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Biogen Idec and Elan have filed for approval for Tysabri (Natalizumab) as first-line treatment for relapsing forms of MS in anti-JC virus (JCV) antibody negative patients
Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn’s disease. It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously namedAntegren. Natalizumab is administered by intravenous infusion every 28 days. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier. Natalizumab has proven effective in treating the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and significantly improving quality of life in people with multiple sclerosis, as well as increasing rates of remission and preventing relapse in Crohn’s disease.
Natalizumab was approved in 2004 by the U.S. Food and Drug Administration (FDA). It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy(PML) when administered in combination with interferon beta-1a, anotherimmunosuppressive drug often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the European Medicines Agency.[1][2][3] By January 2010, 31 cases of PML were attributed to natalizumab.[4] The FDA did not withdraw the drug from the market because its clinical benefits outweigh the risks involved.[5] In the European Union, it has been approved for human use only for the treatment of multiple sclerosis and only then as a monotherapy because the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the patients.
Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 5, 2008.[6]
- Meeting highlights from the Committee for Medicinal Products for Human Use” (pdf). European Medicines Agency. 2009-10-22. Retrieved 2010-08-31.
- Hirschler, B; Cowell D (2009-10-29). “EU agency reports 24th case of Tysabri infection”. Reuters. Retrieved 2010-08-31.
- Clarke T; Orlofsky S; Von Ahn L (2009-06-29). “Biogen reports 10th case of PML brain infection”. Reuters. Retrieved 2010-08-31.
- Jeffrey, S (2010-02-05). “PML Risk Increases With Repeated Natalizumab Infusions: FDA”. Medscape. Retrieved 2010-08-31.
- Hitti, M (2008-08-01). “MS Drug Tysabri Tied to Brain Infection”. WebMD. Retrieved 2010-08-31.
- “Biogen Idec testing Tysabri as a cancer treatment”. The Boston Globe. 2008-09-05. Retrieved 2008-09-05.
FDA approves first flu vaccine made using insect virus
FDA approves first flu vaccine made using insect virus
17 January 2013
The US Food and Drug Administration has approved the world’s first influenza vaccine manufactured using an insect virus.
Flublok, manufactured by Protein Sciences, is produced using a ‘baculovirus expression system’ that does not require the virus to be grown in chicken eggs, as is usually the case.
This means the vaccine can be made quickly in the event of a pandemic and without any of the infectious risk traditionally associated with vaccine manufacture.
Karen Midthun, director of the FDA’s Center for Biologics Evaluation and Research, explained, “The new technology offers the potential for faster start-up of the vaccine manufacturing process in the event of a pandemic, because it is not dependent on an egg supply or on availability of the influenza virus.”
Flublok has three times the amount of hemagglutinin (HA) – the active ingredient in all inactivated influenza vaccines – to help protect against two influenza virus A strains, H1N1 and H3N2, and one influenza virus B strain.
The vaccine is produced by insect cells which are infected by the baculovirus combined with the hemagglutinin gene. The cells are then grown in culture to churn out the protein.
Protein Sciences CEO Manon Cox said, “We use advanced scientific technology to make just the active ingredient of the vaccine without any other viral components. This is the first influenza vaccine on the market to do so.”
The FDA approved Flublok for immunization in adults aged 18 to 49 after it was proved to be 44.6% effective against all circulating influenza virus during a study involving 2,300 people in the US.
The vaccine was indicated as safe to use during a separate study of 2,500 people.
Adverse events included pain at the site of injection, headache, fatigue and muscle aches, events also typical for conventional egg-based, inactivated influenza vaccines.
