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  Compositions and methods for combination antiviral therapyUSPTO Application #: 20060234982Title: Compositions and methods for combination antiviral therapy Abstract: 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, (−)-cis FTC, Emtriva™ and their physiologically functional derivatives. The combinations may be useful 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, and their physiologically functional derivatives, as well as therapeutic methods of use of those compositions and formulations. (end of abstract) Agent: Gilead Sciences Inc - Foster City, CA, US Inventors: Terrence C. Dahl, Mark M. Menning, Reza Oliyai USPTO Applicaton #: 20060234982 - Class: 514081000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai, Nitrogen Containing Hetero Ring, Polycylo Ring System Having A Ring Nitrogen In The System, Nonshared Hetero Atoms In At Least Two Rings Of The Polycyclo Ring System The Patent Description & Claims data below is from USPTO Patent Application 20060234982. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This non-provisional application claims the benefit of Provisional Application Nos. 60/440,308 and 60/440,246, both filed Jan. 14, 2003, which is incorporated herein by reference. FIELD OF THE INVENTION [0002] 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. BACKGROUND OF THE INVENTION [0003] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes at least three enzymes which are required for viral replication: reverse transcriptase (RT), protease (Prt), and integrase (Int). Although 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). Human immunodeficiency virus type 1 (HIV-1) protease (Prt) is essential for viral replication and is an effective target for approved antiviral drugs. 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. Unfortunately, a high percentage, typically 30 to 50% of patients currently fail combination therapy due to the development of drug resistance, non-compliance with complicated dosing regimens, pharmacokinetic interactions, toxicity, and lack of potency. Therefore, there is a need for new HIV-1 inhibitors that are active against mutant HIV strains, have distinct resistance profiles, fewer side effects, less complicated dosing schedules, and are orally active. In particular, there is a need for a less onerous dosage regimen, such as once per day oral dosing, optimally with as few pills as possible. [0004] The use of combinations of compounds can yield an equivalent antiviral effect with reduced toxicity, or an increase in drug efficacy. Lower overall drug doses can reduce the frequency of occurrence of drug-resistant variants of HIV. Many different methods have been used to examine the effects of combinations of compounds acting together in different assay systems (Furman WO 02/068058). Lower doses predict better patient compliance when pill burden decreases, dosing schedules are simplified and, optionally if synergy between compounds occurs (Loveday, C. "Nucleoside reverse transcriptase inhibitor resistance" (2001) JAIDS Journal of Acquired Immune Deficiency Syndromes 26:S10-S24). AZT (zidovudine.TM., 3'-azido, 3'-deoxythymidine) 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-.alpha.. However, it must be noted that combinations of compounds can give rise to increased cytotoxicity. For example, AZT and recombinant interferon-.alpha. have an increased cytotoxic effect on normal human bone marrow progenitor cells. [0005] Chemical stability of combinations of antiviral agents is an important aspect of co-formulation success and the present invention provides examples of such combinations. [0006] There is a need for new combinations of orally-active drugs for the treatment of patients infected with certain viruses, e.g. HIV, that provide enhanced therapeutic safety and efficacy, impart lower resistance, and predict higher patient compliance. SUMMARY OF THE INVENTION [0007] The present invention provides combinations of antiviral compounds, in particular compositions and methods for inhibition of HIV. In an exemplary aspect, 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. [0008] The present invention relates to therapeutic combinations of 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]m- ethoxy]propyl]adenine (GS-7340) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimi- din-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. [0009] 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. For example, FTC includes the single enantiomer emtricitabine. [0010] 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)-4amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin- -2-one (3TC, Lamivudine, Epivir.TM.), and their use in the treatment of HIV infections. [0011] 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]m- ethoxy]propyl]adenine (GS-7340) or a physiologically functional derivative thereof, and (2R,5S,cis)-4amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-- pyrimidin-2-one (emtricitabine) or a physiologically functional derivative thereof. [0012] 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. [0013] Another aspect of the invention is directed to a chemically stable combination antiviral compositions comprising GS-7340 and emtricitabine. In a further aspect of the invention, the chemically stable combinations of GS-7340 and emtricitabine further comprise a third antiviral agent. In this three-component mixture, 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. Preferably, 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. In a particularly preferred embodiment, the invention is directed to a combination of the chemically stable mixture of GS-7340 and emtricitabine together with efavirenz. [0014] 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. [0015] 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. In a further aspect of the present invention, there is provided the use of a combination of the present invention in the manufacture of a medicament for the treatment of any of the aforementioned viral infections or conditions. DETAILED DESCRIPTION OF THE INVENTION [0016] While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. Definitions [0017] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings: [0018] When tradenames are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product. [0019] The term "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. Typically, "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. By way of example and not limitation, in one aspect of the invention, "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. Continue reading... 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