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Yearly Archives: 2013
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Phase III data show Boehringer Ingelheim’s faldaprevir was highly effective in a broad range of patients with genotype-1 hepatitis C
faldaprevir , 801283-95-4 cas no, BI-201335
(1R,2S)-1-{[(2S,4R)-4-[{8-bromo-7-methoxy-2-[2-(2-methylpropanamido)-1,3-thiazol-4-yl]quinolin-4-yl}oxy]-1-[(2S)-2-{[(cyclopentyloxy)carbonyl]amino}-3,3-dimethylbutanoyl]pyrrolidine-2-carboxamido]-2-ethenylcyclopropane-1-carboxylic acid
Molecular Formula: C40H49BrN6O9S
Molecular Weight: 869.82 g.mol-1
2 nd nov 2013
Boehringer Ingelheim today announced new data from its Phase III clinical trial programme, STARTVerso™, which evaluates faldaprevir* in combination with pegylated interferon and ribavirin (PegIFN/RBV). Patients with genotype-1 (GT-1) hepatitis C (HCV) who have not received previous treatment (treatment-naïve: STARTVerso™1&2),1 treatment-experienced patients (STARTVerso™3),2 and HIV co-infected patients (STARTVerso™4)3 participated in this study programme. The results from these and additional studies will be presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), also known as The Liver Meeting®, taking place 1-5 November in Washington, D.C.
Faldaprevir (formerly BI 201335) is an experimental drug candidate for the treatment of hepatitis C. It is being developed byBoehringer-Ingelheim and is currently in Phase III trials.[1]
Faldaprevir is a hepatitis C virus protease inhibitor.
Faldaprevir is being tested in combination regimens with pegylated interferon and ribavirin, and in interferon-free regimens with other direct-acting antiviral agents including BI 207127.
Data from the SOUND-C2 study, presented at the 2012 AASLD Liver Meeting, showed that a triple combination of faldaprevir, BI 207127, and ribavirin performed well in HCV genotype 1b patients.[2] Efficacy fell below 50%, however, for dual regimens without ribavirin and for genotype 1a patients.
- Efficacy and Safety of BI 201335 (Faldaprevir) in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-naïve Genotype 1 Hepatitis C Infected Patients (STARTverso 1). Cliicaltrials.gov. March 6, 2013.
- Interferon-free hepatitis C treatment with faldaprevir proves safe and effective in people with cirrhosis. Alcorn, K. Aidsmap.com. 20 November 2012.
- Bioorganic & Medicinal Chemistry Letters, Volume 23, Issue 14, 15 July 2013, Pages 4267–4271
Synthesis and optimization of a novel series of HCV NS3 protease inhibitors: 4-Arylproline analogs
The following Compound 1):
(1)
wherein B is
; L° is MeO-; L1 is Br; and R2 is and having the chemical name: l-{ [4-[8-Bromo-2-(2-isopropylcarbamoyl-thiazol-4-yl)-7- methoxy-quinolin-4-yloxy]-l-(R)-(2-cyclopentyloxycarbonyl amino-3,3-(S)-dimethyl- butyryl)-pyrrolidine-(S)-2-carbonyl]-amino}-2-(S)-vinyl-cyclopropane-(R)-carboxylic acid, is known as a selective and potent inhibitor of the HCV NS3 serine protease and useful in the treatment of HCV infection. Compound (1) falls within the scope of the acyclic peptide series of HCV inhibitors disclosed in U.S. Patents RE 40,525, 7,514,557 and 7,585,845. Compound (1) is disclosed specifically as Compound # 1055 in U.S. Patent 7,585,845, and as Compound # 1008 in U.S. Patent 7,514,557. Compound (1), and pharmaceutical formulations thereof, can be prepared according to the general procedures found in the above-cited references, all of which are herein incorporated by reference in their entirety. Preferred forms of Compound (1) include the crystalline forms, in particular the crystalline sodium salt form, which can be prepared as described in U.S. Patent Application Publication No. 2010/0093792, also incorporated herein by reference. Data demonstrating the activity of Compound (1) as an inhibitor of the HCV NS3 serine protease and its corresponding demonstrated utility in the treatment of HCV infection in mono-infected patients, can be found in U.S. Patent 7,585,845, as well as in numerous publications presenting the preclinical characterization or clinical trial results with Compound (1). See, e.g., Sulkowski MS, et al, Hepatol (2009), Vol. 50, pg. 2A, Abtract LB3; Sulkowski MS, et al., J Hepatol (2010) Vol. 52, Supp. 1, pgs. S462-S463, Abstract 1190; Berg et al., Hepatol (2010), Vol. 52, Supp. SI, Abstract 804; and White PW, et al., Antimicrob Agents Chemother (2010) 54(11):4611-4618.
Combination therapy regimens directed to administering Compound (1) with an interferon- alpha and ribavirin for the treatment of HCV infection are described in U.S. Patent Application Publication Nos. 2010/0068182 and 2011/0268700.
HIV/HCV coinfected persons tend to have higher HCV viral loads and are less likely to clear the HCV spontaneously. The urgency for treatment of persons who are coinfected is greater than it is for those with HCV infection alone. The course of liver disease is more rapid in HIV/HCV-coinfected persons, including an approximately 2-fold increased risk of cirrhosis, more rapid progression to decompensated liver disease and increased risk for hepatocellular carcinoma (Graham CS, et al., Clin Infect Dis (2001 );33:562-569) .