BOTOX® (onabotulinumtoxinA) Receives U.S. Food and Drug Administration Approval for the Treatment of Overactive Bladder for Adults Who Have an Inadequate Response to or Are Intolerant of an Anticholinergic Medication
BOTOX® (onabotulinumtoxinA) Receives U.S. Food and Drug Administration Approval for the Treatment of Overactive Bladder for Adults Who Have an Inadequate Response to or Are Intolerant of an Anticholinergic Medication
Allergan, Inc. (NYSE:AGN) announced today that the U.S. Food and Drug Administration (FDA) has approved BOTOX® (onabotulinumtoxinA) for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and frequency in adults who have had an inadequate response to or are intolerant of an anticholinergic medication. In two double-blind, randomized, multi-center, placebo-controlled 24-week clinical trials among adults with overactive bladder who had not been adequately managed with anticholinergic treatments, BOTOX® reduced daily urinary incontinence (leakage) episodes as compared to placebo by 50 percent or more by week 12 (reduction of 2.5 episodes from baseline of 5.5 episodes in one study and reduction of 3 episodes from baseline of 5.5 episodes in the second study for those treated with BOTOX® vs. a reduction of 0.9 episodes from a baseline of 5.1 episodes in one study and a reduction of 1.1 episodes from a baseline of 5.7 episodes in the second study for those treated with placebo).1
Allergan has a long-standing commitment to study the potential of BOTOX® to treat a number of different medical conditions
“Allergan has a long-standing commitment to study the potential of BOTOX® to treat a number of different medical conditions,” said Scott Whitcup, M.D., Allergan’s Executive Vice President, Research and Development, Chief Scientific Officer. “With today’s approval, BOTOX® is now approved for 26 different indications in more than 85 countries. Most importantly, today’s FDA approval is a milestone in the treatment of this burdensome condition and will provide a novel option for urologists and their OAB patients.”
While the exact cause is often unknown, OAB is a medical condition that results in an uncontrolled urge to urinate, frequent urination and, in many patients, uncontrollable leakage of urine. In the United States, an estimated 14.7 million adults experience symptoms of OAB with urinary incontinence (unexpected leakage of urine).2 Anticholinergics, which are often prescribed as pills, are used by approximately 3.3 million Americans with OAB, with or without urinary incontinence, to manage their condition.3 It is estimated, however, that greater than 50 percent of these patients stop taking at least one oral medication within 12 months, likely due to an inadequate response to, or intolerance of, the medication.4
“Overactive bladder can be a difficult condition to treat as there have been limited options for patients when currently available medications have failed to provide them with adequate relief,” said Dr. Victor Nitti*, Vice Chairman, Department of Urology and Director of Female Pelvic Medicine and Reconstructive Surgery at NYU Langone Medical Center. “With the approval of BOTOX®, we have a new treatment option to offer these patients that has demonstrated efficacy in reducing urinary leakage and other symptoms of OAB with the effect lasting up to six months.”
The median duration for efficacy with BOTOX® at reducing urinary leakage and other symptoms of OAB in the two clinical studies was 135-168 days compared to 88-92 days with placebo based on qualification for retreatment. To qualify for retreatment, at least 12 weeks must have passed since the prior treatment, post-void residual urine volume must have been less than 200 mL and patients must have reported at least two urinary incontinence episodes over three days. BOTOX® treatment relieves OAB symptoms by temporarily calming muscle contractions by blocking the transmission of nerve impulses to the bladder muscle.
BOTOX Cosmetic (onabotulinum toxin A) For Injection, is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A grown in a medium containing casein hydrolysate, glucose, and yeast extract, intended for intramuscular use. It is purified from the culture solution bydialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying.
The primary release procedure for BOTOX Cosmetic uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to Allergan’s products BOTOX and BOTOX Cosmetic. One Unit of BOTOX Cosmetic corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice. Due to specific details of this assay such as the vehicle, dilution scheme and laboratory protocols, Units of biological activity of BOTOX Cosmetic cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. The specific activity of BOTOX Cosmetic is approximately 20 Units/nanogram of neurotoxin protein complex.
Each vial of BOTOX Cosmetic contains either 50 Units of Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of sodium chloride; or 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.
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COCK SAYS MOM CAN TEACH YOU NMR
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE
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KISUMU, KENYA
Kisumu – Wikipedia, the free encyclopedia
Kisumu is a port city in Kisumu County, Kenya 1,131 m (3,711 ft), with a population of 409,928 (2009 census). It is the third largest city in Kenya, the principal city …
Kisumu CountyKisumu County is one of the new devolved counties of Kenya. Its …
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Kisumu International AirportKisumu International Airport is an airport in Kisumu, Kenya (IATA …
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Boat riding in Kisumu
Local inhabitants near Kisumu, 1911
Clockwise: Lake Victoria Panorama, Kisumu Panorama, sunset at Oginga Odinga street, Downtown, Kiboko Point, Nighttime in Kisumu and Jomo Kenyatta Stadium.
