UA81797C2 - Pharmaceutical dosage of tenofovir disoproxil fumarate and emtricitabine for combination antiviral therapy - Google Patents

Abstract

The present invention relates to therapeutic combinations of [2-(6-amino-purin-9yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester (tenofovir disoproxil fumarate, Viread) and (2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine, Emtriva™, (-)-cis FTC) and their physiologically functional derivatives. The present invention is also concerned with pharmaceutical compositions and formulations of said combinations of tenofovir disoproxil fumarate and emtricitabine, and their physiologically functional derivatives, as well as therapeutic methods of use of those compositions and formulations.

Description

Description of the invention

The invention generally relates to combinations of compounds with antiviral activity, that is, compounds that have 2 anti-HIV properties. In particular, it refers to chemically stable combinations of antiviral agents with different structures.

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 required for viral replication: reverse transcriptase (RT), protease (RII), and integrase (IP). Although 70 drugs targeting reverse transcriptase and protease are widely used and have been shown to be effective, particularly when used in combination, toxicity and the development of resistant strains limit their utility

IRaiena, ebg! M. Epai. U. Mea. (1998) 338:853-860; Kisptap, LLC. O. Maiishte (2001) 410:995-1001). Human immunodeficiency virus type 1 (HIV-1) protease (HIV-1) is essential for viral replication and is an effective target for improved antiviral drugs. , p24, p7, and rb) and three viral enzymes. Combination therapy with CT inhibitors has been shown to be highly effective in inhibiting viral replication to unquantifiable levels over a long period of time. Also, combination therapy with CT and Rii (RI) inhibitors has shown synergistic inhibition HIV replication. Unfortunately, for a high percentage, typically 3 to 5095 patients, combination therapy currently fails due to the development of 20 drug resistance, nonadherence to complex dosing regimens, pharmacokinetic interactions, toxicity, and lack of efficacy. Thus, there is a need for new HIV-1 inhibitors, which are active against mutant strains of HIV, have a clear resistance profile, fewer side effects, less complex dosing regimens, and oral activity. In particular, there is a need for a less burdensome dosing regimen, for example, once a day for oral dosing, ideally with a minimum of 25 pills. heh)

The use of combinations of compounds can provide an equivalent antiviral effect with reduced toxicity or increase the effectiveness of drugs. Lowering total drug doses can reduce the incidence of drug-resistant variants of HIV.

Many different methods were used to study the effects of combinations of compounds that act together in - 30 different analysis systems (Hyptap UUO 02/068058). Lowering doses implies better adherence to the regime on the part of Teh! of the patient, when the medication load is reduced, the dosage regimen is simplified, and, optionally, if there is a synergism between the compounds (omedau, S. 524). AIT (zidovudine, 3-azido, "n 3-deoxythymidine) exhibits synergistic antiviral activity in combination with agents that act on 32 stages of HIV-1 replication, in addition to reverse transcription, including recombinant CO4-soluble castanospermine and recombinant interferon-o . However, it should be noted that combinations of compounds can cause increased cytotoxicity. For example, AT and recombinant interferon-o have an increased cytotoxic effect on normal human bone marrow progenitor cells."

The chemical stability of combinations of antiviral agents is an important aspect of successful co-prescribing, and the present invention therefore provides examples of such combinations. c There is a need for new combinations of orally active drugs for the treatment of patients infected with certain "c" viruses, such as HIV, that provide increased therapeutic safety and efficacy, induce less resistance, and predict better patient compliance.

The present invention provides combinations of antiviral compounds, in particular, compositions and methods of inhibiting HIV.

In an exemplary aspect, the invention encompasses a composition comprising tenofovir disoproxil fumarate CO and emtricitabine having anti-HIV activity. The composition of tenofovir-OR and emtricitabine is chemically stable and - is synergistic and/or reduces the side effects of tenofovir-OE and emtricitabine or one of them. There is a possibility of improving the patient's adherence to the regimen due to the reduced workload and simplified dosing regimen.

This invention relates to therapeutic combinations of diisopropoxycarbonyloxymethyl ester (Ce) fumarate (2-(6b-amino-purin-9-yl)-1-methyl-ethoxymethyl|-phosphonic acid (tenofovir disoproxil fumarate, tenofovir-OBE, TOB, Migeadoe) and ( 2, 55,

Also cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine, Etimatm, (--cis ETS) and their use for the treatment of HIV infections, including infections with HIV mutants that have resistance to nucleoside and/or non-nucleoside inhibitors.The present invention also relates to pharmaceutical compositions and dosage forms of the aforementioned tenofovir disoproxil fumarate combinations

GF) and emtricitabine. Another aspect of the invention relates to a pharmaceutical composition that includes a physiologically functional tenofovir disoproxil fumarate derivative or a physiologically functional emtricitabine derivative. o Therapeutic combinations and pharmaceutical compositions and compositions according to the invention include a combination of PMEA or PMPA (tenofovir) compounds with emtricitabine or /(2K, 55, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane) -5-yl)-(1H)-pyrimidin-2-one (ZTS, lamivudine, Erimigtm) and their use in the treatment of HIV infections.

One aspect of the invention relates to a method of treating or preventing symptoms or effects of HIV infection in an infected animal, comprising administering, i.e., treating said animal with a therapeutically effective amount of a combination comprising diisopropoxycarbonyloxymethyl ester fumarate (2-(6-amino-purin-9-yl )-1-methyl-ethoxymethyl|-phosphonic acid (tenofovir-OB, TOR) or its physiologically functional derivative and (2, 55, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3 -oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or/- its physiologically functional derivative.

Another aspect of the invention relates to a single dose form of a therapeutic combination comprising tenofovir disoproxil fumarate and emtricitabine, or physiologically functional derivatives thereof. The single-dose form can be prescribed for oral or other routes and unexpectedly proved to be chemically stable given the properties of the structurally different components.

Another aspect of the invention relates to a chemically stable combination of an antiviral composition that includes tenofovir disoproxil fumarate and emtricitabine. In yet another aspect of the invention, chemically stable combinations of tenofovir disoproxil fumarate and emtricitabine also include a third antiviral agent. This three-component combination takes advantage of the unique chemical stability of tenofovir disoproxil fumarate and emtricitabine, which allows them to be used in combination with a third antiviral agent. Particularly useful third agents, in addition to others, are, for example, presented in Table A. In an optimal embodiment /5 the third component is an agent approved for anti-viral use in humans, in an even better embodiment it is an MMCTI or a protease inhibitor (PI), in an even better option - MMKTI. In the best embodiment, the invention relates to a combination of a chemically stable mixture of tenofovir disoproxil fumarate and emtricitabine together with efavirenz.

Another aspect of the invention relates to a kit for a patient that includes at least one, typically two, optionally three active ingredients and other antiviral agents selected from tenofovir disoproxil fumarate and emtricitabine, and an information insert that contains instructions for the use of tenofovir disoproxil fumarate and emtricitabine together in combination.

Another aspect of the invention relates to the method of obtaining the above-described combinations, which includes the combination of tenofovir-OE and emtricitabine in a medicine to provide an anti-viral effect. In yet another aspect of the present invention, there is provided the use of a combination according to the present invention for the manufacture of a medicament for the treatment of any of the aforementioned viral infections or conditions. (8)

Although the invention is described in connection with the listed items, it should be understood that the scope of the invention is not limited to these items. Rather, the invention contemplates all alternatives, modifications, and equivalents that may be encompassed within the scope of the present invention as defined by the formula. Unless otherwise indicated, the terms and expressions used by the authors below have the following meanings:

If the authors use brand names, applicants independently include the brand name product and the active pharmaceutical ingredient(s) of that brand name product. uh-

The term "chemical resistance" means that the two main antiviral agents in combination have substantial resistance to chemical degradation. Ideally, they are stable enough in a physical combination for a commercially acceptable shelf life of the combined product. Generally, the term "chemically stable" means that the first component of the mixture does not destroy the second component when these two components are combined in a physical combination to form a pharmaceutical dosage form. Most often, the term "chemically stable" means that the acidity of the first component does not catalyze or otherwise accelerate the acid cleavage of the second component. By way of example, which does not limit the scope of the invention, in one aspect of the invention the term "chemically stable" means that tenofovir disoproxil fumarate does not undergo significant destruction by the acidity of emtricitabine. - c "Substantial" in this context means less than at least about 1095, preferably less than 196, more preferably less than 0.195, more preferably less than 0.0195 acid cleavage of tenofovir disoproxil fumarate in 24 - the one-hour period when the products are in pharmaceutical dosage form.

The terms "synergism" and "synergistic" mean that the effect achieved by the compounds used together is greater than the sum of the effects achieved by the individual compounds, i.e., greater than that which would be expected from the individual compounds. introduction of two active ingredients. A synergistic effect - can be achieved if the compounds: (1) are jointly prescribed and administered or delivered simultaneously in -1 combination composition; (2) delivered alternately or in parallel as separate compositions; or (3) in any

Another mode. When delivered in the case of intermittent therapy, a synergistic effect can be achieved when the compounds (Ce) are administered or delivered sequentially, for example, in separate tablets, pills or capsules, or by different injections in separate syringes. In general, in intermittent therapy, an effective dose of each active ingredient is administered sequentially, ie, serially, whereas in combination therapy, effective doses of two or more active ingredients are administered together. A synergistic antiviral effect means an antiviral effect that is greater than the predicted purely additive effects of the individual compounds of the combination.

The term "physiologically functional derivative" means a physiologically active pharmaceutically active compound

HF) functionality, with equivalent or almost equivalent to tenofovir-OE or emtricitabine when administered in

F combination with another pharmaceutically active compound in combination according to the invention. As used by the authors, the term "physiologically functional derivative" includes any of the following compounds: a physiologically acceptable salt, ether, bo ester, prodrug, solvate, stereoisomer, including enantiomer, diastereomer, or stereoisomerically enriched or racemic mixture, and any other compound that after administration to a recipient is capable of providing (directly or indirectly) such a compound or its antivirally active metabolite or residue. "Bioavailability" is the degree to which a pharmaceutically active agent becomes available to the target tissue after administration of the agent to the body. Increasing the bioavailability of a pharmaceutically active agent can provide a more effective and efficient treatment for patients because, for a given dose, a greater amount of the pharmaceutically active agent is available at given tissue locations.

The compounds of the combinations according to the invention are called "active ingredients" or "pharmaceutically active agents".