Treatment of HCV might improve the tolerability of highly active antiretroviral therapy (HAART) because HCV infection increases the risk of mitochondrial toxicity and hepatotoxicity from HAART (Sulkowski MS, et al., JAMA (2000);283:74-80; Lafeuil!ade A, et al., Lancet (2001);357:280-281 ). Although there is much less published information on treatment outcomes in those who are HIV/HCV-coinfected than in HCV mono-infected patients, all accumulated data demonstrate that sustained virological response (SVR) and cure from HCV infection with pegylated interferon alpha and ribavirin is achieved in a substantially lower proportion of HIV/HCV coinfected patients when compared to HCV mono-infected patients. Factors associated with a poor treatment response (e.g., a high baseline HCV viral load, cirrhosis, and African American race) are present in a higher proportion of HIV/HCV coinfected populations, when compared to HCV monoinfected populations. It is not clear to what extent HIV infection itself diminishes the SVR rate, and to what extent advanced immunosuppression (e.g., CD4+ T lymphocyte count <200/mm3) further reduces response to HCV treatment (Toriani FJ, et al., N Engl J Med (2004);351(5): 438 -50; Nunez M, et al., ARHR (2007); 23(8):972-982).
Thus, there is a continuing high unmet need in the art for therapies that are effective against HCV in patients that are co-infected with HIV.
Bristol-Myers Squibb to Market Japanese Hypertension Drug in China
Bristol-Myers Squibb licensed exclusive China rights to market Coniel, a calcium channel blocker treatment for hypertension and angina pectoris, from Kyowa Hakko Kirin Co. BMS said the transaction, its first China-specific in-licensing deal, demonstrated the company’s long-term commitment to China. Previously, Kyowa Hakko Kirin handled China marketing of the product itself.
O5-methyl O3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Benidipine (INN), also known as Benidipinum or benidipine hydrochloride, is a dihydropyridine calcium channel blocker for the treatment of high blood pressure (hypertension).
![Molecular Structure of 105979-17-7 (3,5-Pyridinedicarboxylicacid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester, (4R)-rel-)](https://i0.wp.com/www.lookchem.com/300w/2010/072/105979-17-7.jpg)
Dosing
Benidipine is dosed as 2–4 mg once daily.[1]
Benidipine is sold as Coniel by Kyowa Hakko Kogyo.
Benidipine is only licensed for use in Japan and selected Southeast Asian countries, where it is sold as 4 mg tablets.
Also known as: 105979-17-7, NCGC00185768-01, Benidipene, AC1LCVDP, SureCN24516, CTK8E8626, AKOS015895389, H007
- Hi-Eisai Pharmaceutical, Inc. “Coniel (benidipine) package insert (Philippines)”.MIMS Philippines. CMPMedica. Retrieved 2008-03-31.
- Hirayama, N. and Shimizu, E.: Acta Cryst., C47, 458 (1991)
Benidipine hydrochloride, A calcium channel protein inhibitor |
|
|
Alternative Name: KW 3049 Chemical Name: (4R)-rel-1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride |
Biological Activity
Orally active antihypertensive agent which displays a wide range of activities in vitro and in vivo. Inhibits L-, N- and T-type Ca2+ channels. Also inhibits aldosterone-induced mineralocorticoid receptor activation. Exhibits cardioprotective and antiartherosclerotic effects.
Technical Data
References
Yao et al (2006) Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel long-acting calcium channel blocker. J.Pharmacol.Sci. 100 243. PMID: 16565579.
Kosaka et al (2010) The L-, N-, T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family. Eur.J.Pharmacol. 635 49. PMID: 20307534.
Benidipine hydrochloride, whose chemical name is (±)-(R*)- 1 ,4-dihydro-2,6-dimethyl-4-(meta-nitrophenyl)-3 ,5-pyridinedica rbolate methyl ester [(R*)-l-benzyl-3-piperidine alcohol ester], belongs to dihydropyridine receptor antagonist. It can bind to dihydropyridine receptors at the binding site with high affinity and high specificity, and shows a strong inhibitory effect on Ca channel. Benidipine not only has an inhibitory effect on muscular (L-type) Ca channel, but also has an inhibitory effect on voltage-dependent N- and T-type Ca channels. It is, up to now, the only calcium antagonist that can inhibit all the three Ca channels mentioned above. Furthermore, benidipine has highly affinity with cell membrane, has vascular selectivity and renal protection effect. Therefore, it is an ideal, safe and effective agent for the treatment of hypertension and renal parenchymal hypertension and angina.
There are two chiral atoms in the molecule of benidipine hydrochloride, which locate on site 4 of the dihydropyridine ring and site 3′ of the side chain piperidine ring. Accordingly, benidipine hydrochloride has 4 optical isomers: (S)-(S)-(+)-a, (R)-(R)-(-)-a, (R)-(S)-(+)^ and (S)-(R)-(-)^, and the active ingredients for drug are the mixture of (S)-(S)-(+)-a and (R)-(R)-(-)-0L Therefore, it is necessary to separate a and β isomers during the post- treatment stage of benidipine hydrochloride preparation.
Based on the order of synthesis of dihydropyridine main ring, there mainly are two groups of total 5 synthesis routes of benidipine hydrochloride. Among them, there are two routes which involve synthesis of the main ring first: 1) acylchloridizing the main ring of dihydropyridine and then linking the side chain to synthesize directlybenidipine hydrochloride; 2) After acylchloridizing the main ring of dihydropyridine, 3-piperidinol and then benzyl is added. The routes involve the synthesis of the main ring later includes the following; 1) synthesizing the main ring via β-aminocrotonate; 2) synthesizing the main ring via acetylacetate ester; 3) the One-pot’ method involving 3-nitrobenzaldehyde, β-aminocrotonate and acetylaceate ester.
Several synthetic routes of benidipine hydrochloride and its analogues have been disclosed in EP0063365A1, EP0161877A2, JP57-171968A, EP0106275 A2, etc. Among them, EP0106275 A2 gave a summary of the synthetic pathways ofbenidipine hydrochloride. In all of the above references, it was mentioned to separate the benidipine hydrochloride prepared through column chromatography and spit it into its a and β isomers, thus obtain the therapeutically active (±)-a-benidipine hydrochloride.