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 Kisumu
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Kisumu panorama, viewed from Lake Victoria
Jomo Kenyatta Stadium
Kisumu Harbour. The green vegetation is water hyacinth
Nairobi University Kisumu Campus
DR ANTHONY MELVIN CRASTO Ph.D
Teijin Pharma to launch Ipsen’s Somatuline® subcutaneous injection in the treatment of acromegaly and pituitary gigantism in Japan
Lanreotide
Thursday, 17 January 2013
Teijin Pharma to launch Ipsen’s Somatuline® subcutaneous injection in the treatment of acromegaly and pituitary gigantism in Japan
Somatuline is a synthetic somatostatin analog developed by Ipsen approved in more than 60 countries worldwide. In Japan, Somatuline is available in a differentiated and enhanced presentation with a pre-filled syringe that does not need reconstitution and with a retractable needle that enhances safety for caregivers; Somatuline’s long-lasting effects enable one administration every four weeks.
Somatuline, used in more than 60 countries worldwide, is highly regarded by the medical profession and patients for its long-lasting effects and user-friendly dosing devices. We are pleased to launch Somatuline in Japan, confident that it will offer patients a beneficial treatment option to control the symptoms of acromegaly, or pituitary gigantism, for improved quality of life.
Lanreotide is a man-made protein that is similar to a hormone in the body called somatostatin. Lanreotide lowers many substances in the body such as insulin and glucagon (involved in regulating blood sugar), growth hormone, and chemicals that affect digestion.
Lanreotide is used to as a long-term treatment in people with acromegaly who cannot be treated with surgery or radiation.
Lanreotide is sometimes given when surgery or radiation treatments have been tried without successful treatment of symptoms.
Lanreotide may also be used for other purposes not listed in this medication guide.
Lanreotide (INN) is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-actinganalogue of somatostatin, like octreotide.
Lanreotide (as lanreotide acetate) is manufactured by Ipsen, and marketed under the trade name Somatuline. It is available in several countries, including the United Kingdom,Australia and Canada, and was approved for sale in the United States by the Food and Drug Administration (FDA) on August 30, 2007.[2]
- (French) “Lanreotide Acetate”. BIAM. March 5, 2001. Retrieved 2007-03-02.
- “FDA Approves New Drug to Treat Rare Disease, Acromegaly” (Press release). U.S. Food and Drug Administration. August 30, 2007. Retrieved 2007-09-06.
- Rens-Domiano S, Reisine T (1992). “Biochemical and functional properties of somatostatin receptors”. J Neurochem 58 (6): 1987–96.doi:10.1111/j.1471-4159.1992.tb10938.x. PMID 1315373.
- “Somatuline LA”. electronic Medicines Compendium. September 17, 2003. Retrieved 2007-03-02.
- Kvols L, Woltering E (2006). “Role of somatostatin analogs in the clinical management of non-neuroendocrine solid tumors”.Anticancer Drugs 17 (6): 601–8. doi:10.1097/01.cad.0000210335.95828.ed. PMID 16917205.
- Susini C, Buscail L (2006). “Rationale for the use of somatostatin analogs as antitumor agents”. Ann Oncol 17 (12): 1733–42.doi:10.1093/annonc/mdl105. PMID 16801334.
- “Somatuline Autogel”. electronic Medicines Compendium. April 12, 2007. Retrieved 2007-04-19.
- Valéry C, Paternostre M, Robert B, Gulik-Krzywicki T, Narayanan T, Dedieu J-C, Keller G, Torres M-L, Cherif-Cheikh R, Calvo P, and Artzner F (2003). “Biomimetic organization: Octapeptide self-assembly into nanotubes of viral capsid-like dimension”. Proceedings of the National Academy of Sciences of America 100 (18): 10258–62. doi:10.1073/pnas.1730609100.
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Additional Somatuline Depot Information
- Somatuline Depot Side Effects Center
- Somatuline Depot FDA Approved Prescribing Information including Dosage
- DR ANTHONY MELVIN CRASTO Ph.D
MOBILE-+91 9323115463GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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:
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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
New Drug Approvals 