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Janssen signs licensing agreement with PATH for development of HIV-1 drug



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Janssen R&D Ireland has signed a licensing agreement with PATH for the early development of a long-acting depot formulation of the human immunodeficiency virus type 1 (HIV-1) drug rilpivirine.

Rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is being developed as potential pre-exposure prophylaxis against HIV infection


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Rilpivirine (TMC278, trade name Edurant) is a pharmaceutical drug, developed by Tibotec, for the treatment of HIVinfection.[1][2] It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-lifeand reduced side-effect profile compared with older NNRTIs, such as efavirenz.[3][4]

Rilpivirine entered phase III clinical trials in April 2008,[5][6] and was approved for use in the United States in May 2011.[7] A fixed-dose drug combining rilpivirine with emtricitabine and tenofovir, was approved by the U.S. Food and Drug Administration in August 2011 under the brand name Complera.[8]

Like etravirine, a second-generation NNRTI approved in 2008, rilpivirine is a diarylpyrimidine (DAPY). Rilpivirine in combination with emtricitabine and tenofovir has been shown to have higher rates of virologic failure than Atripla in patients with baseline HIV viral loads greater than 100,000 copies.

  1.  “TMC278 – A new NNRTI”. Tibotec. Retrieved 2010-03-07.
  2.  Stellbrink HJ (2007). “Antiviral drugs in the treatment of AIDS: what is in the pipeline ?”. Eur. J. Med. Res. 12 (9): 483–95.PMID 17933730.
  3.  Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Béthune MP, Peeters M, Woodfall B (2006).“Short-term antiviral activity of TMC278–a novel NNRTI–in treatment-naive HIV-1-infected subjects”AIDS 20 (13): 1721–6.doi:10.1097/01.aids.0000242818.65215.bdPMID 16931936.
  4.  Pozniak A, Morales-Ramirez J, Mohap L et al. 48-Week Primary Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy in ART-naïve Patients. Oral abstract 144LB.
  5. A Clinical Trial in Treatment naïve HIV-1 Patients Comparing TMC278 to Efavirenz in Combination With Tenofovir + Emtricitabine
  6. A Clinical Trial in Treatment naïve HIV-Subjects Patients Comparing TMC278 to Efavirenz in Combination With 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
  7.  “FDA approves new HIV treatment”. FDA. Retrieved 2011-05-20.
  8.  “Approval of Complera: emtricitabine/rilpivirine/tenofovir DF fixed dose combination”. FDA. August 10, 2011.
  • Rilpivirine hydrochloride, 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) and indicated for the treatment of HIV-1 infection in treatment-naïve adult patients in combination with other antiretroviral agents. The product received marketing approval in the US (brand name Edurant) and is represented by the following general formula (I):

    Figure imgb0001
  • [0003]
    EP1419152 B1 claims amongst others Rilpivirine base and Rilpivirinehydrochloride per se as well as pharmaceutical compositions comprising the same. However, only concrete examples for preparingRilpivirine base are given in said patent but no concrete examples describing the production of the hydrochloride salt are provided.
  • [0004]
    EP1632232 B1 claims amongst others a solid pharmaceutical composition comprising crystalline forms A, B, C or D of Rilpivirinehydrochloride. In addition said patent claims a process for the production of Rilpivirine hydrochloride by reacting Rilpivirine base with hydrochloric acid in the presence of a suitable acid, such as acetic acid.
  • [0005]
    Polymorphism is a phenomenon relating to the occurrence of different crystal forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and varying in physical properties like melting point, XRPD pattern and FTIR spectrum. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up, however they may have distinct advantageous physical properties such as e.g. chemical stability, physical stability, hygroscopicity, solubility, dissolution rate, bioavailability, etc.
  • [0006]
    The bioavailability of a compound intended to be administered orally, is dependent on the compounds solubility in aqueous systems as well as the compounds permeability as mentioned in EP1632232 B1 . Hydrates are known to be less soluble in aqueous systems than anhydrous forms of the same compound. Hence anhydrous forms of Rilpivirinehydrochloride are preferred over hydrated forms. Rilpivirinehydrochloride form D of EP1632232 B1 is a hydrate and thus no suitable candidate for the preparation of an orally administered medicament, whereas form E of the present invention is an anhydrate.
  • [0007]
    The novel polymorph E of Rilpivirine hydrochloride of the present invention shows high solubility in aqueous systems e.g. a higher solubility than forms A and C of EP1632232 B1 and is thus especially suitable for the preparation of an orally administered medicament.
  • [0008]
    In addition the crystalline forms A and C of EP1632232 B1 are difficult to make in a reliable manner as these forms are obtained from the same solvent system. As the polymorphs A and C of Rilpivirinehydrochloride are obtainable from the same solvent system acetic acid/water, the production processes are especially critical and sensitive because the single crystalline forms are only obtainable in pure form in a quite narrow range of temperature as described in the concrete examples A.a) and A.c) of EP1632232 B1 . In contrast form E of the present invention is reliably obtained by crystallization from ethanol as form E is the only polymorph of Rilpivirine hydrochloride obtained from this solvent system.
  • [0009]
    According to example A.b) of EP1632232 B1 form B is obtained by recrystallizing Rilpivirine hydrochloride from propanone using an initial Rilpivirine hydrochloride concentration of 0.3 g/L. However, this concentration is not suitable for up-scaling as larger amounts of Rilpivirine hydrochloride would ask for tremendous solvent volumina and hence the usage of tremendously large reaction vessels. In contrast form E of the present invention is also obtained by applying higher initial Rilpivirine hydrochloride concentrations such as e.g. ≥10 g/L and is thus suitable for large scale production.
  • [0010]
    Hence, aim of the present invention is to circumvent the drawbacks of the known forms A, B, C and D ofEP1632232 B1 by providing an anhydrous polymorph of Rilpivirine hydrochloride, which is obtainable in an easy and reliable manner also in large scale. In addition the novel polymorph shows high solubility in aqueous systems making it especially suitable for the preparation of an orally administered medicament.







  1. medchemnintabelle says:

    Reblogged this on MedCheminAustralia.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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