US20040224916A1 - Compositions and methods for combination antiviral therapy - Google Patents

Compositions and methods for combination antiviral therapy Download PDF

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US20040224916A1
US20040224916A1 US10/757,122 US75712204A US2004224916A1 US 20040224916 A1 US20040224916 A1 US 20040224916A1 US 75712204 A US75712204 A US 75712204A US 2004224916 A1 US2004224916 A1 US 2004224916A1
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emtricitabine
physiologically functional
functional derivative
combination
amino
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Terrance Dahl
Mark Menning
Reza Oliyai
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Gilead Sciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates generally to combinations of compounds with antiviral activity and more specifically with anti-HIV properties. In particular, it relates to chemically stable combinations of structurally diverse anti-viral agents.
  • HIV-1 Human immunodeficiency virus type 1
  • RT reverse transcriptase
  • Prt protease
  • Int integrase
  • drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J. Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001).
  • HIV-1 protease Prt
  • the HIV Prt cleaves the viral Gag and Gag-Pol polyproteins to produce viral structural proteins (p17, p24, p7 and p6) and the three viral enzymes.
  • Combination therapy with RT inhibitors has proven to be highly effective in suppressing viral replication to unquantifiable levels for a sustained period of time. Also, combination therapy with RT and Prt inhibitors (PI) have shown synergistic effects in suppressing HIV replication.
  • AZT zidovudineTM, 3′-azido, 3′-deoxythymidine
  • AZT demonstrates synergistic antiviral activity in vitro in combination with agents that act at HIV-1 replicative steps other than reverse transcription, including recombinant soluble CD4 castanospermine and recombinant interferon- ⁇ .
  • agents that act at HIV-1 replicative steps other than reverse transcription including recombinant soluble CD4 castanospermine and recombinant interferon- ⁇ .
  • combinations of compounds can give rise to increased cytotoxicity.
  • AZT and recombinant interferon- ⁇ have an increased cytotoxic effect on normal human bone marrow progenitor cells.
  • the present invention provides combinations of antiviral compounds, in particular compositions and methods for inhibition of HIV.
  • the invention includes a combination of GS-7340 and emtricitabine which has anti-HIV activity.
  • the combination of GS-7340 and emtricitabine is both chemically stable and either synergistic and/or reduces the side effects of one or both of GS-7340 and emtricitabine. Increased patient compliance is likely in view of the lower pill burden and simplified dosing schedule.
  • the present invention relates to therapeutic combinations of 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine), and their use in the treatment of HIV infections including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors.
  • the present invention is also concerned with pharmaceutical compositions and formulations of said combinations of GS-7340 and emtricitabine.
  • Another aspect of the invention is a pharmaceutical formulation comprising a physiologically functional derivative of GS-7340 or a physiologically functional derivative of emtricitabine, including FTC and 3TC.
  • FTC is 4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one and includes all diastereomers, enantiomers, and mixtures thereof, in any proportion.
  • FTC includes the single enantiomer emtricitabine.
  • Therapeutic combinations and pharmaceutical compositions and formulations of the invention include the combination of phosphonamidate PMEA or PMPA compounds with FTC or (2R,5S,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC, Lamivudine, EpivirTM), and their use in the treatment of HIV infections.
  • One aspect of the invention is a method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to, i.e. treating, said animal with a therapeutically effective amount of a formulation comprising 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340) or a physiologically functional derivative thereof, and (2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or a physiologically functional derivative thereof.
  • GS-7340 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]
  • Another aspect of the invention is a unit dosage form of a therapeutic combination comprising GS-7340 and emtricitabine, or physiological functional derivatives thereof.
  • the unit dosage form may be formulated for administration by oral or other routes and is unexpectedly chemically stable in view of the properties of the structurally diverse components.
  • Another aspect of the invention is directed to a chemically stable combination antiviral compositions comprising GS-7340 and emtricitabine.
  • the chemically stable combinations of GS-7340 and emtricitabine further comprise a third antiviral agent.
  • the unique chemical stability of GS-7340 and emtricitabine is taken advantage of in order to enable the combination with the third antiviral agent.
  • Particularly useful third agents include, by way of example and not limitation, those of Table A.
  • the third component is an agent approved for antiviral use in humans, more preferably, it is an NNRTI or a protease inhibitor (PI), more preferably yet, it is an NNRTI.
  • the invention is directed to a combination of the chemically stable mixture of GS-7340 and emtricitabine together with efavirenz.
  • Another aspect of the invention is a patient pack comprising at least one, typically two, and optionally, three active ingredients selected from GS-7340, emtricitabine, and other antiviral agents, and an information insert containing directions on the use of GS-7340 and emtricitabine together in combination.
  • Another aspect of the invention is a process for preparing the combinations hereinbefore described, which comprises bringing into association GS-7340 and emtricitabine of the combination in a medicament to provide an antiviral effect.
  • a combination of the present invention in the manufacture of a medicament for the treatment of any of the aforementioned viral infections or conditions.
