulin Degludec.”.Drugs. PMID 23145524.
DR ANTHONY MELVIN CRASTO Ph.D
Sihuan’s Drug Nalmefene Hydrochloride Receives Approval for Pharmaceutical Registration from State Food and Drug Administration
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| Nalmefene | |
| 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol |
REVEX (nalmefene hydrochloride injection), an opioid antagonist, is a 6-methylene analogue of naltrexone. The chemical structure is shown below:
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Molecular Formula: C21H25NO3•HCl
Molecular Weight: 375.9, CAS # 58895-64-0
Chemical Name: 17-(Cyclopropylmethyl)-4,5a-epoxy-6-methylenemorphinan-3,14-diol, hydrochloride salt.
Nalmefene hydrochloride is a white to off-white crystalline powder which is freely soluble in water up to 130 mg/mL and slightly soluble in chloroform up to 0.13 mg/mL, with a pKa of 7.6.
REVEX is available as a sterile solution for intravenous, intramuscular, and subcutaneous administration in two concentrations, containing 100 µg or 1.0 mg of nalmefene free base per mL. The 100 µg/mL concentration contains 110.8 µg of nalmefene hydrochloride and the 1.0 mg/mL concentration contains 1.108 mg of nalmefene hydrochloride per mL. Both concentrations contain 9.0 mg of sodium chloride per mL and the pH is adjusted to 3.9 with hydrochloric acid.
Concentrations and dosages of REVEX are expressed as the free base equivalent of nalmefene.
Nalmefene (Revex), originally known as nalmetrene, is an opioid receptor antagonistdeveloped in the early 1970s,[1] and used primarily in the management of alcoholdependence, and also has been investigated for the treatment of other addictions such aspathological gambling and addiction to shopping.
Nalmefene is an opiate derivative similar in both structure and activity to the opiate antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity. As with other drugs of this type, nalmefene can precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively to counteract the effects of strong opioids used in surgery.
Nalmefene differs from naltrexone by substitution of the ketone group at the 6-position of naltrexone with a methylene (CH2) group, which considerably increases binding affinity to the μ-opioid receptor. Nalmefene also has high affinity for the other opioid receptors, and is known as a “universal antagonist” for its ability to block all three.
- US patent 3814768, Jack Fishman et al, “6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS”, published 1971-11-26, issued 1974-06-04
- Barbara J. Mason, Fernando R. Salvato, Lauren D. Williams, Eva C. Ritvo, Robert B. Cutler (August 1999). “A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence”. Arch Gen Psychiatry 56 (8): 719.
- Clinical Trial Of Nalmefene In The Treatment Of Pathological Gambling
- http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf
- “Efficacy of Nalmefene in Patients With Alcohol Dependence (ESENSE1)”.
- “Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan”. thepharmaletter. 22 December 2011.
- Nalmefene Hydrochloride Drug Information, Professional
Takeda Receives FDA Approval For Three New Type 2 Diabetes Therapies
HY A0023, ALOGLIPTIN BENZOATE, NESINA, SYR 322
Takeda Receives FDA Approval For Three New Type 2 Diabetes Therapies
Furiex Pharmaceuticals Inc. Friday 25 jan 2013,confirmed that Takeda Pharmaceutical Company Limited has received approval from the U.S. Food and Drug Administration of three new type 2 diabetes therapies, NESINA (alogliptin) and the fixed-dose combination therapies, OSENI (alogliptin and pioglitazone) and KAZANO (alogliptin and metformin HCl), for the treatment of type 2 diabetes in adults as adjuncts to diet and exercise.
Under its agreement with Takeda, Furiex is entitled to receive a $25 million milestone payment as a result of this approval, as well as royalties on sales in the United States and potential sales-based milestones. Furiex has already been receiving royalty payments from Takeda for the sale of NESINA and LIOVEL in Japan.
“Receiving regulatory approvals for NESINA, OSENI and KAZANO in the U.S. marks an important milestone for Furiex,” said Fred Eshelman, chairman of Furiex.
“These approvals should enable Takeda to build on the success of NESINA in Japan and leverage its more than 20 years of clinical and patient experience in the type 2 diabetes therapeutic area.”
Type 2 diabetes is the most common form of diabetes and has reached epidemic proportions globally. The global health care expenditures to treat and prevent diabetes and its complications were estimated at $471 billion in 2012. In addition to diet and exercise, patients often need to take multiple medications to help manage blood glucose. Because of the chronic nature of this disease, combination therapy is often required to maintain diabetic control over many years of therapy.
NESINA is a DPP-4 inhibitor for the treatment of type 2 diabetes as an adjunct to diet and exercise. DPP-4 inhibitors address insulin deficiency by slowing the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide).