In order to obtain a highly purified benidipine hydrochloride meeting pharmaceutical use, it is necessary to perform multiple recrystallization with acetone and/or ethanol. Moreover, the crystallization condition is relatively strict since it should be performed below freezing point or even below -20 °C . Furthermore, the crystallization process usually need a relatively long time (more than 24 hours).
JP2007-8819A thus disclosed a method for preparing highly purified benidipine hydrochloride meeting pharmaceutical use by first preparing the monohydrate of benidipine hydrochloride.
Because benidipine hydrochloride has a very low solubility, for dissolving in a solvent quickly, benidipine hydrochloride is often grounded into nanoparticles. CN 1794993 A provided a method to grind benidipine hydrochloride into particles of 1.0^50.0 μπι. The mechanical grinding method is performed by grinding larger particles of crystals into desired smaller size of crystals. This method consumes large amount of energy and time, and results in a widely distribution of the crystal particle size.
PEOPLE found the desired sizes of benidipinehydrochloride nanoparticles could be obtained by ultrasonic crystallization technology. Unlike the method of CN 1794993 A, the method according to the present invention obtains crystals from smaller to larger sizes. The distribution of particle sizes in the method of the present invention is relatively narrower since the solvent crystalizes rapidly and steadily in the solution. Overall, the present invention can save time and energy, and is readily for preparation. Summary of the invention
benidipine preparation are disclosed in EP0106275, after JP 2007008819 discloses the industrial preparation methods, Kyowa Hakko Kogyo Co., Japan Institute of Pharmacology at Arzneimittelforschung magazine published a hydrochloric Benidipine physical and chemical properties and stability studies Japanese Pharmacopoeia 15th edition reproduces the drug. Benidipine given above literature its infrared spectrum (IR) in 3170cm “\ 3066 cm-1, 2950cm-1, 2523cm-1, 1694cm-1, 1666cm-1, 1642cm_ \ l533cm_ \ l491cm_ \ l432cm_ \ l348cm_ \ l299cm_ \ l218cm_ \ lll6cm_ \ l088cm_ \
HPLC
Purity test of benidipine hydrochloride (area normalization method): Chromatography conditions
Detector: ultraviolet absorption detector (detection wavelength: 237nm)
Chromatography column: stainless steel column: 4.6 mm x 10 cm, with octadecylsilyl (ODS) silica as filler.
Column temperature: constant, about 25 °C
Mobile phase: mixed solution of 0.05 mol/L potassium dihydrophosphate solution (pH 3.0): methanol : tetrahydrofuran (65:27:8) Flow rate: adjusted to render the retention time of benidipine hydrochloride to be about 20 min.
Chromatogram record time: about 2 times of the peak time of benidipine hydrochloride
CLINICAL TRIALS
http://clinicaltrials.gov/show/NCT00135551
| Benidipine-based Comparison of Angiotensin Receptors, β-blockers, or Thiazide Diuretics in Hypertensive Patients | Completed | Cardiovascular Disease | February 19, 2012 |
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Solanezumab, Eli Lilly’s anti-beta-amyloid monoclonal antibody for Alzheimer’s disease
- immunoglobulin G1-kappa, anti-[Homo sapiens amyloid-beta (Abeta)
peptide soluble monomer], humanized monoclonal antibody;
gamma1 heavy chain [humanized VH (Homo sapiens IGHV3-23*04
(87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens
IGHG1*01, CH3 K130>del (113-441)], (215-219′)-disulfide with
kappa light chain (1’-219’) [humanized V-KAPPA (Homo sapiens
IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1′-112′) -Homo sapiens
IGKC*01 (113′-219′)]; (221-221″:224-224″)-bisdisulfide dimer
neuroprotective agent
C6396H9922N1712O1996S42 955085-14-0
Heavy chain / Chaîne lourde / Cadena pesada
EVQLVESGGG LVQPGGSLRL SCAASGFTFS RYSMSWVRQA PGKGLELVAQ 50
INSVGNSTYY PDTVKGRFTI SRDNAKNTLY LQMNSLRAED TAVYYCASGD 100
YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT 150
VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK 200
PSNTKVDKKV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR 250
TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV 300
LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR 350
DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF 400
LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G 441
Light chain / Chaîne légère / Cadena ligera
DVVMTQSPLS LPVTLGQPAS ISCRSSQSLI YSDGNAYLHW FLQKPGQSPR 50
LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP 100
WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150
VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200
VTHQGLSSPV TKSFNRGEC 219
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro
Intra-H 22-96 139-195 256-316 362-420
22”-96” 139”-195” 256”-316” 362”-420”
Intra-L 23′-93′ 139′-199′
23”’-93”’ 139”’-199”’
Inter-H-L 215-219′ 215”-219”’
Inter-H-H 221-221” 224-224”
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación
292, 292
Solanezumab, Eli Lilly’s anti-beta-amyloid monoclonal antibody for Alzheimer’s disease
The market for Alzheimer’s disease therapies is set to nearly triple between 2012 and 2022, despite increasing genericisation and the fact that few new product launches are expected during this time, according to new forecasts.
The key driver of growth in the AD market will be Eli Lilly’s anti-beta-amyloid monoclonal antibody solanezumab, the first potentially disease-modifying therapy (DMT) to launch for AD, according to the study, from Decision Resources. It reports that solanezumab is expected to launch in the seven major pharmaceutical markets – the US, France, Germany, Italy, Spain, the UK and Japan – starting in 2018 and that, by 2022, the drug is forecast to attain sales in excess of $5 billion in these markets.
More than 85% of solanezumab’s projected total use in 2022 will be in the mild AD market – the population in which the drug is currently being tested – followed by the pre-AD 1-2 years market segment, says the firm, which defines this latter population as those patients who will go on to develop overt AD within the next one to two years.