The term "prodrug" used by the authors refers to any compound that, when introduced into a biological system, forms a medicinal substance, i.e., an active ingredient, as a result of a spontaneous chemical reaction(s) channeled by an enzyme of chemical reaction(s) (reactions) and/or metabolic chemical reaction(s). "Prodrug component" means an unstable functional group that is separated from an active inhibitory compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage, or 7/0 by some other means. oyi Ogyd Oevzidp apa

OemeIortepi (1991), R. Kgodzdaaga-I agzep apa N. Vypddaaga, Edw. Naglood Asadetis Rybiizpegwe, 1113-1911.

Prodrug components can serve to enhance solubility, absorption, and lipophilicity to optimize drug delivery, bioavailability, and efficacy. "Prodrugs", thus, are covalently modified analogues of a therapeutically active compound. "Alkyl" means a saturated or unsaturated, branched, linear, branched or cyclic hydrocarbon radical obtained by removing one hydrogen atom from one carbon atom of the parent alkane, alkene or alkyne. Typical alkyl groups consist of 1-18 saturated and/or unsaturated carbon atoms, such as normal, secondary, tertiary or cyclic carbon atoms. Examples include, but are not limited to: methyl,

Me (-CH»5), ethyl, EC (-CHnoCH»5), acetyl (-С-CH), ethylene, vinyl (-CH-CH»o), 1-propyl, p-Pg, p-propyl 20 . ССНоСНоСН»), 2-propyl, I-Pr, i-propyl (-СН(СН»)»), allyl (-СНСНАСН»), propargyl (-СНСС-СН), cyclopropyl (-С3Н), 1-butyl . -butyl (-СН(СН3)СНоСН»), 2-methyl-2-propyl, Y-Vy, е-butyl (-С(СН»3)з), 1-pentyl, n-pentyl, (-СНоСНОСНОСНоСННУ), o 2-pentyl o (-СН(СНУ)СНоСНУСНУ), o 3-pentyl o (-СН(СНоСНУ)»), 0/0 2-methyl-2-butyl (-ФС(СН3»СНоСН»), cyclopentyl (- SeHe), 3-methyl-2-butyl (-CH(CH3CH(CH»U)"), 3-methyl-1-butyl c 285 ССНоСНоCH(CH3)")), 2-methyl-1-butyl. (-" СНОСН(СНЗ)СНоСН»), 1-hexyl. (-"СНОСНноСНоСНоСНьСН»), 5-hexenyl (-сносСнН.сСнНосСнО.сСниСнН») 1-hexyl (-СН(СНУ)СНоСНоСНоСНУ), o З-hexyl o (- CH(СНСНЗХСНоСНоСН")), o cyclohexyl (-СвН.и4), 2-methyl-2-pentyl. (-С(СНаз)»СНоСНоСН"), 3-methyl-2-pentyl. (СНай)СНоСН»), 4-methyl-2-pentyl (сСнН(СНЗСнНхСНн(СН»я)»), 3-methyl-3-pentyl (- Ф(CH3CHNOCH»)»), 2-methyl-3-pentyl (cCH(CHCHCHNOCH(CH»)»), 2,3-dimethyl-2-butyl (-C(CHCH)bCH(CH»)») and 3 ,3-dimethyl-2-butyl (-СН(СНУС(СН)5. "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms, obtained by removing one hydrogen atom from one carbon atom of the original aromatic ring system. (o) typical aryl groups include, among others, radicals derived from benzene, substituted benzene, naphthalene, i-anthracene, biphenyl, etc.. "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms, connected to a carbon atom, usually a terminal or carbon atom, is a substituted aryl radical. Typical co-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, etc. An arylalkyl group has from b to 20 carbon atoms, for example, an alkyl component, including an alkynyl, alkenyl or alkynyl group, an arylalkyl group has from 1 to 6 carbon atoms, and an aryl component has from 5 to 14 carbon atoms. " 40 "Substituted alkyl", "substituted aryl" and "substituted arylalkyl" mean alkyl, aryl and arylalkyl, 73 c respectively, in which one or more hydrogen atoms are independently substituted by a substituent. Typical substitutes include, among others, -X, -K, -0, -OK, -ZK, -5X -МКо, -МКз, MK, -СХз, -СМ, -ОСМ, -5СМ, -М-0 -O, -MO5, -MO, "» -MO", -Mo, -Mz, MO(-О)К, -Ф(-О)К, -С(О)МАКК -50С-0)507, - 5(-0)2ОН, -5(--0)5Кк, -0О5(-О)2ДОК, -5(-0)2МК, -Ш(5О)К, -OR(-О)ОЖК, -Р( -О)0ОКК -Р(И-ОХХО7», -Р(ОХОН)», -Ф(-О)К, -Ф(-О3Х, -Ф(5)К, -Ф(О)OK, -Ф( О0, 45 -Ш(5)OK,-Ф(0)5К, -С(5)5К, -С(О)МАК, -Ф(5)МАК, -С(МК)МКК, and each X independently is halogen: KE, CI, Bg(ee), or I; and each K is independently -H, alkyl, aryl, heterocycle, or a prodrug component. - "Heteroaryl" and "Heterocycle" refer to a ring system in which one or more ring atoms are by a heteroatom, for example, nitrogen, oxygen, and sulfur. Heterocycles are described in the following publications: Kaigii2Ku, AIap -I K., Keevz, SMU., apa Zshimep, E. Sotrgepepvzime Neiegosusiis Spetivigu (1996) Regdatop Rgezv; Radtsetse, / еео A.; Rgthipsiriez oi Modegp Neiegosusiis Spetivzigu M.A. Vepiatip, Mem/ MogKk, (1968), in particular, in Sections 1, 3, 4, 6, i-o 7 and 9; "pe Spetivi Gu oi Neyegosusiis Sotroitspavz, A zegiev oi Mopodgariv" Yuoip UMPeu b Bopv, Mem/ MogK, 1950 yuY "A rgezepi), in particular, in Volumes 13, 14, 16, 19 and 28. Examples of heterocycles are, among others, 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, Z-pyrazole, 4-pyrazole, pyridazine, 22 pyrimidine, pyrazine, purine, cinnoline, phthalazine, quinazoline, quinoxaline, /3-(1,2,4-M)-triazolyl, 5-(1,2,4-M )-triazolyl, 5-tetrazolyl, 4-(1-O, 3-M)-oxazole, 5-(1-O, 3-M)-oxazole, 4-(1-5, 3-M)-thiazole, o 5-(1-5, 3-M)-thiazole, 2-benzoxazole, 2-benzothiazole, 4-(1, 2, 3-M)-benzotriazole and benzimidazole.

Kkz The stereochemical definitions and notations used by the authors generally correspond to those contained in the publications 5. R. Ragkeg, Ea., MeOgam-NIII! Oisiopagus of Spetis! Tagtz (1984) Meogham--NIII VookK SomPapu, Mem 60 Hogk; apa Eiiei, E. apa U/iep, 5., ZIegeospetivhigu oi Ogdapis Sotroypaz (1994) addendum MMyeu 5 Bopv, Ips., Mem/ Mogk.

Many organic compounds exist in optically active forms, that is, they can rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes ЯО and Я or К and 5 are used to indicate the absolute configuration of the molecule relative to its chiral center(s). The prefixes 4 and 1 or (x) and (-y) are used to indicate the sign of rotation of plane-polarized light by a compound, where (-) or 1 means that the compound is levorotatory. A compound with the prefix (k) or 4 is dextrorotatory. For this chemical structure these compounds, called stereoisomers, are identical except that they are mirror images of each other. A specific stereoisomer is also called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate. The terms " "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomeric species.

The term "chiral" refers to molecules that have the property of not superimposing their mirror counterparts, while the term "achiral" refers to molecules that superimpose their mirror counterparts.

The term "stereoisomers" refers to compounds that have an identical chemical composition but differ in the arrangement of atoms or groups in space. 70 The term "diastereomer" refers to stereoisomers with two or more centers of chirality, the molecules of which are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. A mixture of diastereomers is separated using high-resolution analytical procedures such as electrophoresis and chromatography.

The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposed 7/5 mirror images of each other. AND

ACTIVE INGREDIENTS OF COMBINATIONS

The present invention provides new combinations of two or more active ingredients applied together. In some embodiments, embodiments achieve a synergistic antiviral effect. In other embodiments, a chemically stable combination is obtained. Combinations include at least one active ingredient selected from (1) tenofovir disoproxil fumarate 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 by the authors to denote an antiviral effect that is greater than the predicted purely additive effects of individual components (a) and (b) of the combination.

Tenofovir disoproxil fumarate (also known as Migead?, Tenofovir-OR, Tenofovir disoproxil, TOB, c dv Viv-ROS-RMPA (US patents MeMo5935946, 5922695, 5977089, 6043230, 6069249) is a prodrug of tenofovir and has the following structure: o l . iy. Ya che 30 b - LANGUAGE a : - in B sr nya. J en "from Ya

Chek N V, . in : and a zi

Po' In Sche s "MY I y ee . iiy -sh p kh b y -1- "vv y b i- Shyt snyi 7 chtk -

V. and inii g Ya. -- svi .-y t hi y i " nya ne": yo ya. " , from kV 40 : y She: t. ' o s And what u. I "ya to y r | There are 2 - Sha : 45 there are Z TP; : : and LE. : : so Y : and !

KO che: - b sv y l cat Ko suytsn VIJ y ; including fumarate salt (НОСССНСНСО» ). "I Chemical names of Tenofovir disoproxil are: diisopropoxycarbonyloxymethyl ester of (2-(b-amino-purin-9-yl)-1-methyl-ethoxymethyl|-phosphonic acid; 9-(k)-2-(bis|(isopropoxycarbonyl)oxy |methoxy|phosphinyl|methoxy|propyliadenine; and oo 2,4,6,8-tetraoxa-5-phosphanone organic diacid, 5-|(1K)-2-(6-amino-9H-purin-9-yl)-1 -methylethoxy|methyl/-, bis(i-methylethyl) ester, 5-oxide. Numbers in the SAB register: 201341-05-1; 202138-50-9; 206184-49-8. It should be noted that the ethoxymethyl component of tenofovir has a chiral center. The K-enantiomer is shown (hesishv,

Kkz of the right-hand configuration). However, the invention also includes the 5-isomer. The invention includes all enantiomers, diastereomers, racemates and enriched stereoisomeric mixtures of tenofovir (RMPA) and its physiologically 60 functional derivatives.

RMPA or tenofovir (US patents MOMo 4808716, 5733788, 6057305) has the following structure: b5

I re M k i i . 7 " 7 | ' and m and su, 5 and "y r x c

A: -Wu: . and pre x " MORE ", p

The chemical names of RMPA, tenofovir are: (K)-9-(2-phosphonylmethoxypropyl)adenine; and phosphonic acid,

ЧО1КО)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy|methyl). Number in the CA5 register is 147127-20-6.