OSENI is a fixed dose combination therapy that combines alogliptin and pioglitazone in a single tablet for the treatment of type 2 diabetes in adults as an adjunct to diet and exercise. Pioglitazone is a thiazolidinedione that directly targets insulin resistance, a condition in which the body does not efficiently use the insulin it produces to control blood glucose levels. It is currently approved for use in adults for the treatment of type 2 diabetes as an adjunct to diet and exercise.
KAZANO is a fixed dose combination therapy for the treatment of type 2 diabetes that combines alogliptin and metformin in a single tablet. Metformin is a widely-used diabetes medication that acts primarily by reducing the amount of glucose produced by the liver. These medications work in combination to help patients with type 2 diabetes manage their blood glucose levels.
Nesina® (alogliptin) is a member of a new class of drugs for the oral treatment of type 2 diabetes (T2D). Nesina is being developed and marketed by Takeda Pharmaceuticals. In April 2010, Takeda received regulatory approval from Japan’s Ministry of Health, Labour and Welfare for Nesina and it is now being sold in Japan.
Takeda has resubmitted a new drug application (NDA) with the U.S. Food and Drug Administration (FDA), and has submitted a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA).
As a result of their collaboration, Furiex has rights to royalties and sales-based milestones from Takeda for the sale of Nesina in Japan. Furiex will be entitled to receive regulatory milestones, royalties and sales-based milestones upon marketing approval of Nesina in other countries.
Alogliptin is a DPP-4 inhibitor that slows the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide), which play a major role in regulating blood glucose levels and have the potential to improve pancreatic beta-cell function.
Alogliptin has been studied in 12 Phase III trials including more than 8,000 patients. Pivotal trials demonstrated alogliptin was well-tolerated and it significantly improved glycemic control in T2D patients without raising the incidence of hypoglycemia. Additionally, alogliptin has been shown to enhance glycemic control when used in combination with other commonly prescribed diabetes drugs.
Alogliptin was tested in 329 drug-naive patients with inadequately controlled T2D in a double-blind, placebo-controlled, multicenter study. Patients were randomized to once-daily treatment with 12.5 mg or 25 mg alogliptin or placebo for 26 weeks. The primary efficacy end point was HbA(1c). Alogliptin was well-tolerated and significantly improved glycemic control in these patients with T2D without raising the incidence of hypoglycemia.
DR ANTHONY CRASTO, PhD, ICT Organic chemistry, Currently working with GLENMARK GENERICS LTD research centre as Principal Scientist, process research (bulk actives) at Mahape, Navi Mumbai, India, helping millions, million hits on google on all organic chemistry websites, Hands on experience in developing novel routes for drug molecules and implementation on commercial scale. several international patents published.pushing boundaries, one lakh connections on all networking sites
The U.S. Food and Drug Administration today approved Oxytrol for Women, the first over-the-counter treatment for overactive bladder in women
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| 4-Diethylaminobut-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylethanoate |
January, 25, 2013 — The U.S. Food and Drug Administration today approved Oxytrol for Women, the first over-the-counter treatment for overactive bladder in women ages 18 years and older.
Oxytrol will remain available for men with overactive bladder by prescription only.
Overactive bladder is a condition in which the bladder squeezes too often or squeezes without warning. Symptoms include leaking urine (urinary incontinence), feeling the sudden and urgent need to urinate, and frequent urination. Overactive bladder affects an estimated 33 million Americans, the majority of whom are older women.
Oxytrol for Women contains oxybutynin, a medicine that helps relax the bladder muscle. Oxybutynin belongs to a class of drugs known as anticholinergics. It is the first drug in this class to be made available over-the-counter for treatment of overactive bladder.
Oxytrol for Women is a patch that is applied to the skin every four days. The patch delivers 3.9 milligrams of oxybutynin per day.
“Studies demonstrate that over-the-counter Oxytrol for Women is a safe and effective treatment for overactive bladder,” said Shaw Chen, M.D., Ph.D., deputy director of the Office of Drug Evaluation IV in the FDA’s Center for Drug Evaluation and Research. “Women should make sure to follow the Drug Facts label and consult their doctor if their condition does not improve.”
Oxytrol for Women’s safety and effectiveness for over-the-counter use were established in more than 5,000 subjects participating in nine studies. Overall, results from these studies showed that consumers can understand the information on the label, properly select whether the product is right for them, and use the drug appropriately.
Side effects reported during clinical studies were mild and included skin irritation where the patch was applied, dry mouth and constipation. A leaflet with tips to help manage overactive bladder will be provided with the product.