  • chemical stability means that the two primary antiviral agents in combination are substantially stable to chemical degradation. Preferably, they are sufficiently stable in physical combination to permit commercially useful shelf life of the combination product.
  • “chemically stable” means that a first component of the mixture does not act to degrade a second component when the two are brought into physical combination to form a pharmaceutical dosage form. More typically, “chemically stable” means that the acidity of a first component does not catalyzes or otherwise accelerate the acid decomposition of a second component.
  • “chemically stable” means that GS-7340 is not substantially degraded by the acidity of emtricitabine.
  • “Substantially” in this context means at least about less than about 10%, preferably less than about 1%, more preferably less than about 0.1%, more preferably yet, less than about 0.01% acid degradation of GS-7340 over a 24-hour period when the products are in a pharmaceutical dosage form.
  • synergy and “synergistic” mean that the effect achieved with the compounds used together is greater than the sum of the effects that results from using the compounds separately, i.e. greater than what would be predicted based on the two active ingredients administered separately.
  • a synergistic effect may be attained when the compounds are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • a synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
  • physiologically functional derivative means a pharmaceutically active compound with equivalent or near equivalent physiological functionality to GS-7340 or emtricitabine when administered in combination with another pharmaceutically active compound in a combination of the invention.
  • physiologically functional derivative includes any physiologically acceptable salt, ether, ester, prodrug, solvate, stereoisomer including enantiomer, diastereomer or stereoisomerically enriched or racemic mixture, and any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.
  • Bioavailability is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.
  • the compounds of the combinations of the invention may be referred to as “active ingredients” or “pharmaceutically active agents.”
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s).
  • Prodrug moiety means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. A “prodrug” is thus a covalently modified analog of a therapeutically-active compound.
  • Alkyl means a saturated or unsaturated, branched, straight-chain, branched, or cyclic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne.
  • Typical alkyl groups consist of 1-18 saturated and/or unsaturated carbons, such as normal, secondary, tertiary or cyclic carbon atoms.
  • Examples include, but are not limited to: methyl, Me (—CH 3 ), ethyl, Et (—CH 2 CH 3 ), acetylenic (—C ⁇ CH), ethylene, vinyl (—CH ⁇ CH 2 ), 1-propyl, n-Pr, n-propyl (—CH 2 CH 2 CH 3 ), 2-propyl, i-Pr, i-propyl (—CH(CH 3 ) 2 ), allyl (—CH 2 CH ⁇ CH 2 ), propargyl (—CH 2 C ⁇ CH), cyclopropyl (—C 3 H 5 ), 1-butyl, n-Bu, n-butyl (—CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl, i-Bu, i-butyl (—CH 2 CH(CH 3 ) 2 ), 2-butyl, s-Bu, s-butyl (—CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl, t-Bu
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group 6 to 20 carbon atoms e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • Substituted alkyl mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a substituent.
  • Heteroaryl and “Heterocycle” refer to a ring system in which one or more ring atoms is a heteroatom, e.g. nitrogen, oxygen, and sulfur. Heterocycles are described in: Katritzky, Alan R., Rees, C. W., and Scriven, E. Comprehensive Heterocyclic Chemistry (1996) Pergamon Press; Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry W. A. Benjamin, New York, (1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28.
  • heterocycles include but are not limited to substituents, i.e. radicals, derived from pyrrole, indole, furan, benzofuran, thiophene, benzothiophene, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-imidazole, 4-imidazole, 3-pyrazole, 4-pyrazole, pyridazine, pyrimidine, pyrazine, purine, cinnoline, pthalazine, quinazoline, quinoxaline, 3-(1,2,4-N)-triazolyl, 5-(1,2,4-N)-triazolyl, 5-tetrazolyl, 4-(1-0,3-N)-oxazole, 5-(1-0,3-N)-oxazole, 4-(1-S, 3-N)-thiazole, 5-(1-S, 3-N)-thiazole, 2-benz
  • R and S, d and l or (+) and ( ⁇ ) are employed to designate the sign of rotation of plane-polarized light by the compound, with ( ⁇ ) or 1 or S meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d or R is dextrorotatory.
  • stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer is also referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the present invention provides novel combinations of two or more active ingredients being employed together.
  • a synergistic antiviral effect is achieved.
  • a chemically stable combination is obtained.
  • the combinations include at least one active ingredient selected from (1) GS-7340 and physiologically functional derivatives, and at least one active ingredient selected from (2) emtricitabine and physiologically functional derivatives.
  • the term “synergistic antiviral effect” is used herein to denote an antiviral effect which is greater than the predicted purely additive effects of the individual components (a) and (b) of the combination.
  • GS-7340 is an antiviral prodrug known as: 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine, and has the structure:
  • CAS Registry Numbers for GS-7340 include: 379270-37-8 and for GS-7340 fumarate include: 379270-38-9.
  • the prodrug GS-7340 is the subject of commonly owned, pending application, U.S. Ser. No. 09/909,560, filed Jul. 20, 2001 and Becker et al WO 02/08241.
  • GS-7340 is an isopropyl alanyl phosphonamidate, phenyl ester prodrug of tenofovir (PMPA).