Solanezumab (proposed INN) is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector[1] for patients withAlzheimer’s disease.[2][3]
It binds to the amyloid-β peptides that make up the protein plaques seen in the brains of people with the disease.
2012 results of the EXPEDITION 1 & 2 phase 3 clinical trials were only mildly encouraging.[4][5][6] but were said to be the “first evidence that targeting the amyloid cascade can slow the progression of disease.”[7]
- International Nonproprietary Names for Pharmaceutical Substances (INN, prepublication copy), World Health Organization.
- ClinicalTrials.gov NCT00749216 Solanezumab Safety Study in Japanese Patients With Alzheimer’s Disease
- ClinicalTrials.gov NCT00905372 Effect of LY2062430 on the Progression of Alzheimer’s Disease (EXPEDITION)
- “Lilly’s Solanezumab Slows Down Alzheimer’s Progression”. 9 Oct 2012.
- Solanezumab Did it actually work
- “Eli Lilly’s solanezumab faces grim prospects of attaining conditional FDA approval in mild Alzheimer’s”. 4 Sep 2012.
- “ALZHEIMER’S DRUG SLOWS MEMORY LOSS BY ONE THIRD”. 10 Oct 2012.
yellow coloured SOLANEZUMAB blocks beta amyloid from aa 16 to aa 25
Amyloid precursor protein (APP)
Mitochondria-targeting Cisplatin
Cisplatin is a chemotherapy drug given to more than half of all cancer patients. The drug kills cells very effectively by damaging nuclear DNA, but if tumors become resistant to cisplatin they often grow back.
A new study from the Massachusetts Institute of Technology (MIT) and the University of Toronto offers a possible way to overcome that resistance. The researchers found that when cisplatin was delivered to cellular structures called mitochondria, DNA in this organelle was damaged, leading to cancer cell death. Moreover, the mitochondrial-targeted drug could overcome cisplatin resistance.
“These results suggest that the mitochondria can be an important target for platinum-based drugs,” said Robert Radford, an MIT postdoc and an author of a paper describing the findings in the Oct. 31 online edition of the journal Chemistry & Biology.
Mitochondria-targeting cisplatin might also be effective at lower doses than regular cisplatin, helping to avoid…
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OTC Drug (Meclizine) to Treat Infectious Diseases and Cancer
Meclizine, an over-the-counter drug used for decades to treat nausea and motion sickness, has the potential for new uses to treat certain infectious diseases and some forms of cancer, according to Vishal M. Gohil, Texas A&M AgriLife Research biochemist.
The research on meclizine appears in the current online version of the Journal of Biological Chemistry.
FDA approves Gazyva for chronic lymphocytic leukemia
Drug is first with breakthrough therapy designation to receive FDA approval
The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
read all at
http://www.pharmalive.com/fda-approves-roche-s-gazyva
my old article cut paste
Roche’s new leukaemia drug, Obinutuzumab, superior to Rituxan in clinical trial
JULY 25, 2013 12:52 AM / 6 COMMENTS / EDIT
July 24 2013 | By Márcio Barra
Roche has announced that its experimental leukemia drug GA101, or obinutuzumab, used in combination with chemotherapy, was better than Rituxan at helping people with chronic lymphocytic leukemia live longer without their disease worsening, according to the results from the second phase of the clinical trial. Both drugs were tested and compared in combination with chlorambucil.
Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results
- GA101 is the first glycoengineered, type II anti-CD20 mAb.
Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results
Obinutuzumab (GA101)
| FORMULA | C6512H10060N1712O2020S44 |
|---|
GA101 is the first glycoengineered, type II anti-CD20 monoclonal antibody (mAb) that has been designed for increased antibody-dependent cellular cytotoxicity (ADCC) and Direct CellDeath.1 This agent is being investigated in collaboration with Biogen Idec.
Swiss pharmaceutical company Roche has announced that its early Phase III trial of Leukemia drug obinutuzumab (GA101) demonstrated significantly improved progression-free survival in people with chronic lymphocytic leukemia (CLL).
The positive results yield from stage 1 of a three-arm study called CLL11, designed to investigate the efficacy and safety profile of obinutuzumab (GA101) plus chlorambucil, a chemotherapy, compared with chlorambucil alone in people with previously untreated chronic lymphocytic leukemia (CLL).
This phase of the study met its primary endpoint and an improvement in progression-free survival was achieved; obinutuzumab plus chlorambucil significantly reduced the risk of disease worsening or death compared to chlorambucil alone.
Roche chief medical officer and global product development head Hal Barron said; “the improvement in progression-free survival seen with GA101 is encouraging for people with CLL, a chronic illness of older people for which new treatment options are needed.”
“GA101 demonstrates our ongoing commitment to the research and development of new medicines for this disease.”
Obinutuzumab is Roche’s most advanced drug in development for the treatment of hematological malignancies.
It has been specifically designed as the first glycoengineered, type 2 anti-CD20 monoclonal antibody in development for B cell malignancies.
Afutuzumab is a monoclonal antibody being developed by Hoffmann-La Roche Inc. for the treatment of lymphoma.[1] It acts as an immunomodulator.[2][3] It was renamed obinutuzumab in 2009.[4]
References
- Robak, T (2009). “GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies”. Current opinion in investigational drugs (London, England : 2000) 10 (6): 588–96. PMID 19513948.
- Statement On A Nonproprietary Name Adopted By The Usan Council – Afutuzumab,American Medical Association.