Tenofovir disoproxil fumarate (OR) is a nucleotide reverse transcriptase inhibitor approved in

in the United States in 2001 for the treatment of HIV-1 infection in combination with other antiretroviral agents. Tenofovir disoproxil fumarate or Migeade (Syeai bsiepse, Ips.) is the fumarate salt of tenofovir disoproxil. MigeadU can have the following names: (U 9-(k)-2-(bis|(isopropoxycarbonyl)oxy|methoxy|phosphinyl|methoxy|propyl|adenine fumarate (1:17); or 2,4,6,8-tetraoxa -5-phosphononanorganic diacid, 5-((1K)-2-(6b-amino-9H-purin-9-yl)-1-methylethoxy|methyl|-, bis(i-methylethyl) ester, 5-oxide, ( 2E)-2-butenedioate (1:1). CA5 registry number 202138-50-9. zo Physiologically functional derivatives of tenofovir disoproxil fumarate are PMEA (adefovir, 9-(K)-2-(phosphonomethoxy)ethyl)adenine) and compounds of RMPA. Examples of combinations are PMEA or the compound RMPAU FI in combination with emtricitabine or ZTS. PMEA and compounds of RMPA have the structures: m

I sa -

Shk - BI so

To tn in -v I yad g. I and la. breath - | she --, | sha zh t i y 5 I y y Z so SCHI chi sce Y What re) y y, nyyy y tsii s :. "m Y shchi:

PE

(F. where PMEA (VZ is H) and RMPA (KZ is C.-Cv alkyl, C4-Cv substituted alkyl or CH»OMKU, where KZ is C.-Cv

Ho) alkyl, C4-Cv hydroxyalkyl or C.4-Ce haloalkyl. BEZ and B/ are independently H or C-Cb alkyl. B" and B? are independently H, MH", MNE or ME", where B is C.-Cb alkyl. B' and BK? are independently H, C.4-Cv alkyl, C4-Cv 60 substituted alkyl, Sv -Coo aryl, Ce-Coo substituted aryl, Ce6-Coo arylalkyl, Ce-Coo substituted arylalkyl, acyloxymethyl esters -"СНеОС(-ОВС (for example, РОМ) or acyloxymethyl carbonates -СНоС(-:FOОВЗ (for example, РОС), where KU is C.-Cb alkyl, C1-Cv substituted alkyl, Cv-Coo aryl or Cv-C2o substituted aryl. For example, B" and BK? can be pivaloyloxymethoxy, РОМ, -СНоОС(-О)С(СН 3)5 ; 65 -CH.OF(OOS(CH")z; or ROS, -CHgOS(-O)OSH(CH 3)". Also, for example, tenofovir has the following structure, where in is СНа, and 8, B, 87 , 25, B and B" are H. Dialkylphosphonates are obtained according to the methods described in the publications:

Ohtsazvi ei ai. (1974) Bupipevziv 490; Boomers! her a. (1990) Teigapeadgop I ek. 3261; US patent Mo5663159.

The RMPA-compound can be enantiomerically enriched or purified (a single stereoisomer), where the carbon atom carrying the KZ can be the B- or b-enantiomer. The RMPA compound can be a racemate, that is, a mixture of B- and C-stereoisomers.

Adefovir (9-(2-phosphonomethoxyethyl)adenine, where K.-K; - H) is a typical PMEA compound |US patents

MoMo4808716, 47242331). As bis-pivalate prodrugs, Adefovir dipivoxil, also known as bis--"OM PMEA, (B5-K7 - H, EC! and B? - -CH.OS(-O)C(CH)5, pivoxyl, ROM, pivaloyloxymethoxy), is effective against infections

HIV and hepatitis B infections (US patents MoMo5663159, 6451340). Adefovir dipivoxil has shown 70 little to moderate synergistic inhibition of HIV replication in combination with other compounds that have activity against HIV, including RMPA, a4t, daasC, nelfinavir, ritonavir, and saquinavir. (1997)

Apiimiga! Kezeagsi 36:91-97)|.

The invention includes all enantiomers, diastereomers, racemates and enriched mixtures of stereoisomers of PMEA and

RMPA and their physiologically functional derivatives.

Emtricitabine ((-)U-cis-ETS, Etigimat), a single enantiomer of ETS, is a potent nucleoside reverse transcriptase inhibitor approved for the treatment of HIV (US Pat. 5814639, 5914331, 6114343, 6180639, 6215004; MO 02/070518). The only enantiomer of emtricitabine has the following structure: mi : a o ts! and from Where: : these E. g t B u ; as. "I t; cha

I don't know. and F schy: Y. Shose. t same viti is | M --

And you and co

The chemical names of emtricitabine are: (-)-cis-ETS; p-1-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane; (2K,55)-5-fluoro-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl|cytosine; and « 4-amino-5-fluoro-1-(2-hydroxymethyl-|1 . chiral centers, in the 2nd and 5th positions of the C with oxathiolane ring, and thus can exist in the form of two pairs of optical isomers (ie, "" enantiomers) and their mixtures, including racemic mixtures. Thus, ETS can be the cis- or 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 mixtures of stereoisomers of emtricitabine and their physiologically functional derivatives. For example, the invention includes such physiologically functional derivatives as - 11 racemic mixture of enantiomers (2, 55, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-( 1H)-pyrimidin-2-one (emtricitabine) and its

Ш- mirror image of (25, approx, "se 20 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 suitable amount. The invention also includes mixtures of cis- and trans-forms of ETO. "and Physiologically functional derivatives of emtricitabine include 1,3 oxathiolane nucleosides, which have the following structure:

In the structure of 1,3 oxathiolane nucleoside B presented above, there is a nucleic acid base that includes 65 any nitrogen-containing heterocyclic component capable of forming Watson-Crick hydrogen bonds when paired with a complementary nucleic acid base or nucleic acid base analog,

for example, purine, 7-deazapurine or pyrimidine. Examples of B are natural bases of nucleic acids: adenine, guanine, cytosine, uracil, thymine and secondary components and analogues of natural bases of nucleic acids, for example, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8 -azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-b-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine,

B-fluorocytosine, Bb-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, b-thioguanine, 4-thiothymine, 4-thiouracil,

O5-methylguanine, Mb-methyladenine, O-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, pyrazolo|3,4-O|pyrimidines (US patents MoMob, 143,877 and 6,127,121; MO 01/38584 | and ethenoadenine | Gaztap 70 (1989), see Rgasiisa! Napdrook oi Viospetivhigu apa Moiesshiag Vioiodu, pp. 385-394, SKS Rgezv, Vosa Kap, E11.

Nucleic acid bases B can be attached in native nucleic acid configurations to the 1,3-oxathiolane component through a covalent bond between M-9 of purines, for example, adenine-O-yl and guanin-9-yl, or M-1 of pyrimidines, for example, thymin-1-yl and cytosin-1-yl | Viaskrygpi, Sat. apa sSai, M.

Edw. "OMA apa EMA zvigysiige" ip Misiewis Asiiv ip Spetivigu apa Vioiodu. 274 Edyop, (1996) Ohio Opimegvyu 75 Rgezv, pp. 15-81).

Also, in the structure of 1,3 oxathiolane nucleoside presented above, K is H, C.-C-v alkyl, C.4-C18 substituted alkyl, Co-Si alkenyl, Co-Si substituted alkenyl, Co-Si alkynyl, Co-Si substituted alkynyl, Cs-Coo aryl, Ce-Coo substituted aryl, Co-Coo heterocycle, Co-Coo substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy or prodrug component.

Physiologically functional derivatives of emtricitabine also include ZTS (lamivudine, ErimigF), a reverse transcriptase inhibitor approved in the United States for the treatment of HIV-1 infection in combination with AT as

Sotrbimikyu (SiakhoztiKiipe). US Patent MoMo5859021; 5905082; 6177435; 5627186; 6417191. Lamivudine (US patents MoMo5587480, 5696254, 5618820, 5756706, 5744596, 568164, 5466806, 5151426) has the following structure: I ko Sho a so talos shh z y ". and shk n still and z l-y

Shi t. is -e and and sh- - in -e and SCHE sho sh « liu She. With " shk i o s r y . , " For example and for some cases of therapeutic use of ZTS can be a physiologically functional derivative of emtricitabine in combination with tenofovir-OE or a physiologically functional derivative of tenofovir-OBK. (o e | It is clear that tenofovir-SUOE and emtricitabine and their physiologically functional derivatives can exist in - keto- or enol tautomeric forms, and the use of any of their tautomeric forms is covered by the scope of the present invention. , that is, with the presence of no more than about 595 (wt/wt) of the corresponding enantiomer. o PRODRUGS "I The invention includes all prodrugs of tenofovir and emtricitabine. Typical prodrugs of tenofovir are tenofovir disoproxil fumarate (TOR, Mihead?t). A large number of different the structure of prodrugs was described for phosphoric acids |Rgeetap apa Kozv, Rgodgevz5v ip Medisipai Spetivigu. 34:112-147 (1997)). A popular class of prodrugs is the acyloxyalkyl ester, which was first used as prodrugs for carboxylic acids and later applied to phosphates and phosphonates |see Ragdiyag ei ai. (1983) 3. Rpagt. All together. 72:324; and also (F, US Patents MOMo 4816570, 4968788, 5663159 and 5792756). Later, acyloxyalkyl ester was used for

Ho) delivery of phosphoric acids through cell membranes and to increase oral bioavailability. Close to the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester can also increase oral bioavailability as a component of the prodrugs in the combination compounds according to the invention. Aryl esters of phosphorus groups, in particular, phenyl esters, are reported to increase oral bioavailability (Oyeyi atbegi ei ai. (1994) 3). Honey. Spent 37:498). Phenyl esters have also been described that contain a carboxylic ester in the ortho-position to the phosphate (Kpatpei apa Togtepse, (1996) 9. Med. Spec. 39:4109-4115). Benzyl esters are reported to form the parent phosphoric acid. In some cases, substituents in the ortho- or para-position can accelerate hydrolysis. Benzyl analogues with adilated phenol or alkylated phenol can form a phenol compound through the action of enzymes, for example, esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to form phosphoric acid and a quinonemethide intermediate compounds

Examples of this class of prodrugs are described in the publication MiisNei! e( AI. (1992) ). Spent Zos. RegKip Tgapv. 1 2345;

Vgook ei aI., MO 91/19721. Other benzylic prodrugs have been described, which contain a group containing a carboxylic ester attached to benzylic methylene (Sialieeg ei aI., UMO 91/19721). Thio-containing prodrugs have been reported to be useful for intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group where the thiol group is either an esterified acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide forms a free intermediate thio-compound, which subsequently decomposes into phosphoric acid and episulfide (Resp ei ai. (1993) Apiimigai Kev., 22.155-174; /o Vegpapa ei a. (1996) U. Mei. Spet. 39:4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds.