  • GS-7340 is active against both cowpox and vaccinia viruses at concentrations of 20 to 100 ⁇ M. GS-7340 is 1000 times more effective than tenofovir against HIV in culture. GS-7340 has an S-configuration at the phosphorus. This S-configuration diastereomer is 10-fold more effective than the diastereomer with the R-configuration (Nucleosides, Nucleotides and Their Biological Applications—XIV International Roundtable (Part II), San Francisco, Calif., USA).
  • GS-7340 was effective against HIV and HBV in a variety of cell types.
  • the most potent compounds displayed an EC50 value of 0.0008 ⁇ M against HIV, and a half-life of 103 min in plasma.
  • the prodrugs have demonstrated oral bioavailability, stability and ability to rapidly convert to tenofovir inside lymphatic cells.
  • GS-7340 is 100-fold more effective than tenofovir against HIV in culture, and the diastereomer with an S-configuration at the P group is 10-fold more effective than that with an R-configuration.
  • GS-7340 is in phase I/II trials for the potential treatment of HIV and other viral infections.
  • GS-7340 includes all combinations of stereochemistry at the three designated centers as well as all diasteromeric and racemic mixtures. Examples include R,R,R; R,R,S; R,S,R; S,R,R; R,S.S; S,R.S; S,S,R; and S,S,S compounds and their racemic, enantiomerically enriched and partially racemic mixtures.
  • PMPA U.S. Pat. Nos. 4,808,716, 5,733,788, 6057305
  • the chemical names of PMPA include: (R)-9-(2-phosphonylmethoxypropyl)adenine; and phosphonic acid, [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl].
  • the CAS Registry number is 147127-20-6.
  • Physiologically functional derivatives of GS-7340 include phosphonamidate PMEA (adefovir, 9-((R)-2-(phosphonomethoxy)ethyl)adenine) and PMPA compounds.
  • exemplary combinations include a phosphonamidate PMEA or PMPA compound in combination with emtricitabine or a physiologically functional derivative.
  • Phosphonamidate PMEA and PMPA compounds have the structures:
  • R 6 and R 8 are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 6 -C 20 arylalkyl, C 6 -C 20 substituted arylalkyl.
  • R 7 is the side chain of any naturally-occurring or pharmaceutically acceptable amino acid and which, if the side chain comprises carboxyl, the carboxyl group is optionally esterified with an alkyl or aryl group.
  • R 7 may be H, CH 3 or CH(CH 3 ) 2 .
  • R 11 is amino, alkylamino, oxo, or dialkylamino.
  • R 12 is amino or H. Exemplary embodiments include where R is methyl, R 6 is phenyl, and R 8 is methyl, ethyl, or isopropyl.
  • Phosphonamidate PMEA and PMPA compounds may be prepared from the corresponding dialkyl phosphonates which may be prepared according to the methods of: Quast et al (1974) Synthesis 490; Stowell et al (1990) Tetrahedron Lett. 3261; U.S. Pat. No. 5,663,159.
  • the phosphonamidate PMEA and PMPA compound may be enantiomerically-enriched or purified (single stereoisomer) where the carbon atom bearing R 5 may be the R or S enantiomer when R 5 is not H.
  • the phosphonamidate PMEA and PMPA compound may be a racemate, i.e. a mixture of R and S stereoisomers.
  • the invention includes all enantiomers, diastereomers, racemates, and enriched stereoisomer mixtures of phosphonamidate PMEA and PMPA compounds.
  • Emtricitabine ( ⁇ )-cis-FTC, EmtrivaTM), a single enantiomer of FTC, is a potent nucleoside reverse transcriptase inhibitor approved for the treatment of HIV (U.S. Pat. Nos. 5,047,407, 5,179,104, 5,204,466, 5,210,085, 5,486,520, 5,538,975, 5,587,480, 5,618,820, 5,763,606, 5,814,639, 5,914,331, 6,114,343, 6,180,639, 6,215,004; WO 02/070518).
  • the single enantiomer emtricitabine has the structure:
  • the chemical names for emtricitabine include: ( ⁇ )-cis-FTC; ⁇ -L-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane; (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine; and 4-amino-5-fluoro-1-(2-hydroxymethyl-[1,3]-(2R,5S)-oxathiolan-5-yl)-1H-pyrimidin-2-one.
  • the CAS Registry numbers include: 143491-57-0; 143491-54-7.
  • FTC contains two chiral centers, at the 2 and 5 positions of the oxathiolane ring, and therefore can exist in the form of two pairs of optical isomers (i.e. enantiomers) and diastereomeric and racemic mixtures thereof.
  • FTC may be either a cis or a trans isomer or mixtures thereof. Mixtures of cis and trans isomers are diastereomers with different physical properties. Each cis and trans isomer can exist as one of two enantiomers or mixtures thereof including racemic mixtures.
  • the invention includes all enantiomers, diastereomers, racemates, and enriched stereoisomer mixtures of emtricitabine, and physiologically functional derivatives thereof.