- International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
- International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
-
OBINUTUZUMAB ISMONOCLONAL ANTIBODY TYPE Whole antibody SOURCE Humanized (from mouse) TARGET CD20
Biosimilar drugs in Portugal
November 1 ,2013 | By Márcio Barra
What follows is a list of Biosimilar drugs available in Portugal. This data has been compiled from the INFOMED database, managed by the Portuguese National Competent Authrority on Medicines, INFARMED. The Portuguese Marketing approval date was also provided. In the Market Status, you may find “no data” on some drugs. This means that the drug in question has no information displayed on the INFOMED database, save for its name.
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Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment
FUSIDIC ACID, 6990-06-3
2-[(1S,2S,5R,6S,7S,10S,11S,13S,14Z,15R,17R)-13-(acetyloxy)-5,17-dihydroxy-2,6,10,11-tetramethyltetracyclo[8.7.0.02,7.011,15]heptadecan-14-ylidene]-6-methylhept-5-enoic acid
Taksta (CEM-102)
Clinical-stage pharmaceutical firm Cempra has secured orphan drug status from the US Food and Drug Administration (FDA) for its drug candidate Taksta (CEM-102) to treat patients with prosthetic joint infections (PJI).
Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment
TAKSTATM (CEM-102)
Fusidic acid is a bacteriostatic antibiotic that is often used topically in creams and eyedrops, but may also be given systemically as tablets or injections. The global problem of advancing antimicrobial resistance has led to a renewed interest in its use recently.
Fusidic acid acts as a bacterial protein synthesis inhibitor by preventing the turnover ofelongation factor G (EF-G) from the ribosome. Fusidic acid is effective primarily ongram-positive bacteria such as Staphylococcus species, Streptococcus species, and Corynebacterium species. Fusidic acid inhibits bacterial replication and does not kill the bacteria, and is therefore termed bacteriostatic.
Fusidic acid is a true antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo Laboratories in Ballerup, Denmark and released for clinical use in the 1960s. It has also been isolated from Mucor ramannianus and Isaria kogana. The drug is licensed for use as its sodium salt sodium fusidate, and it is approved for use under prescription in South Korea, Japan, UK, Canada, Europe, Australia, New Zealand, Thailand, India and Taiwan. A different oral dosing regimen, based on the compound’s Pharmacokinetic/pharmacodynamic (PK-PD) profile is in clinical development in the U.S. as Taksta.
Fusidic acid (TAKSTATM, CEM-102) is an antibiotic with a long history of safety and efficacy outside the United States. Cempra has exclusive rights to the supply of the compound for the U.S. market. Fusidic acid is orally active against gram-positive bacteria, including all S. aureus strains such as HA-MRSA and CA-MRSA. A novel dosing regimen has been successfully evaluated in a Phase II trial in patients with acute bacterial skin and skin structure infections (aBSSSI). Cempra is conducting a Phase II trial of TAKSTA for patients with prosthetic joint infections.
Profile of TAKSTA (CEM-102)
Prosthetic joint infections (PJI) occur in about 1% of hip replacements and 2% of knee replacements, translating to an incidence rate of about 10,000 per year in the U.S. at current hip and knee arthroplasty rates. There are few good options to treat these serious staphylococcal, often MRSA infections, which require long-term antibiotic treatment. Current therapy in the U.S. is with intravenous antibiotics such as vancomycin. An oral drug that can be safely administered for a long period of time could improve care and quality of life for these patients.
TAKSTA has shown potent activity against a large number of S. aureus strains, including CA-MRSA, HA-MRSA and linezolid-resistant strains, isolated in the U.S over a 10 year period. Its broad S. aureus coverage makes it useful for a broad range of clinical applications. Because of its safety and tolerability profile, TAKSTA could be ideal for patients suffering from staphylococcal infections that require long-term therapy such as patients with PJIs.
Cempra has developed a unique oral loading dose regimen to optimize key pathogen coverage and minimize drug resistance development. This regimen is incorporated in our Phase II trial to treat PJIs with TAKSTA in combination with rifampin, which is commonly used with injectible antibiotics such as vancomycin to treat PJIs.
Research on TAKSTA
Publications
The links for the articles go to subscription-based sites and may require a fee to view the article.
In Vitro Activity of CEM-102 (Fusidic Acid) Against Prevalent Clones and Resistant Phenotypes of Staphylococcus aureus
DF Sahm, J Deane, CM Pillar, P Fernandes
Antimicrobial Agents and Chemotherapy. June 2013 57: 4535-4346
http://aac.asm.org/content/57/9/4535
Efforts to Support the Development of Fusidic Acid in the United States
P Fernandes, D Pereira
Clinical Infectious Disease. June 2011 52:S542-6
http://www.ncbi.nlm.nih.gov/pubmed/21546632
Case report: Treatment of Chronic Osteomyelitis
CR Wolfe
Clinical Infectious Disease. June 2011 52:S538-41
http://cid.oxfordjournals.org/content/52/suppl_7/S538.long
The Safety Record of Fusidic Acid in Non-US markets: A Focus on Skin Infections