Ester prodrugs according to the invention are independently selected from the following groups: (1) mono-, di- and triphosphate esters of tenofovir or emtricitabine or any other compound which, when administered to humans, can provide (directly or indirectly) the aforementioned mono-, di - or triphosphate ester, (2) esters of carboxylic /5 Acids, (3) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (4) amino acid esters (for example, alanine, I -valyl, or I -isoleucyl); (5) phosphonate; and (6) phosphonamidate esters.

Ester groups (1)-(6) can be replaced by linear or branched C.4-C-alkyl (for example, methyl, p-propyl, butyl or p-butyl); C5-C4io cycloalkyl; Alkoxyalkyl (for example, methoxymethyl); arylalkyl (for example, benzyl); aryloxyalkyl (for example, phenoxymethyl); C1-C0 aryl (e.g., phenyl, optionally substituted, e.g., halogen, C 4-C, alkyl, C-C, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ) , , , , , , , , , , , , , , , , , , , , , , , , , , -сн,гос(-Ф)ов (for example, РОС) where KZ is C-C alkyl, C--Cv substituted alkyl, C-C0 aryl or Ce-C20 substituted aryl. For example, ester groups can be: - СНОС(хО)С(СН 3)з, -"СНоС(ООС(СН 35)3 or -СНОС(-ООСН(СН 3)»). с

Examples of the aryl component present in such esters are a phenyl or substituted phenyl group. at

Many components of phosphate prodrugs are described in US patent Mob312662; dopez her ai (1995) Apiimiga| Kezeagsi 27:1-17; Kisega ei ai. (1990) AIUB Caves. Thread Keigo Migivez 6:491-501; Riapiadov ei ai. (1991) 9). Honey. Spent 34:1408-14; New Mpeg ei aiYi. (1992) Apiitishor. Adepiv SPetoijpeg. 36:2025-29; NozvieTseg ei aiYi. (1990) ..

VioI. Spent 265:611127; and Zidaidnzi her a. (1999) 3. Med. Spent 42:4122-28. -

A pharmaceutically acceptable prodrug is a compound that is metabolized in the host, for example, hydrolyzed or oxidized, either by enzymes or by general acid or base solvolysis, to form the active ingredient. Typical examples of prodrugs of the active ingredients of the combinations of the invention have biologically unstable protective groups on the functional component of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, esterified, -- deesterified, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, or subjected to other changes or transformations of the functional group, including the formation or breaking of chemical bonds on prodrugs.

CHEMICAL RESISTANCE OF THE PHARMACEUTICAL COMPOSITION «

The chemical stability of the active ingredients in the pharmaceutical composition is important to minimize the formation of contaminants and ensure a sufficient shelf life. The active ingredients, tenofovir-c disoproxil fumarate and emtricitabine, in the pharmaceutical composition according to the invention have relatively low pKa values, which indicate the potential for causing acid hydrolysis of the active ingredients. is" Emtricitabine, which has a pKa of 2.65 (Etigima tm Rhodisi Ipzegi, Sied Zsiepsevs, Ips. 2003, which can be purchased through diiegd.soti, undergoes hydrolytic deamination of the 5-fluorocytosine nucleic acid base to form the 5-fluorouridine nucleic acid base. Tenofovir disoproxil fumarate, which has a pKa of 3.75 about GMtsap her. ei ai. "Oedgadayop Kipeisv oi Ohusagropuiokhuteyu! Rgodgidv oi RIpozrpopaifev ip o boiIshiop", - Rpagtasetsshiisai Kezeagspy (2001) Moi. 18, Mo. 2, 234-237), also subjected to hydrolytic deamination of the exocyclic amine of the adenine base of the nucleic acid and hydrolysis of one or both ROS-ester groups -i (US patent Mo5922695). It is desirable to form a therapeutic combination of tenofovir disoproxil fumarate and "c 20 emtricitabine and their physiologically functional derivatives with minimal contamination and sufficient stability.

The combinations of the present invention provide combined pharmaceutical dosage forms that are chemically resistant to acid cleavage of: (1) a first component (such as tenofovir disoproxil fumarate and physiologically functional derivatives); (2) a second component (such as emtricitabine and physiologically functional 29 derivatives; and (3) optionally, a third component that has antiviral activity. The third component includes anti-HIV agents that include: protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NRTIs) and integrase inhibitors.io) Examples of third active ingredients that are administered in combination with the first and second components are shown in

Tables A. The first and second components are defined in the section presented above entitled: ACTIVE 60 INGREDIENTS OF THE COMBINATIONS.

SALT

Any reference to any of the compounds in the compositions according to the invention also includes any physiologically acceptable salt thereof. Examples of physiologically acceptable salts of tenofovir-OR, emtricitabine and their physiologically functional derivatives are salts derived from an appropriate base such as an alkali metal bo (e.g., sodium), an alkaline earth metal (e.g., magnesium), ammonium, and MXA" (where X is C-C4 alkyl), or an organic acid such as fumaric acid, acetic acid, succinic acid. Physiologically acceptable salts of a hydrogen atom or an amino group are salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isothionic, 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.

Physiologically acceptable salts of a hydroxy group compound include the anion of the aforementioned compound in combination with an acceptable cation, such as Ma" and MX" (where X is independently selected from H or C-C alkyl).

For therapeutic use, the salts of the active ingredients of the combinations according to the invention are physiologically acceptable, that is, they are salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable can also be used, for example, for obtaining or purifying a physiologically acceptable compound. All salts, whether derived from a physiologically acceptable acid or base, are encompassed within the scope of this invention.

INTRODUCTION OF COMPOSITIONS

Although it is possible to administer the active ingredients of the combination separately as monotherapy agents, it is preferred to administer them as pharmaceutical co-prescribing agents. A two-component or three-component combination is administered simultaneously or sequentially. When sequentially administered, the combination is administered once, twice, or three times.

Preferably, the two-component or three-component combinations are administered in a single pharmaceutical dosage form. In an even more preferred embodiment, the two-component combination is administered as a single oral dosage form, and the three-component combination is administered as two identical oral dosage forms. Examples are one tablet of tenofovir disoproxil fumarate and emtricitabine or two tablets of tenofovir disoproxil fumarate, emtricitabine and efavirenz.

It should be considered that the compounds of the combination can be administered: (1) simultaneously by combining the compounds in a joint formulation or (2) alternately, that is, with the delivery of the compounds serially, sequentially, in parallel, or simultaneously in separate pharmaceutical compositions. In intermediate therapy, the delay in the introduction of the second and, optionally, the third active ingredient, should not be such that the benefits of the synergistic therapeutic effect of the combination of active ingredients are lost. With either route of administration (1) or (2), ideally, the combination should be administered in such a way as to achieve a peak plasma concentration of each /-|h of the active ingredients. For some HIV-positive patients, an oral, co-prescription combination regimen that involves taking one pill once a day may be appropriate. The effective peak concentration in plasma of the active ingredients of the combination is a concentration in the range of approximately 0.001 to 100 µM. The optimal peak plasma concentration is achieved by determining the prescription and dosage regime for a specific patient. It should also be understood that tenofovir-OE and emtricitabine or physiologically functional derivatives of either, whether administered simultaneously or sequentially, may be administered separately, in multiple amounts, or in any combination thereof. Generally, in intermittent therapy (2), an effective dose of each compound is administered serially, and in co-prescribing therapy (1), effective doses of two or more compounds are administered together.

PRESCRIPTION OF COMBINATIONS «

If the individual components of the combination are administered separately, each of them is usually present as a pharmaceutical composition. References to compositions below refer, unless otherwise indicated, to compositions containing any combination or component compound thereof. It is understood that the administration of the combination according to the invention "" by means of a single patient kit or patient kits containing each composition, according to an information insert which instructs the patient on the correct use of the invention, is a desirable additional feature of the present invention. The invention also includes a dual a kit that includes, in the case of separate administration, a composition of tenofovir disoproxil fumarate and emtricitabine or a physiologically functional derivative of either or both of them. - Combination therapy according to the invention includes: (1) a combination of tenofovir-OEE and emtricitabine or (2) -And a combination that contains a physiologically functional derivative of either or both of them.

The combination is formulated in unit dose form, which includes a constant amount of each active ingredient, pharmaceutical ingredient for a periodic, for example, daily, dose or subdose of the active ingredients. "I Pharmaceutical compositions according to the present invention include a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic agents. Pharmaceutical compositions that contain the active ingredient can exist in any form suitable for the intended method of administration. For oral use, for example, tablets, pills, lozenges, aqueous or oily suspensions, dispersed powders or granules, (F, emulsions, hard or soft capsules, syrups or elixirs (Ketipdiop'z Ripagtaseciisa! Zsiepsez (Mask Rybiizpipa) are obtained

Ho) So., Eaviop, RA)). Compositions intended for oral administration are prepared according to any method known to those skilled in the art for the manufacture of pharmaceutical compositions, and such compositions 60 may contain one or more agents, including antioxidants, sweeteners, flavors, colors, and preservatives, in order to providing a composition acceptable for internal reception. Tablets containing the active ingredient admixed with a non-toxic pharmaceutically acceptable excipient suitable for tableting are acceptable. Such fillers can be, for example, inert diluents, such as calcium and sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, 65 calcium or sodium phosphate; granulating or disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic;

and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be coated by known methods, including microencapsulation, to slow down disintegration and absorption in the gastrointestinal tract, and thus ensure a sustained action over a longer period. Example,

A time-delay material such as glyceryl monostearate or glyceryl distearate is applied alone or with a wax.

Oral compositions may also exist as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as pregelatinized starch, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with 7/0 Water or an oily medium such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions according to the invention contain active materials mixed with fillers acceptable for the production of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic, and dispersing or wetting agents such as a natural phosphatide (e.g., lecithin), an alkylene oxide condensation product with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (e.g., heptadecaethyleneoxyethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid, and hexitic anhydride (e.g., polyoxyethylene sorbitol monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl or p-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavors, and one or more sweeteners, such as sucrose, sucralose, or saccharin.

Oil suspensions are formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain a thickener such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners, such as those indicated above, and flavoring agents are added to provide a composition acceptable for oral administration. These compositions are preserved by adding an antioxidant such as (8) ascorbic acid, BNT, etc.