  • the invention includes physiological functional derivatives such as the 1:1 racemic mixture of the enantiomers (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) and its mirror image (2S, 5R, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, or mixtures of the two enantiomers in any relative amount.
  • the invention also includes mixtures of cis and trans forms of FTC.
  • GS-7340 and emtricitabine may exist in keto or enol tautomeric forms and the use of any tautomeric form is within the scope of this invention.
  • GS-7340 and emtricitabine will normally be utilized in the combinations of the invention substantially free of the corresponding enantiomer, that is to say no more than about 5% w/w of the corresponding enantiomer will be present.
  • Physiologically functional derivatives of emtricitabine include 1,3 oxathiolane nucleosides having the structure:
  • B is a nucleobase including any nitrogen-containing heterocyclic moiety capable of forming Watson-Crick hydrogen bonds in pairing with a complementary nucleobase or nucleobase analog, e.g. a purine, a 7-deazapurine, or a pyrimidine.
  • a complementary nucleobase or nucleobase analog e.g. a purine, a 7-deazapurine, or a pyrimidine.
  • B include the naturally occurring nucleobases: adenine, guanine, cytosine, uracil, thymine, and minor constituents and analogs of the naturally occurring nucleobases, e.g.
  • Nucleobases B may be attached in the configurations of naturally-occurring nucleic acids to the 1,3 oxathiolane moiety through a covalent bond between the N-9 of purines, e.g. adenin-9-yl and guanin-9-yl, or N-1 of pyrimidines, e.g. thymin-1-yl and cytosin-1-yl (Blackburn, G. and Gait, M. Eds. “DNA and RNA structure” in Nucleic Acids in Chemistry and Biology, 2 nd Edition, (1996) Oxford University Press, pp. 15-81).
  • purines e.g. adenin-9-yl and guanin-9-yl
  • N-1 of pyrimidines e.g. thymin-1-yl and cytosin-1-yl
  • R is H, C 1 -C 18 alkyl, C 2 l-C 18 substituted alkyl, C 2 -C 18 alkenyl, C 2 -C 18 substituted alkenyl, C 2 -C 18 alkynyl, C 2 -C 18 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocycle, C 2 -C 20 substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy, or a prodrug moiety
  • Physiologically functional derivatives of emtricitabine also include 3TC (lamivudine, Epivir®), a reverse transcriptase inhibitor approved in the United States for the treatment of HIV-1 infection in combination with AZT (Zidovudine) as Combivir® (GlaxoSmithKline).
  • 3TC U.S. Pat. Nos. 5,859,021; 5,905,082; 6,177,435; 5,627,186; 6,417,191.
  • 3TC U.S. Pat. Nos. 5,587,480, 5,696,254, 5,618,820, 5,756,706, 5,744,596, 568,164, 5,466,806, 5,151,426) has the structure:
  • 3TC may be a physiologically functional derivative of emtricitabine in combination with GS-7340 or a physiologically functional derivative of GS-7340.
  • the invention includes all prodrugs of GS-7340 and emtricitabine. Whereas GS-7340 is a prodrug form of a PMPA compound, GS-7340 may bear additional prodrug moieties which confer advantageous properties.
  • GS-7340 is a prodrug form of a PMPA compound
  • GS-7340 may bear additional prodrug moieties which confer advantageous properties.
  • a large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997).
  • a commonly used prodrug class is the acyloxyalkyl ester, which was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos.
  • acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
  • a close variant of the acyloxyalkyl ester strategy, the alkoxycarbonyloxyalkyl ester, may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
  • Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498).
  • Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho- or para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C—O bond to generate the phosphoric acid and the quinone methide intermediate.
  • enzymes e.g. esterases, oxidases, etc.
  • prodrugs examples include Mitchell et al (1992) J. Chem. Soc. Perkin Trans. I 2345; Brook et al WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier et al WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide.
  • Prodrug esters in accordance with the invention are independently selected from the following groups: (1) mono-, di-, and tri-phosphate esters of GS-7340 or emtricitabine or any other compound which upon administration to a human subject is capable of providing (directly or indirectly) said mono-, di, or triphosphate ester; (2) carboxylic acid esters (3) sulfonate esters, such as alkyl- or aralkylsulfonyl- (for example, methanesulfonyl); (4) amino acid esters (for example, alanine, L-valyl or L-isoleucyl); (5) phosphonate; and (6) phosphonamidate esters.
  • Ester groups (1)-(6) may be substituted with; straight or branched chain C 1 -C 18 alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl); C 3 -C 12 cycloalkyl; alkoxyalkyl (for example, methoxymethyl); arylalkyl (for example, benzyl); aryloxyalkyl (for example, phenoxymethyl); C 5 -C 20 aryl (for example, phenyl optionally substituted by, for example, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or amino; acyloxymethyl esters —CH 2 C( ⁇ O)R 9 (e.g.
  • POM or acyloxymethyl carbonates —CH 2 C( ⁇ O)OR 9 (e.g. POC) where R 9 is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • ester groups may be pivaloyloxymethoxy, POM, —CH 2 C( ⁇ O)C(CH 3 ) 3 ; —CH 2 C( ⁇ O)OC(CH 3 ) 3 ; or POC, —CH 2 C( ⁇ O)OCH(CH 3 ) 2 .