CN Kraus, BW Burnstead
Clinical Infectious Disease. June 2011 52:S527-37
http://cid.oxfordjournals.org/content/52/suppl_7/S527.long
A Randomized, Double-Blind Phase 2 Study Comparing the Efficacy and Safety of an Oral Fusidic Acid Loading-Dose Regimen to Oral Linezolid in the Treatment of Acute Bacterial Skin and Skin Structure Infections
JC Craft, SR Moriarty, K Clark, D Scott, TP Degenhardt, JG Still, GR Corey, A Das, P Fernandes
Clinical Infectious Disease. June 2011 52:S520-26
http://cid.oxfordjournals.org/content/52/suppl_7/S520.long
Application of Pharmacokinetic-Pharmacodynamic Modeling and the Justification of a Novel Fusidic Acid Dosing Regimen: Raising Lazarus from the Dead
BT Tsuji, OO Okusanya, JB Bulitta, A Forrest, SM Bhavnani, P Fernandes, PG Ambrose
Clinical Infectious Disease. June 2011 52:S513-19
http://cid.oxfordjournals.org/content/52/suppl_7/S513.long
Pharmacokinetics and Safety of Single, Multiple, and Loading Doses of Fusidic Acid in Healthy Subjects
JG Still, K Clark, TP Degenhardt, D. Scott, P. Fernandes, M. J. Gutierrez
Clinical Infectious Disease. June 2011 52:S504-12
http://cid.oxfordjournals.org/content/52/suppl_7/S504.long
Activity of Fusidic Acid Against Extracellular and Intracellular Staphylococcus aureus: Influence of pH and Comparison with Linezolid and Clindamycin
S Lemaire, F Van Bambeke, D Pierard, PC Appelbaum, PM Tulkens
Clinical Infectious Disease. June 2011 52:S493-503
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long
Characterization of Global Patterns and the Genetics of Fusidic Acid Resistance
DJ Farrell, M Castanheira, I Chopra
Clinical Infectious Disease. June 2011 52:S487-92
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long
In Vitro Antimicrobial Findings for Fusidic Acid Tested Against Contemporary (2008-2009) Gram-Positive Organisms Collected in the United States
RN Jones, RE Mendes, HS Sader, M Castanheira
Clinical Infectious Disease. June 2011 52:S477-86
http://cid.oxfordjournals.org/content/52/suppl_7/S477.long
New Rules for Clinical Trials in Patients with Acute Bacterial Skin and Skin Structure Iinfections: Do not Let the Perfect be the Enemy of the Good
GR Corey, ME Stryjewski
Clinical Infectious Disease. June 2011 52:S469-76
http://cid.oxfordjournals.org/content/52/suppl_7/S469.long
Introduction: Fusidic Acid Enters the United States
RC Moellering, GR Corey, ML Grayson
Clinical Infectious Disease. June 2011 52:S467-8
http://cid.oxfordjournals.org/content/52/suppl_7/S467.long
Evaluation of the Pharmacokinetics-Pharmacodynamics of Fusidic Acid Against Staphylococcus aureus and Streptococcus pyogenes Using In Vitro Infection Models: Implications for Dose Selection
OO Okusanya, BT Tsuji, JB Bulitta, A Forrest, CC Bulik, SM Bhavnani, P Fernandes, PG Ambrose
Diagnostic Microbiology & Infectious Disease. June 2011 70:101-11
http://www.ncbi.nlm.nih.gov/pubmed/21513848
In Vitro Activity of Fusidic Acid (CEM-102, Sodium Fusidate) Against Staphylococcus aureus Isolated from Cystic Fibrosis Patients and its Effect on the Activities of Tobramycin and Amikacin against Pseudomonas aeruginosa and Burkholderia cepacia
P McGhee, K Credito, L Beachel, PC Appelbaum, K Kosowaska-Shick
Antimicrobial Agents and Chemotherapy. June 2011 55:2417-19
http://www.ncbi.nlm.nih.gov/pubmed/21513848
Occurrence and Molecular Characterization of Fusidic Acid Resistance Mechanisms Among Staphylococcus spp. From European Countries (2008)
Castanheira, M., AA Watters, RE Mendes, DJ Farrell, RN Jones
Antimicrobial Agents and Chemotherapy. April 2010 65:1353-8
http://jac.oxfordjournals.org/content/65/7/1353.long
Update on Fusidic Acid (CEM-102) Tested Against Neisseria gonorrhoeae and Chlamydia trachomatis
R Jones, D Biedenbach, P Roblin, S Kohlhoff, M Hammerschlag
Antimicrobial Agents and Chemotherapy. October 2010 54: 4518-4519
http://aac.asm.org/cgi/content/citation/54/10/4518
Fusidic Acid Resistance Rates and Prevalence of Resistance Mechanisms Among Staphylococcus spp. Isolated in North America and Australia, 2007-2008
M Castanheira, AA Watters, JM Bell, JD Turnidge, RN Jones
Antimicrobial Agents and Chemotherapy. September 2010 54: 3614-3617
http://www.ncbi.nlm.nih.gov/pubmed/20566766
Spectrum of Activity, Mutation Rates, Synergistic Interactions, and the Effects of pH and Serum Proteins for Fusidic Acid (CEM-102)
D Biedenbach, P Rhomberg, R Mendes, R Jones
Diagnostic Microbiology & Infectious Disease. March 2010 66: 301-307
http://www.dmidjournal.com/article/S0732-8893(09)00424-6/abstract
Performance of Fusidic Acid (CEM-102) Susceptibility Testing Reagents: Broth Microdilution, Disk Diffusion, and Etest Methods as Applied to Staphylococcus aureus
R Jones, M Castanheira, P Rhomberg, L Woosley, M Pfaller
Journal of Clinical Microbiology. March 2010 48: 972-976
http://jcm.asm.org/cgi/content/abstract/48/3/972
Evaluation of the Activity of Fusidic Acid Tested Against Contemporary Gram-Positive Clinical Isolates From the USA and Canada
M Pfaller, M Castaneira, H Sader, R Jones
International Journal of Antimicrobial Agents. March 2010 35: 282-287
http://www.ijaaonline.com/article/S0924-8579(09)00510-X/abstract
Quantitative and qualitative assessment of antibiotic activity against Staphylococcus aureus biofilm.
Siala, W., M. P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke.
Abstr. 6th Am. Soc. Microbiol. Conf. Biofilms, abstr A-179.