Dispersible powders and granules according to the invention, suitable for making an aqueous suspension by adding water, involve the presence of an active ingredient mixed with a dispersant or wetting agent, sometimes with a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified above. Additional fillers may also be present, 9 such as sweeteners, flavors and colors. uh-

Pharmaceutical compositions according to the invention can also exist in the form of an oil-in-water emulsion or a liposomal composition. The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers are natural resins such as gum arabic and tragacanth, natural phosphatides such as soy lecithin, esters or partial esters derived from fatty acids and hexitic anhydrides such as sorbitol monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitol monooleate. The emulsion may also contain sweeteners and flavorings. Syrups and elixirs are formulated with sweeteners such as glycerin, sorbitol or sucrose. Such compositions may also contain a sedative, a preservative, a flavoring agent, or a coloring agent.

Pharmaceutical compositions according to the invention can exist in the form of a sterile injectable composition, for example, a sterile injectable aqueous or oily suspension. This suspension is formulated by methods known to those skilled in the art using the aforementioned acceptable dispersing or wetting agents and suspending agents. The sterile injectable composition may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Acceptable neutral carriers and solvents that may be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fatty oils are traditionally used as solvents or suspending medium. For this, any soft fatty oil is used (Ce), including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are also used in injectable compositions.

Pharmaceutical compositions according to the invention are administered by parenteral, for example, intravenous, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, intramuscular or subcutaneous injections, or are administered by infusion. In the best version, they are used in the form of a sterile aqueous solution, which may contain other substances, for example,

HF) a sufficient amount of salts or glucose, which make the solution isotonic with blood. If necessary, water

F solutions are appropriately buffered (optimally - to a pH of 3 to 9). The preparation of a suitable parenteral composition under sterile conditions is carried out by standard pharmaceutical methods well known to specialists in this field.

Pharmaceutical compositions according to the invention are also administered intranasally or by inhalation and delivered in the form of dry powder inhalation compositions or an aerosol from an aerosol container under pressure or a nebulizer using a suitable propellant gas, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane such as 1,1 ,1,2-tetrafluoroethane (NES 65 134a), carbon dioxide or other acceptable gas. In the case of an aerosol under pressure, the unit dose is limited by the use of a valve that ensures the delivery of a measured amount. The pressurized container or spray can contain a solution or suspension of the composition, for example, when using a mixture of ethanol and propellant gas as a solvent, and can additionally contain a lubricant, for example, sorbitol trioleate. Capsules and ampoules (made, for example, of gelatin) for use in an inhaler or insufflator are prescribed as follows

IN WHICH they contain powder mixtures of a compound of formula (I) and a suitable powder base such as lactose or starch. Aerosol or dry powder compositions are optimally composed in such a way that each measured dose or "cloud" contains from 20 μg to 20 mg of the composition for delivery to the patient. The total daily dose in the case of an aerosol is from 2Omkg to 2Omg, which can be administered in a single dose or, more often, in several doses during the day. 70 The amount of active ingredient that is combined with the carrier material to form a single-dose form may vary depending on the subject being treated and the particular mode of administration. For example, a sustained-release composition intended for oral administration to a human may contain from about 1 to 100 ug of active material combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 9595 of the total amount of the composition ( mass:mass). 7/5 Pharmaceutical compositions are prepared in such a way as to provide easily measured amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of active ingredient per milliliter of solution to provide the possibility of infusing an acceptable volume at a rate of about 30 ml/h. As mentioned above, compositions according to the present invention, suitable for oral administration, may exist as separate units, such as capsules or tablets, each of which contains a given amount of active ingredient; as powders or granules; as a solution or 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 is also used as a bolus, electuary or paste.

The combinations according to the invention can exist as pharmaceutical compositions in unit dosage form.

A convenient single-dose composition contains active ingredients in any amount from c about Mg to g each, for example, from 10 d 30Omg. Synergistic effects of tenofovir-OE in combination with emtricitabine are achieved in a wide range, for example, from 1:50 to 50:1 (tenofovir-OR'emtricitabine). In one embodiment (8), the ratio may be from about 1:10 to about 10:1. In another embodiment, the weight/weight ratio of tenofovir and emtricitabine in a co-prescribed combination dosage form, such as a pill, tablet, or capsule, is about 1, i.e., provides about equal amounts of tenofovir-OE and emtricitabine. In other examples of co-prescribing, more or less tenofovir than ETS may be provided. For example, 300mg of tenofovir-OE and 200mg of emtricitabine can be co-prescribed in a ratio of 1.5:1 (tenofovir-OR:emtricitabine). In one embodiment, each compound is used in combination in an amount in which it exhibits antiviral activity when used separately. Typical

Compositions A, B, C, 0, E and E (Examples) have a ratio of 12:1 to 1:1 (tenofovir-OR: emtricitabine). In the same

With Typical Compositions A, B, C, O, E and E, the amount of tenofovir-SUOE and emtricitabine from 25 mg to so

ZOOmg The scope of the invention includes other ratios and amounts of compounds of the above-mentioned combinations.

The unit dosage form may also include tenofovir-UE and emtricitabine, or physiologically functional derivatives of either, and a pharmaceutically acceptable carrier.

Those skilled in the art will appreciate that the amount of active ingredients in the combinations of the invention required for therapeutic use may vary depending on various factors, including the nature of the condition being treated and the age and condition of the patient, and its final determination rests with the physician or practitioner. Factors to be considered include the route of administration and nature of the formulation, the subject's body weight, age and general condition, and the nature and severity of the disease being treated. For example, in the Phase III emtricitabine monotherapy study, patients were dosed

Between 25 mg and 200 mg twice a day for two weeks. At each dose regimen greater than or equal to 20 .mu.g, 98 percent (1.75 10) or greater viral suppression was observed. A single daily dose of 200 mg of emtricitabine reduced the viral load by an average of 99 percent (1.92 Id 10). Migeadt (tenofovir-OR) has been approved by the Food and Drug Administration (FDA) for the treatment and prevention of HIV infection as a 300-milligram tablet for oral administration. Etigima tm 5p (emtricitabine) was approved by the GOA for the treatment of HIV as a 200-milligram tablet for oral ix) use. It is also possible to combine any two active ingredients in a single dosage form for simultaneous or sequential administration with a third active ingredient. The three-component combination is administered simultaneously or sequentially. With sequential administration, the combination is administered two or three times. Third active ingredients have anti-HIV activity and include protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NRTIs), and integrase (F) inhibitors. Examples of third active ingredients for administration in combination with tenofovir-OR, emtricitabine and their physiologically functional derivatives are shown in Table A.

Table A in 5,6 dihydro-5-azacytidine 5-aza 2'deoxycytidine 5-azacytidine 5-yl-carbocyclic 2'-deoxyguanosine (BM5200,475) 9 (arabinofuranosyl)guanine; 9-(2" deoxyribofuranosyl)guanine 65 9-(2'-deoxyg2'fluororibofuranosyl)-2,6-diaminopurine 9-(2'-deoxyg'fluororibofuranosyl)guanine

9-(2'i-deoxyribofuranosyl)-2,6 diaminopurine 9-(arabinofuranosyl)-2,6 diaminopurine

Abakavir, / LadepF

Acyclovir, ASU; 9-(2-hydroxyethoxylmethyl)guanine

Adefovir dipivoxil, Nerzegaya amdoxyvir, OARO

Amprenavir, Adepegazeyu agaA; 9-8-O-arabinofuranosyladenine (Vidarabine) 70 atazanivir sulfate (Keua(ahv)

JSC; 3-azido-2,3'-dideoxythymidine, Zidovudine, (Keihomigk) vno -)-(1Ta,26,Za)-9-(2,3-bis(hydroxymethyl)cyclobutylguanine vM5200,475; 5-yl-carbocyclic 2 '-deoxyguanosine

Buciclovir; (K) 9-(3,4-dihydroxybutyl)guanine

Urge); 1-4-O-arabinofuranosyl-E-5-(2-bromovinyl)uracil (Sorivudin)

Kalanolide A

Capavirin sro; carbocyclic 2'-deoxyguanosine

Cidofovir, NRMRS; (5)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine

Klevudin, I-EMAI; 2'-fluoro-5-methyl-p-I -arabino-furanosyluracil

Sotrimige (lamivudine/zidovudine)

Citallen; (|1-(4-hydroxy-1",2'-butadienyl)cytosine а4сС; 3-deoxy-2,3'-didehydrocytidine

BAROB; (-)-8-0-2,6-diaminopurine dioxolane Ha aaA; 2,3'-dideoxyadenosine o aaARK; 2,6-diaminopurine-2,3-dideoxyriboside aas; 2',3'-dideoxycytidine (Zalcitabine) aa; 2,3'-dideoxyinosine, didanosine, (Midekh?, Midech? EC)

Delavirdine, Kezgyriog -

Didanosine, aa, MidekhF); 2',3'-dideoxyinosine rxho; dioxolan guanosine F

E-5-(2-bromovinyl)-2'--deoxyuridine

Efavirenz, Zyviimayu

Enfuvirtides, Hygeope -

E-aha-A; fluoroarabinosyladenosine (Fludarabine) p

Eros; (-)-B8-Y-5-fluoro-1-(2-(hydroxymethyl)-1,3-dioxolane|cytosine

REA; 2'-deoxy-2'-fluoro-1-8-O-arabinofuranosyl-5-ethyluracil

US; 1-(2-deoxy-2-fluoro-p-O-arabinofuranosyl)-5-iodocytosine "

IAC; 1-(2-deoxy-2-fluoro-p-O-arabinofuranosyl)-5-iodouridine

EGO; 2,3-dideoxy-3'-fluoroguanosine - with EI T; 3'-deoxy-3'-fluorothymidine "» Fludarabine; E-aga-A; fluoroarabinosyladenosine " EMAI; 2-Fluoro-5-methyl-p-I -arabino-furanosyluracil

Emmas 15 Foscarnet; phosphonoformic acid, REA and ERMPA; 9-(3-fluoro-2-phosphonylmethoxypropyl)adenine Ganciclovir, OSM; 9-(1,3-dihydroxy-2-propoxymethyl)guanine 5-7340:9-I(K-2-I(((5)-((5)-1-(isopropoxycarbonyl)ethylIiamino|-phenoxyphosphinyl)methoxy| propyl|adenine and HRMPA; (5)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine "se 50 HRMPS; (5)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (Cidofovir)

Hydroxyurea, Ogohiabye Indinavir, Stihimape Kaiyigaf (lopinavir/ritonavir) "m Lamivudine, ZTS, Erimigtm; (2K, 55, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)- (1H)-pyrimidin-2-one

I-a4cS; And -3'-deoxy-2",3'-didehydrocytidine

I-aas; I -2,3'-dideoxycytidine 59 I-gads; 1-3-deoxy-2,3'-didehydro-5-fluorocytidine