  • An exemplary aryl moiety present in such esters comprises a phenyl or substituted phenyl group.
  • Many phosphate prodrug moieties are described in U.S. Pat. No. 6,312,662; Jones et al (1995) Antiviral Research 27:1-17; Kucera et al (1990) AIDS Res. Hum. Retro Viruses 6:491-501; Piantadosi et al (1991) J. Med. Chem. 34:1408-14; Hosteller et al (1992) Antimicrob. Agents Chemother. 36:2025-29; Hostetler et al (1990) J. Biol. Chem. 265:611127; and Siddiqui et al (1999) J. Med. Chem. 42:4122-28.
  • prodrugs refer to a compound that is metabolized in the host, for example hydrolyzed or oxidized, by either enzymatic action or by general acid or base solvolysis, to form an active ingredient.
  • Typical examples of prodrugs of the active ingredients of the combinations of the invention have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, esterified, deesterified, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, or other functional group change or conversion involving forming or breaking chemical bonds on the prodrug.
  • the chemical stability of the active ingredients in a pharmaceutical formulation is of concern to minimize the generation of impurities and ensure adequate shelf-life.
  • the active ingredients, GS-7340 and emtricitabine, in the pharmaceutical formulations of the invention have relatively low pKa values, indicative of the potential to cause acidic hydrolysis of the active ingredients.
  • Emtricitabine, with a pKa of 2.65 (EmtrivaTM Product Insert, Gilead Sciences, Inc. 2003, available at gilead.com) is subject to hydrolytic deamination of the 5-fluoro cytosine nucleobase to form the 5-fluoro uridine nucleobase.
  • Tenofovir, with a pKa of 3.8 (Yuan L.
  • the combinations of the present invention provide combination pharmaceutical dosage forms which are chemically stable to acid degradation of: (1) a first component (such as GS-7340, and physiological functional derivatives; (2) a second component (such as emtricitabine, and physiological functional derivatives; and (3) optionally a third component having antiviral activity.
  • the third component includes anti-HIV agents and include: protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and integrase inhibitors.
  • Exemplary third active ingredients to be administered in combination with first and second components are shown in Table A. First and second components are as defined in the above section entitled: ACTIVE INGREDIENTS OF THE COMBINATIONS.
  • any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of GS-7340, emtricitabine and their physiologically acceptable derivatives include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 alkyl).
  • Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X is independently selected from H or a C 1 -C 4 alkyl group).
  • salts of active ingredients of the combinations of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • a two-part or three-part combination may be administered simultaneously or sequentially.
  • the combination may be administered in one, two, or three administrations.
  • two-part or three-part combinations are administered in a single pharmaceutical dosage form. More preferably, a two-part combination is administered as a single oral dosage form and a three-part combination is administered as two identical oral dosage forms. Examples include a single tablet of GS-7340 and emtricitabine, or two tablets of GS-7340, emtricitabine, and efavirenz.
  • the compounds of the combination may be administered: (1) simultaneously by combination of the compounds in a co-formulation or (2) by alternation, i.e. delivering the compounds serially, sequentially, in parallel or simultaneously in separate pharmaceutical formulations.
  • alternation therapy the delay in administering the second, and optionally a third active ingredient, should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients.
  • the combination should be administered to achieve peak plasma concentrations of each of the active ingredients.
  • a one pill once-per-day regimen by administration of a combination co-formulation may be feasible for some HIV-positive patients.
  • Effective peak plasma concentrations of the active ingredients of the combination will be in the range of approximately 0.001 to 100 ⁇ M. Optimal peak plasma concentrations may be achieved by a formulation and dosing regimen prescribed for a particular patient. It will also be understood that GS-7340 and emtricitabine, or the physiologically functional derivatives of either thereof, whether presented simultaneously or sequentially, may be administered individually, in multiples, or in any combination thereof. In general, during alternation therapy (2), an effective dosage of each compound is administered serially, where in co-formulation therapy (1), effective dosages of two or more compounds are administered together.
  • the combination therapies of the invention include: (1) a combination of GS-7340 and emtricitabine or (2) a combination containing a physiologically functional derivative of either or both thereof.
  • the combination may be formulated in a unit dosage formulation comprising a fixed amount of each active pharmaceutical ingredient for a periodic, e.g. daily, dose or subdose of the active ingredients.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared for oral administration ( Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including antioxidants, sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example pregelatinized starch, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example pregelatinized starch, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, sucralose, or saccharin.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as sucrose, sucralose, or saccharin.