Oxytrol for Women is marketed by Merck, based in Whitehouse Station, N.J.
Oxybutynin (Ditropan, Lyrinel XL, Lenditro (South Africa)) is an anticholinergic medication used to relieve urinary and bladder difficulties, including frequent urination and inability to control urination (urge incontinence), by decreasing muscle spasms of the bladder.[2] It competitively antagonizes the M1, M2, and M3 subtypes of the muscarinic acetylcholine receptor. It also has direct spasmolytic effects on bladder smooth muscle as a calcium antagonist and local anesthetic, but at concentrations far above those used clinically. It is available orally in generic formulation or as the brand-names Ditropan, Lyrinel XL, or Ditrospam, as a transdermal patch under the brand name Oxytrol, and as a topical gel under the brand name Gelnique.
Oxybutynin is also a possible treatment of hyperhidrosis (hyper-active sweating).[3][4][5]
- = eng&code = 67903 “Product Information”. Drug Product Database. Retrieved 2011-08-13.
- Chapple CR. “Muscarinic receptor antagonists in the treatment of overactive bladder”. Urology (55)5, Supp. 1:33-46, 2000.
- Tupker RA, Harmsze AM, Deneer VH (2006). “Oxybutynin therapy for generalized hyperhidrosis.”. Arch Dermatol 142 (8): 1065–6. doi:10.1001/archderm.142.8.1065. PMID 16924061.
- Mijnhout GS, Kloosterman H, Simsek S, Strack van Schijndel RJ, Netelenbos JC. (2006). “Oxybutynin: dry days for patients with hyperhidrosis.”. Neth J Med 64 (9): 326–8. PMID 17057269.
- Schollhammer M, Misery L. (2007). “Treatment of hyperhidrosis with oxybutynin.”. Arch Dermatol. 143 (4): 544–5. doi:10.1001/archderm.143.4.544. PMID 17438194.
USFDA Approves first systemic antisense drug Kynamro (mipomersen sodium) Injection for treatment of Homozygous Familial Hyperholesterolemia
G*-C*-C*-U*-C*-dA-dG-dT-dC-dT-dG-dmC-dT-dT-dmC-G*-C*-A*-C*-C*[d= 2′-deoxy,*= 2′-O-(2-methoxyethyl)]
with 3’→5′ phosphorothioate linkages
cas no 629167-92-6
USFDA Approves first systemic antisense drug Kynamro (mipomersen sodium) Injection for treatment of Homozygous Familial Hyperholesterolemia
30 January 2013
Sanofi and its subsidiary Genzyme, and Isis Pharmaceuticals Inc today announced that the U.S. Food and Drug Administration (FDA) has approved its New Drug Application (NDA) for KYNAMRO(mipomersen sodium) injection. KYNAMRO, given as a 200 mg weekly subcutaneous injection, has been approved as an adjunct to lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (TC), and non-high density lipoprotein-cholesterol (non HDL-C) in patients with homozygous familial hypercholesterolemia.
In the United States, HoFH, an orphan indication, occurs in approximately one in one million individuals. For those with HoFH, heart attacks and death often occur before age 30.
Mipomersen (previously ISIS 301012, trade name Kynamro) is a cholesterol-reducing drug candidate. It is an antisense therapeutic that targets the messenger RNA forapolipoprotein B.[1][2][3] It is administered as a weekly injection.Structure
The compound is a ‘second-generation’ antisense oligonucleotide; the nucleotides are linked with phosphorothioate linkages rather than the phosphodiester linkages of RNA andDNA, and the sugar parts are deoxyribose in the middle part of the molecule and 2′-O-methoxyethyl-modified ribose at the two ends. These modifications make the drug resistant to degradation by nucleases, allowing it to be administered weekly. The drug accumulates in the liver, which is convenient since apolipoprotein B predominantly acts there.
The complete sequence is
G*-C*-C*-U*-C*-dA-dG-dT-dC-dT-dG-dmC-dT-dT-dmC-G*-C*-A*-C*-C*[d= 2′-deoxy,*= 2′-O-(2-methoxyethyl)]
with 3’→5′ phosphorothioate linkages.[4]
- Merki E, Graham MJ, Mullick AE, et al. (August 2008). “Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice”.Circulation 118 (7): 743–53. doi:10.1161/CIRCULATIONAHA.108.786822. PMID 18663084.
- El Harchaoui K, Akdim F, Stroes ES, Trip MD, Kastelein JJ (2008). “Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins”. Am J Cardiovasc Drugs 8 (4): 233–42.doi:10.2165/00129784-200808040-00003. PMID 18690757.