F! I-gaas; I-2',3'-dideoxy-5-fluorocytidine

Lopinavir ki Nelfinavir, Migaserke

Nevirapine, Migatipeyu 60 Oxetanocin A; 9-(2-deoxy-2-hydroxymethyl-p-O-erythro-oxetanosyl)adenine

Oxetanocin 0; 9-(2-deoxy-2-hydroxymethyl-p-O-erythro-oxetanosyl)guanine

Penciclovir

RMEBVAR; 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine 65 RMPA, tenofovir; (K)-9--2-phosphonylmethoxypropyl)adenine

PRA; phosphonoacetic acid

Ribavirin; 1-84-YUO-ribofuranosyl-1,2,4-triazole-3-carboxamide

Ritonavir, Mogmigeo

Saquinavir, Ipmigaze?b), Rogiomaseyu

Sorivudin, Vmaga; 1-4-O-arabinofuranosyl-E-5-(2-bromovinyl)uracil

Stavudin, a4t, 7egikyu; 2,3'-didehydro-3'--deoxythymidine

Trifluorothymidine, TET; Trifluorothymidine

Titigimige (abacavir sulfate/lamivudine/zidovudine)

Vidarabin, agaA; 9-4-O-arabinofuranosyladenine

Zalcitabine, NimiafF, aas; 2',3':dideoxycytidine

Zidovudin JSC, Keigomige; 3'-azido-2",3'-dideoxythymidine 7-opamig, 5-propynyl-1-arabinosyluracil

Another aspect of the present invention relates to a three-component combination that includes tenofovir-OE, ETS and 9-((k)-2-((5)-((5)-1-(isopropoxycarbonyl)ethylamino)phenoxyphosphinyl|methoxy|propyl|adenine, also 75 is designated by the authors as 35-7340, which has the following structure: yo - zak: и и. о ДИ со -

And ko "DY: o. but I : y z y Z : sv yai iv o. a y g g" in se ke and "V I: gi shcha sta A o

E and L. and not yet: in , "Zh. vv - her and KE. I and E-- V g shk cha and Ne V i Y x I (e) ; ze R 7 I e chu po izad a r sa s Y --- ' y sho ; 55-7340 is a prodrug of tenofovir and is the subject of US application serial number 09/909,560, filed on July 20, 2001, which is jointly owned and pending, and the patent in the name of VesKeg ei a. MO ts 02/08241. "» For example, a three-component unit dose may contain from 1 mg to 1000 mg of tenofovir disoproxil fumarate, from 1 mg to 1000 mg of emtricitabine and from 1 mg to 1000 mg of the third active ingredient. Another feature of the present invention is that the unit dosage form may also include tenofovir-OE, (se) emtricitabine, a third active ingredient or physiologically functional derivatives of the three active ingredients, and a pharmaceutically acceptable carrier. - The combinations according to the present invention give patients more freedom due to multi-dose regimens - AND drug treatment and facilitate proper adherence to the regimen, which requires remembering and following a complex schedule of daily dosing. By combining tenofovir disoproxil fumarate and emtricitabine in a single-dose form, the required daily regimen can be represented by a single dose or by two or three sub-doses per day. The co-prescribed combination of tenofovir-OE and emtricitabine is administered as one pill once daily.

Another aspect of the invention relates to a kit for a patient that includes at least one active ingredient: tenofovir disoproxil fumarate, emtricitabine or a physiologically functional derivative of any of the combination of compounds and an information package or insert for the product that contains instructions for the use of (F) the combination according to an invention km Separation of active ingredients in pharmaceutical powders and granules is a widely recognized problem that leads to incompatibility of dispersions of active ingredients in final dosage forms. One of the main 60 factors that contribute to separation is the size, shape and density of the particles. Separation creates particular problems when trying to formulate a single homogeneous tablet that contains many active ingredients that have different densities in different particle sizes. Flow agents are substances traditionally used to improve the flow characteristics of granules and powders by reducing friction between particles. See publication Iiereptap, Gasptap, 5 Zspmagi. RNagtaseciisai Yuozade Rogte: Tariyeeiv. Moiishte 1. p. 177-178 65 (1989), incorporated by the authors by reference. Flow agents are usually added to pharmaceutical compositions just prior to tablet compression to facilitate the flow of granular material into the die cavities of tablet presses. Flowing agents include: colloidal silicon dioxide, asbestos-free talc, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metal stearates, calcium stearate, magnesium stearate, zinc stearate, vieagozhei C, starch, starch 1500, magnesium lauryl sulfate and magnesium oxide.

A typical composition of tablet A contains colloidal silicon dioxide (Examples). Fluidity agents are used to increase and promote the homogeneity of the mixed composition when prescribing anti-HIV drugs | US patent

Mob 1139201. The new compositions according to the present invention may contain flow agents to ensure and maintain the homogeneity of the active ingredients during processing before stamping tablets. 70 The present invention provides pharmaceutical compositions by combining the active ingredients tenofovir-OE and emtricitabine or their physiologically functional derivatives in a sufficiently homogenized form and a method of using such pharmaceutical compositions. The purpose of this invention is to use flow agents to reduce the separation of active ingredients in pharmaceutical compositions during the processing of the material before stamping. Another purpose of this invention is to provide a pharmaceutical composition /5 By combining the active ingredients tenofovir-OE and emtricitabine or their physiologically functional derivatives with a pharmaceutically acceptable fluidizing agent, which results in a mixture characterized by a pharmaceutically acceptable degree of homogeneity.

Compositions according to the invention include compositions suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) use. The compositions may exist in dosage unit form and may be prepared by any means known to those skilled in the pharmaceutical art. Such methods are another feature of this invention and include the step of binding the active ingredients to the carrier, which includes one or more auxiliary ingredients, and maintaining chemical stability. In general, the compositions are obtained by uniformly and thoroughly binding the active ingredients with liquid carriers or finely dispersed solid carriers, or both, followed by product formation if necessary. (8)

Compositions according to the present invention, suitable for oral administration, can exist as separate units, such as capsules, ampoules or tablets, each of which contains a given amount of active ingredients; as powders or granules; as a solution or 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 exist as a bolus, electuary or paste.

The tablet is made by compression or molding, optionally with one or more auxiliary (22) ingredients. Stamped tablets are obtained by pressing in a suitable machine the active ingredients in an edible, free-flowing form, such as powders or granules, optionally mixed with a binder (eg, povidone, gelatin, hydroxypropyl methylcellulose), a lubricant, an inert diluent, and a preservative. , a disintegrator (for example, sodium starch glycolate, cross-linked povidone, cross-linked with sodium carboxymethyl cellulose), surfactant or dispersant. Molded tablets are made by casting a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and may be formulated to provide a sustained or controlled release of the active ingredients they contain, using, for example, cellulose ether derivatives (eg, hydroxypropyl methylcellulose) - with or methacrylate derivatives in different proportions to ensure the desired release profile. Tablets may optionally have an enteric coating to ensure release in parts of the digestive system other than the stomach.

Compositions suitable for topical oral administration include lozenges that include the active ingredients in an aromatic base such as sucrose and gum arabic or tranacanth; lozenges that include the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes that include the active ingredient in a suitable liquid carrier. Compositions for rectal administration may exist in the form of suppositories on a suitable basis, which includes, for example, cocoa butter or salicylates. Local administration is also carried out with the help of a transdermal means of 5p ontophoresis. (Ce) Compositions suitable for vaginal administration may exist in the form of pessaries, tampons, creams, gels, pastes, foams, or aerosol compositions that contain, in addition to the active ingredient, carriers deemed acceptable by those skilled in the art.

Compositions suitable for penile use for prophylactic or therapeutic use may exist in the form of condoms, creams, gels, pastes, foams or aerosol compositions that contain, in addition to the active ingredient, carriers that are considered acceptable by those skilled in the art.

GF) Pharmaceutical compositions suitable for rectal administration in which the carrier is solid, preferably

The variant exists in the form of single-dose suppositories. Acceptable carriers are cocoa butter and other materials commonly used in the art. Suppositories are formed by mixing the active combination with the softened or molten carrier(s) after cooling and molding.

Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the solution isotonic with the blood of the intended recipient; aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners; liposomes or other microparticulate systems, 65 designed to target the compound to blood components or one or more organs. The compositions may exist in sealed containers for single or multiple doses, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid vehicle, such as water for injection, immediately prior to administration. Solutions and suspensions for injections prepared for immediate administration are obtained from sterile powders, granules and tablets of any type described above.

Typical dosage compositions are those containing a daily dose or daily sub-dose of the active ingredients as indicated above, or their respective parts. It should be understood that in addition to the ingredient specifically indicated above, compositions according to the present invention may include other agents conventional in the art that are relevant to the type of composition in question, for example, agents that are suitable for oral administration, 7/0 may include such agents as sweeteners, thickeners and flavoring agents.

The compounds of the combination according to the present invention are prepared in a conventional manner known to those skilled in the art. Tenofovir disoproxil fumarate is prepared, for example, as described in US Pat. No. 5,977,089. Methods of obtaining ETS are described in UMO patent 92/14743, incorporated by the authors by reference.

APPLICATION OF COMPOSITION

The compositions of the present invention are administered to a human or other mammal in a safe and effective amount as described by the authors. This safe and effective amount may vary depending on the type and size of the mammal being treated and the desired results of the treatment. Any of the various methods of packaging tablets, pills, or other solid dosage forms suitable for oral administration that prevent disintegration of the components of the present invention are acceptable for packaging applications known to those skilled in the art. Combinations are packed in glass or plastic bottles. Tablets, pills, or other solid dosage forms suitable for oral administration may be packaged and contained in various packaging materials, which optionally include a desiccant, such as silica gel. Packaging may be provided in the form of blister packaging for single doses. For example, a package may contain one blister pack of tenofovir-OE and a second blister pack of emtricitabine pills, tablets or capsules. high school

The patient should take one dose, such as a pill, from one tray and one from the other. Alternatively, the package may contain a blister pack of the co-prescribed combination of tenofovir-OE and emtricitabine (8) in a single pill, tablet or capsule. Like other combinations and packages, combinations according to the invention provide physiologically functional derivatives of tenofovir-OE and ETO.

The packaging material may also have labeling and printed information relating to the pharmaceutical composition. In addition, the package from the manufacturer may contain a brochure, notice, note, booklet or prospectus containing information about the product. This form of information about a pharmaceutical product in the pharmaceutical industry is called an "advertising insert." An advertising insert may be added or included in the pharmaceutical product. The advertising insert and any labeling of the products communicates information related to the pharmaceutical composition. Information and labeling provide various forms of information used by physicians and patients, including information on composition, dosage, and various other parameters required by regulatory agencies such as the Food and Drug Administration.