  • sweetening agents such as sucrose, sucralose, or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid, BHT, etc.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions or liposome formulations.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • compositions of the invention may be injected parenterally, for example, intravenously, intraperitoneally, intrathecally, intraventricularly, intrastemally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • compositions of the invention may also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container or a nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFC 134a), carbon dioxide or other suitable gas
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFC 134a), carbon dioxide or other suitable gas
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebuliser may contain a solution or suspension of the composition, e.g. using a mixture of ethanol and the propellant as the solvent, which may additional contain a lubricant, e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch. Aerosol or dry powder formulations are preferably arranged so that each metered dose or “puff” contains from 20 ⁇ g to 20 mg of a composition for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 20 ⁇ g to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • a time-release formulation intended for oral administration to humans may contain approximately from about 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • the combinations of the invention may conveniently be presented as a pharmaceutical formulation in a unitary dosage form.
  • a convenient unitary dosage formulation contains the active ingredients in amounts of from about 1 mg to 1 g each, for example, 100 mg to 300 mg.
  • the synergistic effects of GS-7340 in combination with emtricitabine may be realized over a wide ratio, for example 1:50 to 50:1 (GS-7340: emtricitabine). In one embodiment, the ratio may range from about 1:10 to 10:1. In another embodiment, the weight/weight ratio of GS-7340 to emtricitabine in a co-formulated combination dosage form, such as a pill, tablet, caplet or capsule will be about 1, i.e.
  • each compound will be employed in the combination in an amount at which it exhibits antiviral activity when used alone.
  • 150 mg GS-7340 and 200 mg emtricitabine can be co-formulated in a ratio of 0.75:1 (GS-7340: emtricitabine).
  • each compound will be employed in the combination in an amount at which it exhibits antiviral activity when used alone.
  • Exemplary Formulations A, B, C, D, E, and F have ratios of 0.125:1 to 1.5:1 (GS-7340:emtricitabine).
  • Exemplary Formulations A, B, C, D, E, and F use amounts of GS-7340 and emtricitabine ranging from 25 mg to 200 mg. Other ratios and amounts of the compounds of said combinations are contemplated within the scope of the invention.
  • a unitary dosage form may further comprise GS-7340 and emtricitabine, or physiologically functional derivatives of either thereof, and a pharmaceutically acceptable carrier.
  • the amount of active ingredients in the combinations of the invention required for use in treatment will vary according to a variety of factors, including the nature of the condition being treated and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or health care practitioner.
  • the factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated.
  • doses ranging from 25 mg to 200 mg twice-a-day for two weeks. At each dose regimen greater or equal to 200 mg, a 98-percent (1.75 log10) or greater viral suppression was observed.
  • EmtrivaTM emtricitabine
  • EmtrivaTM has been approved by the FDA for the treatment of HIV as a 200 mg oral tablet.
  • any two of the active ingredients in a unitary dosage form for simultaneous or sequential administration with a third active ingredient may be administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or three administrations.
  • Third active ingredients have anti-HIV activity and include protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and integrase inhibitors.
  • PI protease inhibitors
  • NRTI nucleoside reverse transcriptase inhibitors
  • NRTI non-nucleoside reverse transcriptase inhibitors
  • integrase inhibitors integrase inhibitors.
  • Another aspect of the present invention is a three-part combination comprising GS-7340, emtricitabine, and tenofovir.
  • Tenofovir DF also known as Viread®, Tenofovir disoproxil fumarate, Tenofovir disoproxil, Tenofovir, TDF, Bis-POC-PMPA (U.S. Pat. Nos. 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249) has the structure:
  • Tenofovir disoproxil includes: [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester; and 2,4,6,8-tetraoxa-5-phosphanonanedioic acid, 5-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]-, bis(1-methylethyl) ester, 5-oxide.
  • the CAS Registry numbers include: 201341-05-1; 202138-50-9; 206184-49-8.
  • the ethoxymethyl unit of tenofovir has a chiral center.
  • the R (rectus, right handed configuration) enantiomer is shown.
  • the invention includes the S isomer, as well.
  • the invention includes all enantiomers, diastereomers, racemates, and enriched stereoisomer mixtures of tenofovir and physiologically functional derivatives thereof.
  • Tenofovir DF is a new nucleotide reverse transcriptase inhibitor recently approved in the United States for the treatment of HIV-1 infection in combination with other antiretroviral agents.
  • Tenofovir disoproxil fumarate or Viread® (Gilead Science, Inc.) is the fumarate salt of tenofovir disoproxil.
  • Viread® may be named as: 2,4,6,8-Tetraoxa-5-phosphanonanedioic acid, 5-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]-, bis(1-methylethyl) ester, 5-oxide, (2E)-2-butenedioate (1:1).
  • the CAS Registry number is 202138-50-9.
  • a typical unitary dosage may contain 1 mg to 1000 mg of GS-7340, 1 mg to 1000 mg of emtricitabine, and 1 mg to 1000 mg of the third active ingredient.
  • a unitary dosage form may further comprise GS-7340, emtricitabine, the third active ingredient, or physiologically functional derivatives of any of the active ingredients thereof, and a pharmaceutically acceptable carrier.
  • Combinations of the present invention enable patients greater freedom from multiple dosage medication regimens and ease the needed diligence required in remembering and complying with complex daily dosing times and schedules.
  • the desired daily regimen may be presented in a single dose or as two or more sub-doses per day.