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Activity of Fusidic Acid Against Methicillin-resistant Staphylococcus Aureus (MRSA) Isolated from CF Patients
Prabhavathi Fernandes, Donald Anderson, K. Kosowska-Shick, P. McGhee, L. Beachel and P.C. Appelbaum
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Evaluation of L6 Ribosomal Protein Alterations in Fusidic Acid-Resistant Staphylococcus aureus: Fitness Cost and Time Kill Analysis
M Castanheira, RN Jones, LN Woosley, RE Mendes, GJ Moet, DJ Farrell
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Fusidic Acid Activity and Coverage of Gram-positive Pathogens Associated with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the USA (2008-2010)
RN Jones, DJ Farrell, HS Sader, M Castanheira
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Activity of Fusidic Acid Tested Against Contemporary Staphylococcus aureus Collected from United States Hospitals
M. Castanheira, R.E. Mendes, P.R. Rhomberg, R.N. Jones
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Pharmacokinetics-Pharmacodynamics (PK-PD) of CEM- 102 (Sodium Fusidate) Against Streptococcus pyogenes Using In Vitro Pharmacodynamic Models (IVPM)
B. T. Tsuji, A. Forrest, P. A. Kelchlin, T. Brown, P. N. Holden, O. O. Okusanya, S. M. Bhavnani, P. Fernandes, P. G. Ambrose
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Activity of CEM-102 (sodium fusidate) against 40 MRSA from Cystic Fibrosis Patients
Cynthia Todd, Pamela Mcghee, and Peter Appelbaum
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Ability of CEM-102 (Fusidic Acid), Linezolid, Daptomycin to Select Resistant S.aureus Mutants at Steady-state Serum Levels
K. Kosowska-Shick, P. Mcghee, L. Beachel, P. C. Appelbaum;
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CEM-102 (Fusidic Acid) Maintains Potency against Resistant MRSA and Prevalent Hospital Acquired, Community Acquired,and Epidemic MRSA Clones
C.M. Pillar, M.K. Torres, D.F. Sahm and P. Fernandes
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In Vitro Activity Of Fusicic Acid (CEM-102) Against Resistant Strains Of Staphylococcus aureus
J. dubois, P. Fernandes
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Trade names and preparations
- Fucidin (of Leo in Canada and the US)
- Fucidin H (topical cream with corticosteroid – Leo)
- Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India)
- Fucidine (of Leo in France)
- Fucidin (of Leo in Norway)
- Fucidin (of Adcock Ingram, licenced from Leo, in South Africa)
- Fucithalmic (of Leo in the UK, the Netherlands, Denmark and Portugal)
- Fucicort (topical mixture with hydrocortisone)
- Fucibet (topical mixture with betamethasone)
- Ezaderm (topical mixture with betamethasone)(of United Pharmaceutical “UPM” in Jordan)
- Fuci (of pharopharm in Egypt)
- Fucizon (topical mixture with hydrocortisone of pharopharm in Egypt)
- Foban (topical cream in New Zealand)
- Betafusin (cream mixture with betamethasone valerate in Greece)
- Fusimax (of Schwartz in India)
- Fusiderm (topical cream and ointment by indi pharma in India)
- Fusid (in Nepal)
- Fudic (topical cream in India)
- Fucidin (후시딘, of Dong Wha Pharm in South Korea)
- Stanicid (in Serbia)
- Dermy (Topical cream of W.Woodwards in Pakistan)
- Fugen Cream (膚即淨軟膏 in Taiwan)
- Phudicin Cream (in China; 夫西地酸[24])
- Dermofucin cream ,ointment and gel (in Jordan)
- Optifucin viscous eye drops (of API in Jordan)
- Verutex (of Roche in Brazil)
- TAKSTA (of Cempra in U.S.)
- Futasole (of Julphar in Gulf and north Africa)
- Stanicid (2% ointment of Hemofarm in Serbia)
- Fuzidin (tablets of Biosintez in Russia)
- Fuzimet (ointment with methyluracil of Biosintez in Russia)
- Axcel Fusidic Acid(2% cream and ointment of Kotra Pharma, Malaysia)
MORE INFO
Fusidic acid (FA) is a tetracyclic triterpenoid or fusidane (steroidal) antibiotic derived from the fungus Fusidium coccineum that inhibits bacterial protein synthesis. FA is effective against gram-positive bacteria such as Staphylococcusspecies and Corynebacterium species (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005)). FA also has moderate activity against Group A beta-hemolytic streptococci, or Streptococcus pyogenes (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, inAntimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Skov et al., Diag. Micro. Infect. Dis. 40:111-116 (2001)).
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Fusidic acid, chemically (3α, 4α, 8α, 9α, 11α, 13α, 14α, 16α, 17Z)-16-(Acetyloxy)-3,11-dihydroxy-29-nordammara-17(20), 24-dien-21-oic acid, is an antibacterial agent. It is a well-known antibiotic with a unique steroid-like tetracyclic ring system structure, and it is the most potent of a small family of steroidal antibiotics, the fusidanes. It is produced by fermentation under controlled conditions of the fungus Fusidium Coccineum.
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The excellent distribution in various tissues, low degree of toxicity and allergic reactions and the absence cross-resistance with other clinically used antibiotics has made fusidic acid a highly valuable antibiotic,especially for skin and eye infections. The drug is used clinically both in its acid form, and as the sodium salt (Fusidin®), however Fusidin® is more favored one because of its better solubility in water, enabling a fast absorption from gastro-intestinal tract. As a result, it is more preferable to use sodium salt of fusidin in oral solid forms.
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Fusidin® has the actions and uses of fusidic acid, and it has been shown that it ameliorates the course of several organ-specific immuno-inflammatory diseases such as chronic uveitis, Behcet’s disease, type I diabetes mellitus, Guillain-Barre syndrome, hepatitis, sepsis, pancreatitis, formalin-induced edema, multiple sclerosis, and scleroderma, whereby fucidin formulations have a great importance in pharmaceutical production.