ANALYSIS OF COMBINATIONS

Combinations according to the invention will be tested for anti-HIV activity and sensitivity and cytotoxicity in laboratory-adapted cell lines such as MT2 and peripheral blood mononuclear cells (PBMCs) according to standard assays designed to test compounds against

HIV, for example, according to UUO patent 02/068058 and US patent Mob475491. Analyzes of the combinations are carried out with different concentrations of the compounds of the combinations for the determination of Есв5о by means of serial dilutions.

TYPICAL COMPOSITIONS

The following examples also describe and illustrate specific embodiments that are within the scope of this invention. Methods and compositions, as a rule, are described in Ketipdiop's publication

Rpagtaseciisa! Zsiepsez | Mask Rybiizpipud So., Easiop, RA). The examples are presented solely for illustration purposes and should not be construed as limiting, as many variations are possible without departing from the spirit and scope of the invention. The following examples are provided for illustration purposes only and do not in any way limit the scope of the invention. "Active ingredient" means tenofovir disoproxil fumarate, (Ce) emtricitabine or a physiologically functional derivative of any of them. «m Tablet composition

The typical compositions A, B, C, O, E and E presented below are obtained by wet granulation of the ingredient with an aqueous solution, addition of finely granulated components, followed by addition of magnesium stearate and pressing.

Composition A: o mg/tablet di Tenofovir disoproxil fumarate Zoo 60 Emtricitabine 200

Microcrystalline cellulose 200

Lactose monohydrate 175

Croscarmellose sodium 516)

Pregelatinized starch 50 65 Colloidal silicon dioxide 5

Magnesium stearate 10 total: 1000

Composition B: 2 mg/tablet

Tenofovir Disoproxil Fumarate Zoo Emtricitabine 100

Microcrystalline Cellulose 200

Lactose monohydrate 180 to Sodium starch glycolate 516)

Pregelatinized starch 50

Magnesium stearate 10 total: 900

Composition C: mg/tablet

Tenofovir Disoproxil Fumarate 200 Emtricitabine 200

Microcrystalline cellulose 200

Lactose monohydrate 180

Sodium starch glycolate 516)

Pregelatinized starch 50

Magnesium stearate 10 s 29 in total: 900 Ge)

Composition 0: mg/tablet -

Tenofovir Disoproxil Fumarate Zoo Fo Emtricitabine 25

Microcrystalline cellulose 200 -

Lactose monohydrate 180 "-

Sodium starch glycolate 516)

Pre-gelatinized starch 50 g)

Magnesium stearate 10 in total: 825

Composition E: "8 s mg/tablet h Tenofovir disoproxil fumarate 200 units" Emtricitabine 25

Microcrystalline cellulose 200

Lactose monohydrate 180 (ee) Sodium starch glycolate 516) - Pregelatinized starch 50

Magnesium stearate 10 -| in total: 725 mg Composition E: mg/tablet

Tenofovir Disoproxil Fumarate 100 Emtricitabine 100

Microcrystalline cellulose 200 (F. Lactose monohydrate 180 ko Sodium starch glycolate 516)

Pregelatinized starch 50 bo Magnesium stearate 10 total: 700

Composition C (composition of controlled release):

This composition is prepared by wet granulation of the ingredients with an aqueous solution followed by the addition of magnesium stearate and pressing.

mg/tablet

Tenofovir Disoproxil Fumarate Zoo Emtricitabine 200

Hydroxypropyl. methylcellulose 112

Lactose V.R. 53

Pre-gelatinized starch V.R. 28

Magnesium stearate 7 in total: 700

The release of the medication begins within a period of approximately 6-8 hours and is completed after 12 hours.

Compositions of capsules

Composition N:

The composition for the capsule is prepared by mixing the ingredient and filling a double hard gelatin or hydroxypropyl methylcellulose capsule. mg/capsule

Active ingredient BOO0

Microcrystalline cellulose 143

Sodium starch glycolate 25

Magnesium stearate 2 in total: 670

Composition I (capsule of controlled release): see

The composition for a controlled-release capsule presented below is prepared by extruding ingredients a, b and c using an extruder, followed by spheronization of the extrudate and drying. The dried granules are then coated with a release control membrane (9) and filled into double hard gelatin or hydroxypropyl methylcellulose capsules. m mg/capsule b (a) Active ingredient 500 (5) Microcrystalline Cellulose 125 - (c) Lactose BP. 125 h: (4) Eethylcellulose 13

In total: 763 so

Composition.) (Oral suspension):

Active ingredients are mixed with the ingredient and in the form of a dry powder. Add purified water and mix before use. - c Active ingredient BOOmg "c Confectioner's sugar 2000mg " Simethicone ZbOmg

Methylparaben ZOmg

Propylparaben 1Omg (omg) Flavoring, peach 5OOmg ko h Purified water a.5. up to 5.0 Oml Composition K (suppository): 20 One-fifth of Umierzoi H15 is melted in a vessel with a steam jacket at a maximum temperature of 459°C. The active ingredients are sieved through a 200 micron sieve and added to the molten base while mixing using a 5-mm egg gop equipped with a cutting head until a uniform dispersion is achieved.

Keeping the mixture at a temperature of 459C, the rest of UMyerzo is added to the suspension! NI5 and stir to ensure a homogeneous mixture. The entire slurry is passed through a 250 micron stainless steel sieve and allowed to cool to 40°C while stirring. At a temperature from 382C to 402C, place 2.02 g

GF! mixture into appropriate 2-milliliter plastic molds. Suppositories are allowed to cool to room temperature. co mg/suppository

Active ingredient BOO0 bo Solid fat, V.R. (Miervoi NI5 - Oupatii Mobei) 1770 in total: 2270

COMBINED TABLET WITH A FIXED DOSE

A fixed-dose combination tablet of 300mg tenofovir disoproxil fumarate (TOR)/200mg 65 emtricitabine was formulated using a wet granulation/fluidized bed drying process using conventional methods. See: OZ 5935946; I. Uotsipo (Edyog). Tabieiipd Zresiisayop Mapia! 517 units Avvzosiaiop, MUMUazpipdiop, OS, (2001); |. Iasptap, N. Iiereptap (eaiiogv).

Rpagtaseciisai bozade ERogtv: Tabrievev (Mo! 2), MagseI YuOeKkKeg Ips., Mem/ Mogk, 185-202 (1981); 9. T. Gei apa 3.

M. Meulop, 9. RIapt. Rnaptasoi. 20, 657-659 (1968); 05 RIaptasorrhoea 24-Myope! Rogtshagu 19, "Tabiye

Fragility", Sparieg "1216", Rade 2148 (2000).

The influence of the water level during granulation (from 4095 to 5095 (wt/wt)) and the time of raw mass formation was studied on the physicochemical properties of the final powder mixture and its characteristics regarding the homogeneity of the mixture and its compressibility (tablet thickening). In addition, content homogeneity, stability, and dissolution characteristics were determined for TOG/emtricitabine fixed-dose combination tablets. 70 Prescribing equipment

The equipment included a high-shear mixer equipped with a high-pressure tank and spray nozzle for adding granulating water, and a fluidized bed dryer, grinder, drum mixer, rotary tablet press and dust collector.

Prescribing process

The dried, finely ground powder was mixed with finely granulated microcrystalline cellulose and croscarmellose sodium and then mixed with magnesium stearate. Powder samples were taken after mixing with magnesium stearate. Samples of the mixture were evaluated for bulk density, granulometric composition and compressibility. The powder mixture mixed with magnesium stearate was pressed into tablets on a stamping machine.

Materials

Table 1 below gives the quantitative composition of the tablet composition with TOR/emtricitabine. sch 2v

Pre-yellowish Fokhmal MER. 50111111 90111111010110000000

Croscarmellose natyu MAE 000001006901001111000600111111010000ot

Lactovy monohydrate, MEERYA 00000080 t mya F

Purified water OVRER Svv i- -

b Water removed during drying.

Equipment for characterization «

Moisture content was measured by shrinkage using a heating lamp/balance system. A sample of the powder mixture was taken using a sampler equipped with cameras to determine the homogeneity of the powder-c mixture. Duplicate samples were taken from each of several locations in the mixer. The analysis of the homogeneity of the mixture was carried out on one sample from each location. is" Particle size analysis of the final powder mixture was determined by sieving a several-gram sample through a sieve using an ultrasonic filter. The amount of the final powder mixture retained on each sieve and in the fine fraction collector was determined by calculating the mass difference between the sieves and the fine fraction collector (se) before and after the test. The geometric mean diameter of the particles was calculated by logarithmic weighting of the scattering of the sifted material.

The bulk density was determined by filling the graduated cylinder with the final powder mixture and measuring the mass difference between the empty and filled graduated cylinder per unit volume.

Tablets were characterized for friability using a friability tester, a hardness tester, a thickness micrometer equipped with a printer, and scales. "I Compression characteristics were determined using a rotary press for tablets, equipped with a perforator with beveled edges and a flat surface, designed for a mass of 400 mg. The powder mixtures were pressed using the set pressure of the upper perforator from approximately 100 to 250MPa. Apparent normalized ejection force was determined and normalized for tablet thickness and diameter.

Tablet hardness was determined using a hardness tester. The thickness of the tablet, o, was determined using a micrometer, and the weight of the tablet was determined using pharmacy scales.

Kkz Wet granulation

The powders were mixed in a granulator and then granulated using water. because the speed of the impeller and chopper was maintained in the mixer at a constant low level during the operations of granulation and the formation of raw mass. After adding water, the impeller and chopper were stopped and the granulator tank was opened to check the consistency and structure of the granules. The lid was closed and the raw mass formation phase was carried out. Acceptable pellets had 4095 (w/w) and 6095 (w/w) water, respectively.

Wet grinding 65 To facilitate the uniform drying process, each wet granulate was subjected to deagglomeration using a grinder equipped with a sieve and an impeller. The ground wet granules were loaded. in a fluidized bed dryer immediately after wet grinding.

Drying in a fluidized bed

The ground wet granules were dried using a set inlet air temperature of about 702 and an air flow rate of about 100 psi. The given OO was approximately 1.095 in a range of no more than (MMT) 1.595. The total fluidized bed drying time ranged from 53 to 75 minutes. Terminal

The GO ranged from 0.495 to 0.795 for all dried portions. The final temperature of gas pumping for all portions was from 472C to 5020C.

Dry grinding

All dried granules were ground by passing through a perforated sieve. The chopper was equipped with a square impeller and turned on. Batches were ground and manually transferred to the M-mixer.