  • the combination of co-formulated GS-7340 and emtricitabine may be administered as a single pill, once per day.
  • a further aspect of the invention is a patient pack comprising at least one active ingredient GS-7340, emtricitabine or a physiologically functional derivative of either of the combination and an information package or product insert containing directions on the use of the combination of the invention.
  • Segregation of active ingredients in pharmaceutical powders and granulations is a widely recognized problem that can result in inconsistent dispersions of the active ingredients in final dosage forms.
  • Some of the main factors contributing to segregation are particle size, shape and density. Segregation is particularly troublesome when attempting to formulate a single homogenous tablet containing multiple active ingredients having different densities and different particle sizes.
  • Glidants are substances that have traditionally been used to improve the flow characteristics of granulations and powders by reducing interparticulate friction. See Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms: Tablets, Volume 1, p. 177-178 (1989), incorporated herein by reference.
  • Glidants are typically added to pharmaceutical compositions immediately prior to tablet compression to facilitate the flow of granular material into the die cavities of tablet presses.
  • Glidants include: colloidal silicon dioxide, asbestos free talc, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate, and magnesium oxide.
  • Exemplary Tablet Formulation A has colloidal silicon dioxide (Examples).
  • Glidants can be used to increase and aid blend composition homogeneity in formulations of anti-HIV drugs (U.S. Pat. No. 6,113,920).
  • the novel compositions of the present invention may contain glidants to effect and maintain homogeneity of active ingredients during handling prior to tablet compression.
  • the present invention provides pharmaceutical formulations combining the active ingredients GS-7340 and emtricitabine, or physiologically functional derivatives thereof, in a sufficiently homogenized form, and a method for using this pharmaceutical formulation.
  • An object of the present invention is to utilize glidants to reduce the segregation of active ingredients in pharmaceutical compositions during pre-compression material handling.
  • Another object of the present invention is to provide a pharmaceutical formulation combining the active ingredients GS-7340 and emtricitabine, or physiologically functional derivatives thereof, with a pharmaceutically acceptable glidant, resulting in a mixture characterized by a pharmaceutically acceptable measure of homogeneity.
  • Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods represent a further feature of the present invention and include the step of bringing into association the active ingredients with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients therein using, for example, cellulose ether derivatives (e.g., hydroxypropyl methylcellulose) or methacrylate derivatives in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • cellulose ether derivatives e.g., hydroxypropyl methylcellulose
  • methacrylate derivatives in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredients in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylates.
  • Topical administration may also be by means of a transdermal iontophoretic device.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for penile administration for prophylactic or therapeutic use may be presented in condoms, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents; and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Exemplary unit dosage formulations are those containing a daily dose or daily subdose of the active ingredients, as hereinbefore recited, or an appropriate fraction thereof. It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners and flavoring agents.
  • the compounds of the combination of the present invention may be obtained in a conventional manner, known to those skilled in the art.
  • Tenofovir disoproxil fumarate can be prepared, for example, as described in U.S. Pat. No. 5,977,089. Methods for the preparation of FTC are described in WO 92/14743, incorporated herein by reference.
  • compositions of the present invention are administered to a human or other mammal in a safe and effective amount as described herein. These safe and effective amounts will vary according to the type and size of mammal being treated and the desired results of the treatment. Any of the various methods known by persons skilled in the art for packaging tablets, caplets, or other solid dosage forms suitable for oral administration, that will not degrade the components of the present invention, are suitable for use in packaging. The combinations may be packaged in glass and plastic bottles. Tablets, caplets, or other solid dosage forms suitable for oral administration may be packaged and contained in various packaging materials optionally including a dessicant, e.g. silica gel. Packaging may be in the form of unit dose blister packaging.
  • a package may contain one blister tray of GS-7340 and another blister tray of emtricitabine pills, tablets, caplets, or capsule.
  • a patient would take one dose, e.g. a pill, from one tray and one from the other.
  • the package may contain a blister tray of the co-formulated combination of GS-7340 and emtricitabine in a single pill, tablet, caplet or capsule.
  • the combinations of the invention include physiological functional derivatives of GS-7340 and emtricitabine.
  • the packaging material may also have labeling and information related to the pharmaceutical composition printed thereon.
  • an article of manufacture may contain a brochure, report, notice, pamphlet, or leaflet containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as a “package insert.”
  • a package insert may be attached to or included with a pharmaceutical article of manufacture.
  • the package insert and any article of manufacture labeling provides information relating to the pharmaceutical composition.
  • the information and labeling provides various forms of information utilized by health-care professionals and patients, describing the composition, its dosage and various other parameters required by regulatory agencies such as the United States Food and Drug Agencies.
  • the combinations of the inventions may be tested for in vitro activity against HIV and sensitivity, and for cytotoxicity in laboratory adapted cell lines, e.g. MT2 and in peripheral blood mononuclear cells (PBMC) according to standard assays developed for testing anti-HIV compounds, such as WO 02/068058 and U.S. Pat. No. 6,475,491.