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Fusidin® can be presented in various formulations that differ significantly in their pharmacokinetic behaviors such as oral tablets, oral suspensions, intravenous formulations and topical preparation. Considering oral tablets, many of the early clinical studies were performed with capsule containing sodium fusidate. This was also the formulation marketed for many years in several countries. It is currently available as an oral tablet containing the sodium salt. Originally the sodium salt was available as an enteric-coated form but later it was reformulated as a film-coated tablet that appears to be better tolerated and gives higher blood levels.
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Fusidic acid sodium salt was used in capsules as well as in tablets which were coated enterically. However by this enteric coating, the active fusidic acid sodium salt was not released before the tablets reached the part of the gastrointestinal tract in which the enteric coating would be dissolved. Depending on the time of passage through the stomach together with the food and the pH in the gastrointestinal tract, this led to unpredictable variations in the blood concentration of the patient undergoing treatment. Because of these adverse differences in blood concentration, the tablets without enteric coating were produced. Now, sodium fusidate is available in tablet, oral solution and injection form
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PCT/WO9603128 A (LEO PHARMACEUTICALS PRODUCTS LTD. ET.AL.) describes the preparation of fusidic acid sodium salt tablets without an enteric coating by using dry granulation method in which a roller compactor was used. The compacted material so produced was size reduced to form a granulate having a bulk density in the range 0.45 to 0.9 g/m3 which was then formed into tablets.
FA was developed for clinical use in the 1960s and it is approved for human use outside of the United States, such as in the UK, Canada, Europe, Israel, Australia and New Zealand. It is typically prescribed at doses of 500 mg TID for treating skin and skin structure infections caused by Staphylococcus aureus (A. Bryskier,Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals(Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Collignon et al., Int’l J. Antimicrobial Agents 12:S45-S58 (1999); D. Spelman, Int’l J. Antimicrobial Agents 12:S59-S66 (1999)), although some physicians have routinely prescribed the compound at 500 mg BID for treating skin and skin structure infections due to the long half-life of the compound (Fusidic Acid, in Principles and Practice of Infectious Diseases, 6th ed. (Mandell et al. eds., Elsevier, 2006)).
Treatment using FA has been well studied and it is generally regarded as safe when administered to humans, as evidenced by the fact that the drug has been in continuous use for more than 40 years. There are, however, several characteristics of FA that have prevented use of the drug against a wider spectrum of bacteria and in the treatment in additional types of infection. For example, approved dosing regimens have been shown to select for bacterial resistance, such as in S. aureus. Approved dosing regimens provide low multiples of the MIC and as a result, S. aureus resistant mutants can be selected after the first day of dosing. Once resistance has developed, FA is not effective against the resistant strains. Resistance is reported to occur if FA is used as a single drug as the resistance frequency at 4 and 8 times the MIC is in the range of 10−6 or 10−8 (Evans et al., J. Clin. Path. 19:555-560 (1966); Hansson et al., J. Mol. Biol.348:939-949 (2005), Jensen et al., Acta Pathol Microbiol Scand. 60:271-284 (1964); Besier et al., Antimicrob. Agents Chemo., 49(4):1426-1431 (2005); Gemmell et al., J. Antimicrobial Chemo. 57:589-608 (2006)).
The dosage of the drug cannot be simply increased as a means of avoiding development of resistance. It is difficult to achieve high concentrations of FA in the blood due to the substantial protein binding of the drug (approximately 95-97%) (K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Coutant et al., Diagn Microbiol Infect Dis 25:9-13 (1996); D. Reeves, J. Antimicrob. Chemo. 20:467-476 (1987); J. Turnidge, Int’l J. Antimicrobial Agents12:S23-S34 (1999); Rieutord et al., Int’l J. Pharmaceutics 119:57-64 (1995)). Moreover, high dosages of FA are not well-tolerated by patients receiving the drug. High doses of FA (e.g., 1 gram TID) are required if the drug is to be used in the treatment of bone and joint infections, less susceptible bacteria and other serious infections. However, treatment regimens using high doses of the drug induce nausea and vomiting and are rejected by patients (Fusidic Acid, inPrinciples and Practice of Infectious Diseases, 6th ed. (Mandell et al. eds., Elsevier, 2006); K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Nordin et al., Eur. J. Clin. Res. 5:97-106 (1994)).
In view of the tremendous costs associated with the de novo development of new anti-bacterials, expanding the indications for drugs that have already been demonstrated to be safe and effective is strongly needed. Overcoming the limitations on the uses of FA would broaden the population of bacterial infections against which it could be used and thus meet this need.
In a specific commercial pharmaceutical formulation, fusidic acid is presently marketed [see Monographs in the European Pharmacopeia 5.0] as a hemihydrate, which is the only hemihydrate form which has been described.
Patent GB 930,786 discloses salts of fusidic acid with organic and inorganic bases, solvates of fusidic acid, namely a benzene solvate and a methanol solvate. This patent further discloses an unspecified fusidic acid form with IR absorption bands (KBr) at 1265, 1385, 1695, 1730 and 3450 cm“1 and having a specific rotation [α]D 22 of minus 9 degrees (1% solution in CHCI3) obtainable by crystallisation of the methanol solvate of fusidic acid from ether. However, this form is distinct from the form of the present invention evident from the depicted IR spectrum in GB 930,786 which indicates that this form actually corresponds to the presently marketed hemihydrate form.
Solvates and salts of fusidic acid have also been disclosed in British patent GB 999,794. Patent ES 2208110 discloses two solvent free crystalline forms offusidic acid called Form I and Form II, and a crystalline hemihydrate called Form III which is identical to the presently marketed hemihydrate, respectively. The crystalline forms were identified and characterised by IR spectroscopy, differential scanning calorimetry, X-ray diffraction and melting points.
Patent WO 96/03128 discloses tablets containing a sodium salt form of fusidicacid and WO 86/03966 describes an ophthalmic gel composition comprising an undefined form of suspended fusidic acid.
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