- Athyros VG, Kakafika AI, Tziomalos K, Karagiannis A, Mikhailidis DP (July 2008). “Antisense technology for the prevention or the treatment of cardiovascular disease: the next blockbuster?”. Expert Opin Investig Drugs 17 (7): 969–72.doi:10.1517/13543784.17.7.969. PMID 18549334.
- Statement on a nonproprietary name adopted by the USAN council: Mipomersen sodium
FDA APPROVES BIOTESTS BIVIGAM TO TREAT PRIMARY HUMORAL IMMUNODEFIECIENCY
FDA APPROVES BIOTESTS BIVIGAM TO TREAT PRIMARY HUMORAL IMMUNODEFIECIENCY
Jan 31, 2013,
Biotest Pharmaceuticals Corporation (BPC), a wholly owned U.S. subsidiary of Biotest AG, recently announced the U.S. Food and Drug Administration’s (FDA) approval of BIVIGAM™, its new intravenous immune globulin, for the treatment of patients with Primary Humoral Immunodeficiency (PI).
BIVIGAM is the first new intravenous immune globulin (IVIG) to be approved by the FDA with a validated assay for measuring potential thrombogenic activity. Thrombin generation tests are utilized to detect procoagulant activity. BPC plans to begin shipments of the product shortly.
To reduce the risk of thromboembolic events that PI patients have experienced in the past with alternative products, BPC initiated the development and validation of a TGA test in close cooperation with the FDA. Every lot of BPC’s BIVIGAM will be screened before release to assure the product fulfills the stringent release criteria pertaining to the threshold levels of Factor XIa. Increased Factor XIa has been identified as one of the risk factors associated with thromboembolic events following immune globulin intravenous therapy.
BIVIGAM is a sugar-free, glycine stabilized intravenous immune globulin that was approved by the FDA on December 19, 2012 and is available in 50 mL (5 gram) and 100 mL (10 gram) tamper-evident vials. The product uses a label with an integrated hanger and the packaging material is latex free. It is manufactured in a state-of-the-art US facility and will be available exclusively for patients and healthcare professionals in the USA. For Full Prescribing Information and more information about the product, the indication and additional services, please visit www.BIVIGAM.com.
BIVIGAM is a purified, sterile, ready-to-use preparation of concentrated humanimmunoglobulin G (IgG) antibodies. The distribution of IgG subclasses is similar to that of normal plasma.19,20 The active ingredient is human immunoglobulin purified from source human plasma and processed using a modified classical Cohn Method 6 / Oncley Method 9 fractionation procedure. BIVIGAM contains 100 ± 10 mg/mL protein, of which not less than 96% is human immunoglobulin obtained from source human plasma. It is formulated in water for injection containing 0.100-0.140 M sodium chloride, 0.20-0.29 M glycine, 0.15–0.25% polysorbate 80, and pH 4.0–4.6. BIVIGAM contains ≤ 200 μg/mL of IgA.
Each plasma donation used for the manufacture of BIVIGAM is collected from FDA licensed facilities and undergoes rigorous testing. Plasma donations must test negative for hepatitis B virus (HBV) surface antigen (HBsAg), antibodies to human immunodeficiency virus (HIV) strains 1 and 2 (anti-HIV-½), and antibodies to the hepatitis C virus (anti-HCV) as determined by enzyme immuno assay (EIA). In addition, each plasma unit must test negative and/or non-reactive for HIV RNA, HCV RNA, HBV DNA, Hepatitis A Virus (HAV) RNA, and Parvovirus B19 (B19 virus) DNA as determined by Nucleic Acid Amplification Testing (NAT) of plasma minipools. NAT for B19 virus DNA is also performed on a sample of the manufacturing pool and the limit for B19 virus DNA in a manufacturing pool is set not to exceed 104 IU/mL.
The manufacturing process of BIVIGAM employs three steps to remove/inactivateadventitious viruses to minimize the risk of virus transmission. The steps are “Precipitation and removal of fraction III” during cold ethanol fractionation, classical “Solvent/detergent treatment” and “35 nm virus filtration”. In compliance with current guidelines, the steps have been separately validated in a series of in vitro experiments for their capacity to inactivate or remove both enveloped and non-enveloped viruses.
Precipitation and removal of fraction III removes both enveloped and non-enveloped viruses, solvent/detergent treatment represents a virus inactivation step for enveloped viruses, and 35 nm virus filtration removes both enveloped and non-enveloped viruses by size exclusion. In addition to the steps above, low pH during several steps of the production process contributes to virus inactivation. The results of virus validation studies for BIVIGAM are shown in Table 3, expressed as log10 reduction factors.
New Drug Approvals 