  • Combination assays may be performed at varying concentrations of the compounds of the combinations to determine EC 50 by serial dilutions.
  • exemplary formulations A, B, C, D, E, and F are prepared by wet granulation of the ingredients with an aqueous solution, addition of extragranular components and then followed by addition of magnesium stearate and compression.
  • mg/tablet Formulation A GS-7340 150 emtricitabine 200 Microcrystalline Cellulose 200 Lactose Monohydrate 325 Sodium Starch Glycollate 60 Pregelatinized Starch 50 Colloidal silicon dioxide 5
  • Formulation C GS-7340 50 emtricitabine 200 Microcrystalline Cellulose 200 Lactose Monohydrate 330 Croscarmellose Sodium 60 Pregelatinized Starch 50
  • This formulation is prepared by wet granulation of the ingredients with an aqueous solution, followed by the addition of magnesium stearate and compression.
  • mg/tablet GS-7340 300 emtricitabine 200 Hydroxypropyl Methylcellulose 112 Lactose B.P. 53 Pregelatinized Starch B.P. 28 Magnesium Stearate 7 total: 700
  • Drug release takes place over a period of about 6-8 hours and is complete after 12 hours.
  • a capsule formulation is prepared by admixing the ingredients and filling into a two-part hard gelatin or hydroxypropyl methylcellulose capsule.
  • mg/capsule Active Ingredient 500 Microcrystalline Cellulose 143 Sodium Starch Glycollate 25 Magnesium Stearate 2 total: 670
  • the following controlled release capsule formulation is prepared by extruding ingredients a, b, and c using an extruder, followed by spheronization of the extrudate and drying. The dried pellets are then coated with release-controlling membrane (d) and filled into a two-piece, hard gelatin or hydroxypropyl methylcellulose capsule.
  • mg/capsule (a) Active Ingredient 500 (b) Microcrystalline Cellulose 125 (c) Lactose B.P. 125 (d) Ethyl Cellulose 13 total: 763
  • active ingredients are admixed with the ingredients and filling them as dry powder. Purified water is added and mixed well before use. Active Ingredient 500 mg Confectioner's Sugar 2000 mg Simethicone 300 mg Methylparaben 30 mg Propylparaben 10 mg Flavor, Peach 500 mg Purified Water q.s. to 5.00 ml
  • Witepsol H15 is melted in a steam-jacketed pan at 45° C. maximum.
  • the active ingredients are sifted through a 200 micron sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45° C., the remaining Witepsol H15 is added to the suspension and stirred to ensure a homogenous mix.
  • the entire suspension is passed through a 250 micron stainless steel screen and, with continuous stirring, is allowed to cool to 40° C. At a temperature of 38° C. to 40° C., 2.02 g of the mixture is filled into suitable, 2 mL plastic molds. The suppositories are allowed to cool to room temperature.
  • a fixed dose combination tablet of GS-7340 and emtricitabine, or their physiologically functional derivatives may be formulated using a wet granulation/fluid-bed drying process using conventional methods. See: U.S. Pat. No. 5,935,946; L. Young (editor). Tableting Specification Manual 5 th ed., American Pharmaceutical Association, Washington, D.C., (2001); L. Lachman, H. Lieberman (editors). Pharmaceutical Dosage Forms: Tablets (Vol 2), Marcel Dekker Inc., New York, 185-202 (1981); J. T. Fell and J. M. Newton, J. Pharm. Pharmacol. 20, 657-659 (1968); US Pharmacopeia 24-National Formulary 19, “Tablet Friability”, Chapter ⁇ 1216>, Page 2148 (2000).
  • a pharmaceutical composition comprising an effective amount of a compound of the formula:
  • R 5 is H or CH 3 ;
  • R 6 and R 8 are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 6 -C 20 arylalkyl, and C 6 -C 20 substituted arylalkyl;
  • R 7 is the side chain of any naturally-occurring or pharmaceutically acceptable amino acid and where if the side chain comprises carboxyl, the carboxyl group is optionally esterified with an alkyl or aryl group;
  • R 11 is amino, alkylamino, oxo, or dialkylamino; and
  • R 12 is amino or H;
  • B is selected from adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O 6 -methylguanine, N 6 -methyla
  • R is selected from H, C 1 -C 18 alkyl, C 1 -C 18 substituted alkyl, C 2 -C 18 alkenyl, C 2 -C 18 substituted alkenyl, C 2 -C 18 is alkynyl, C 2 -C 18 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocycle, C 2 -C 20 substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy or a physiologically functional derivative thereof; and
  • a pharmaceutically acceptable carrier [0142] a pharmaceutically acceptable carrier.
  • R 8 is CH 3 , CH 2 CH 3 , or CH(CH 3 ) 2 .
  • E A composition of embodiments A through D wherein, in formula 2, B is cytosine or a 5-halocytosine and R is H.
  • a pharmaceutical formulation of embodiments A through F further comprising a third active ingredient selected from the group consisting of a protease inhibitor, a nucleoside or nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, and an integrase inhibitor.
  • a method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal a pharmaceutical composition of embodiments A through G.

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