Mix

Each batch was mixed using an M-mixer. In one group of three compositions, with an initial amount of 12 kg of materials, after mixing, the final powder mixture for pressing was obtained in the amount of 10.5 kg of 75 (87.595) to 11.1 kg (92.595). The final bulk density of the powder mixture was from 0.48 to 0.58 g/cm3, and the average geometric diameter of the particles was from 112 to 221 µm. The percentage of water and the time of formation of the raw mass affected the particle size and bulk density of the final powder mixture.

Mixing of powders for both tenofovir-OER and emtricitabine gave a mean (n-10) strength index for tenofovir-SUOE ranging from 100.695 to 102.895 of the specified batch strength, and the relative mean deviation (RMV) ranged from 0.595 to 1.795. The mean strength index (n-10) for emtricitabine ranged from 101.395 to 104.195 of the set strength for the lots with a relative mean deviation (RMV) of 0.695 to 1.795.

The moisture level of the final powder mixture was between 0.895 and 1.195 00.

Stamping tablets

The final mixtures were compressed using a rotary tablet press and the tablets were covered with film. Ge

Three compositions of 300 g (Table 2) were granulated in a granulator equipped with tank 1-Y. The amount of intragranular components was determined by the total size of the batch of ZOOg. The compositions in batches 1 and 2 differed in the amount of microcrystalline cellulose, which was 30956 and 2095 (w/w), respectively.

Batches 2 and 3 were identical except for the type of binder. Batch 2 contained 595 (w/w) pregelatinized starch and batch C contained 595 (w/w) povidone as a binding agent. Cha

F

- zv co

Crosscarmeloa natyu MER 1110010000050000010008600160

Lacquer monohydrate MER 0000010008000001000086001000vo « o no s Cleaned ode oPER 1111111011a110111a11111a . and? (se) After adding water, the impeller and chopper were stopped and the tank of the granulator was opened to check the consistency and structure of the granules. To achieve a similar granule consistency, batches 1, 2 and Z were granulated with 4595, 4095 and 3095 (w/w) of water, respectively. The lid was closed and the raw mass formation phase was carried out. - All batches had a raw mass formation time of 30 seconds, as a result of which acceptable granulation was achieved.

Wet pellets from all batches were manually screened through a sieve for deagglomeration. The resulting i-th granules were dried on pallets in a convection oven set at 602C for approximately 20 hours to 00 "and "1.095. The dried granules from all batches were sifted by hand through a sieve. In order for the granules to fit into a small (30Oml) M-mixer, the portion size of the final mixture was adjusted to 100g. Part, 81g obtained as a result of the mixture from Batch 1, was mixed with 15g of microcrystalline cellulose, 3g of croscarmellose sodium and 1g of 2o magnesium stearate. 8bg of the resulting granules from Batch 2 and Batch C were mixed with 10g of microcrystalline cellulose, 3g of croscarmellose sodium and 1g of magnesium stearate. i) Purity analysis was carried out by HLC (high-performance liquid chromatography) with phase reversal. The impurities related to tenofovir disoproxil fumarate and emtricitabine were characterized and measured in the main mass of API (active pharmaceutical ingredient) before formulation in three batches, 60 as shown in Table 2, and then again after formulation in the final tab summers Contaminants include by-products of hydrolysis of exocyclic amino groups of tenofovir disoproxil fumarate and emtricitabine and hydrolysis of disoproxil (ROS) esters of tenofovir disoproxil fumarate. In each lot, the total amount of impurities related to tenofovir disoproxil fumarate and emtricitabine was less than 195 after formulation and tablet manufacturing. b5 Physicochemical properties of tenofovir disoproxil fumarate and emtricitabine tablets were determined by appearance, water content, indicated strength, content of pollutants and decomposition products, and tablet dissolution. Stability studies were performed on medications packaged in packaged product storage systems that are identical to intended clinical and commercial packaged product storage systems. No signs of discoloration or cracking of tablets were observed during the stability study.

Film-coated tablets of tenofovir disoproxil fumarate and emtricitabine showed satisfactory stability at 402C/75905 KH (relative humidity) for up to six months when packaged and stored with a silica gel desiccant. No significant loss (defined as decay » - 595) of the indicated strength of tenofovir-OE or emtricitabine was observed after six months at 4029/7595 KN when packaged and stored with a desiccant. The increase in total degradation products was 1.595 for tenofovir-OE and 0.6-0.796 for emtricitabine after 70 six months at 402C/7595K when packaged and stored with 3 grams of desiccant.

All publications and patent applications cited by the authors are incorporated by reference, just as they would be if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

Although specific embodiments have been described in detail above, it will be clear to those skilled in the art that numerous modifications can be made to the claims without departing from their essence. All these modifications are covered by the scope of the claims.

Options for implementing the invention:

A1. A pharmaceutical composition that includes an effective amount of a compound of the formula: 2 . t not What. IN

KE M SHK zh shi "I'm looking for DG (y shchi chh sh sh

Sho. It

Riv Ne "ya, (o) pe, -KE and | pe

Sh ke | Mr.

R t YN "Zhe -

Zh g 1 tk iy. - in t 3o By da pnrud F i y - in shk And what t. t o: - dn ; ach ' zt z yy y oz Shan (ge) h - SHE ssh ik. si v: ovi « a o s svy; t co; . and (0) where KE! Yes? independently selected from H, C.4-Cv alkyl, C--Cv substituted alkyl, Cbe-Coo aryl, Cc-Coo co substituted aryl, Cc-Coo arylalkyl, Cc-Coo substituted arylalkyl, acyloxymethyl esters -CHNOS(- :O)B - and acyloxymethyl carbonates -"СНОС(-FOORB), where KZ is C.-Cv alkyl, C--Cv substituted alkyl, Cbe-Coo aryl-1 and Ce-Coo substituted aryl;

BZ is selected from H, C1-Ce alkyl, C1-Ce substituted alkyl or SNOR, where BZ is C1-Ce alkyl, C4-C8 (Ce) hydroxyalkyl and C4-C8 haloalkyl; "M VE? and KE? independently chosen from among H, MN", MNE and MK", where K is C.4-Ce alkyl; and 25 and KE" are independently selected from H and C.4-Cv alkyl; or its physiologically functional derivative; in combination with an effective amount of the compound of the formula ko 60 b5

W ryn puppies gi

TE no Ky y - Kv n Yu, kt t F. y i de B is selected from among adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, t 7-deaza-8-azaguanine, 7 -deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-b-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine, 5-chlorocytosine,

B5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, b-thioguanine, 4-thiothymine, 4-thiouracil, Ob-methylguanine,

M9-methyladenine, O-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole and pyrazolo!|3,4-O|pyrimidine; and

K is selected from H, C1-C8 alkyl, C1-C8 substituted alkyl, C0-C8 alkenyl, C0-C8 substituted alkenyl, C0-C8 alkynyl, C0-C10 substituted alkynyl, C0-C0 aryl, C0- Co substituted aryl, C2-C20 heterocycle, Co-Coo substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy; or its physiologically functional derivative; and (8) a pharmaceutically acceptable carrier.

B2. The composition according to embodiment At, in which in formula 1 B " and BK? are independently selected from

H, C4-C6 alkyl, C--C6 substituted alkyl, C6-C6 aryl, C6-C6 substituted aryl, C6-C6 arylalkyl, C6-C6 substituted arylalkyl, acyloxymethyl esters -СНоОС(-О)К9 and // acyloxymethyl carbonates Fo -Sn.os(-Fov 9. where BZ is C.-Cv alkyl, C4-Cv substituted alkyl, Cv-Coo aryl and Cv-Coo substituted aryl; and 23, c", ve", 5 and B" are independently H or C.-Cv alkyl. -

C3. The composition according to the embodiment of AT, in which in the formula 2 B is cytosine or 5-halocytosine. - ri. A composition according to an embodiment of AT, in which in formula 1, B " and B? are independently selected from

Co H, C4-Ce alkyl, C--Cv substituted alkyl, Ce-Coo aryl, Cc-Coo substituted aryl, Cc-Coo arylalkyl, Ce-C2o co substituted arylalkyl, acyloxymethyl esters -СНоОС(-О)Б? and / acyloxymethyl carbonates -СН-ОосС(хFOОВ), where B is C.-Ce alkyl, C4-Cv substituted alkyl, Ce-Coo aryl and Ce-Coo substituted aryl; and

BZ, B, c", B and KE" are independently H or C-C alkyl; and in formula 2, B is cytosine or 5-halocytosine.

E5. The composition according to embodiment О 4, in which in the formula 1 B! and B? independently choose from among H, c acyloxymethyl esters -СНООС(-О)ВО and acyloxymethyl carbonates -СН»ОС(-ООВУ, where КО is С.-С5 "with alkyl; and КЗ, 7, 5, Kb and K/ independently is H or C-C alkyl; and in formula 2, B is cytosine or "5-halocytosine, and K is H.

Ev. The composition according to embodiment E5, in which in the formula 1 B! and B? are independently chosen from among H and CO 395 -CHgOS(-:FOOSH(CH 3)"; BZ is -CHu; and B, 5, 9 tav is H; and in formula 2, B is 5-fluorocytosine, and B. is N. 07. Pharmaceutical composition, which includes a pharmaceutically effective amount of fumarate - disopropoxycarbonyloxymethyl ester of 1(2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl-phosphonic acid (tenofovir disoproxil fumarate) or its physiologically functional derivative and fPharmaceutically effective - amount of (2,55,)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one "about 50 (emtricitabine) or its physiologically functional derivative; and a pharmaceutically acceptable carrier.

H8. A pharmaceutical composition according to embodiments A1 to 7, which also includes a third active

Another 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. 19. Pharmaceutical composition according to variants of embodiment with AT! by HB in the form of a dosage unit. 59 310. A method of treatment or prevention of symptoms or effects of HIV infection in an infected animal, which

GF) includes administering to the above-mentioned animal a pharmaceutical composition in accordance with embodiments A1 to 19.

Claims (2)

The formula of the invention 1. Oral pharmaceutical dosage form containing tenofovir disoproxil fumarate, emtricitabine and Zyviima. 2. Stable oral dosage form containing tenofovir disoproxil fumarate 30 905 wt./wt., emtricitabine 20 905 wt./wt., peptized starch 5 90 wt./wt., croscarmellose sodium b 905 wt./wt., because lactose monohydrate 8 95 wt./wt., microcrystalline cellulose ZO 95 wt./wt., magnesium stearate 1 95 wt./wt. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, MZ, 11.02.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. with (8) ch (2) cha ch- so - s;" so - - (This) that F) ko 60 b5