TWI230610B - Dosage kits and pharmaceutical compositions for treating HIV infections - Google Patents

Abstract

The present invention relates to therapeutic combinations of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1592U89), 3'-azido-3'-deoxythymidine (zidovudine) and (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC) (or, alternatively to 3TC, (2R,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (FTC)) which have anti-HIV activity. The present invention is also concerned with pharmaceutical compositions containing said combinations and their use in the treatment of HIV infections including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors.

Description

1230610 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention (1) The present invention relates to (1 S, 4R) -cis · 4- [2 · amino-6 with anti-HIV activity -(Cyclopropylamino) -9Η · Buyin-9-yl] _2-pentyl-1-methyl (1592U89), 31-azido-31-azido-thorax (zidovudine) and (2R, Cis) _4_amino-1- (2-hydroxymethyl-1,3-oxothiocarb-5-yl)-(1Η) · pyrimidin-2-one (3TC) (or (2R, cis Formula) Therapeutic combination of 4-amino_5_fluoro-1_ (2-merylmethyl-1,3_oxothiopent-5-yl H1H) -pyrimidin-2-one (FTC instead of 3TC) The present invention also relates to a pharmaceutical composition comprising the combination and its use in the treatment of HIV infections, including infections with HIV mutant strains resistant to nuclear tritium and / or non-nuclear tritium inhibitors. Azide chest Glycosides are currently identified as important and beneficial chemotherapeutic agents for the treatment and / or prevention of related clinical conditions such as AIDS, AIDS-related complex (ARC), AIDS dementia complex (ADC), and For the treatment of patients with asymptomatic HIV infection or anti-HIV antibody positive. Treatment with azidothymidine prolongs the asymptomatic period and delays the death of symptomatic patients with HIV infection. With the widespread clinical application of azidothorax in the treatment of such infections and conditions, it has been observed By extension of treatment in some examples, the virus may develop a specific degree of resistance to azidothym and therefore lose sensitivity to the drug. The therapeutic agent 1592U89 (European specification EPO434450) is a promising anti-HIV chemistry Candidate for treatment (23rd International Conference on Antiviral Research, April 1995), which exhibits potent activity against HIV, low cytotoxicity and excellent penetration into the brain, and is associated with AIDS and HIV such as ADC Treatment of sexual central nervous system conditions is important. Nuclear tritium analogues containing oxanine residues instead of sugar residues, for example, this paper size applies Chinese National Standard (CNS) A4 (210X297 mm) (please (Read the precautions on the back before filling this page) 1230610 A7 B7__ 5. Description of the invention (2), see the nuclear tritium class described in European Patent Specification No. 382526, especially 4-amino_1- (2-tamarind -1,3-oxothiophene-5_yl)-(1Η) _ρMiyodo-2- 嗣 (BCH-189) has been found to have anti-HIV activity. BCH-189 is a pair of racemic mixtures And although the enantiomers are equally effective against HIV, the (-) _ enantiomer is considerably less cytotoxic than the (+) _ enantiomer. The (-)-enantiomer has a chemical name (2R, cis ) -4-Amino-1-hydroxymethyl-1,3-oxothiocarb-5-yl)-(1H) · Xiaodian-2-one, now called 3TC or lamivudine. Another selective oxanine nucleoside analogue is described in International Specification No. W092 / 14743 (2R, cis) -4 · amino_5-fluoro-1 · (2 · hydroxymethyl-1,3 -Oxothiopent-5-yl) _ (1H) _pyrimidin-2 · one, generally referred to as FTC or 524W91. At present, most of the treatments for HIV infection are based on monotherapy of nuclear tritium reverse transcriptase inhibitors, such as azidothymidine, didanosine (ddl), zalcitabine (ddC), and stavudine (D4T). However, these drugs eventually become less effective due to the generation of HIV-resistant mutants or due to toxicity. Therefore, novel treatments are needed. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The combination of azide thorax and ddC or ddl has shown the desired results in HIV-infected patients (New Eng. J. Med 1992, 329 (9) 581-587, and Program Abstract 1993 9R International Conference on AIDS, abstract US-B25-1). The combination of azide chest falcon and 3TC has also been studied and widely reported. It should be noted, however, that these results are surprising because drugs with the same site of action are often antagonistic or additive (Rev Infect · Dis 1982, 4, 255-260). Surprisingly, it has been found that through the combination of 1592U89, azide chest flea, and 3TC, a synergistic anti-HIV effect is obtained: The result is -5- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 1230610 A7 B7 V. Description of the invention (3) Surprisingly, because all three drugs act on the same molecule, HIV reverse transcriptase. The characteristics of the present invention are that the application of this drug combination will provide a synergistic antiviral effect, more complete viral suppression, a longer period of viral suppression, limit the generation of drug-resistant HIV mutants and allow drug-related Better control of toxicity. Compound FTC can be used as an alternative to 3TC. Therefore, according to one aspect, the present invention provides a combination comprising 1592U89 or a physiologically functional derivative thereof, azide thorium or a physiologically functional derivative thereof, and 3TC (or, optionally, FTC Replace 3TC) or its physiologically functional derivative. It will be recognized that azidothymidine can exist in keto or enol tautomeric forms and the use of any tautomeric form is within the scope of the present invention. 3TC and 1592U89 will generally be provided in a form substantially free of relevant enantiomers, that is, no more than about 5% w / w of related enantiomers, preferably no more than about 2% w / w, especially Will exist at less than 1% w / w. As used in this article, the proper term "physiologically functional derivative" includes any physiologically acceptable salt of 1592U89, azide breast tincture, or 3TC, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please Read the notes on the back before filling out this page) Ethers, esters, salts of this ester; or any of its solvents and their physiologically functional derivatives; or can be provided (directly or indirectly) when applied to a recipient ) This compound or any other compound of the antiviral active metabolite or its residue. 0 Preferred esters according to the present invention are uniquely selected from the following groups: (1) carboxylic acid esters in which the carboxylic acid moiety of the ester group The non-carbonyl part is selected from the linear or branched chain (for example, methyl, chromo-propyl, f-butyl, or 5L-butyl), -6- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1230610 A7 B7 5. Description of the invention (4) Cycloalkyl, alkoxyalkyl (eg, methoxymethyl), aralkyl (eg , Benzyl), aryloxyalkyl For example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, haloyl, Cw alkyl, or c1-4 alkoxy), or amine; (2) sulfonate (E.g., alkyl- or aralkylsulfonyl) (for example, methanesulfonyl); (3) amino esters (for example, L-valinyl or L. isoleucine); and (4) Phosphonates. In this ester, unless stated otherwise, any beneficially-derived alkyl group contains from 1 to 18 carbon atoms, especially from 1 to 6 carbon atoms', more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in the g-class may advantageously contain 3 to 6 carbon atoms. Any aryl moiety present in the ester may advantageously contain a phenyl group. Any of the above Any reference to the compound also includes references to its physiologically acceptable salts. Particularly preferred esters are azide chest: g :, 3TC (which can be selectively protected) or FTC or can provide when applied to the human body ( Directly or indirectly) the mono-, di-, and triphosphates of any other compound of mono-, di-, and triphosphates. 1592U89 is preferred The organism is ㈠carbovir's triphosphate vinegar. Examples of physiologically acceptable salts of 1592U89, azidothymidine or 3TC and their physiologically acceptable derivatives include derivatives derived from alkali metals (eg, sodium), alkaline earths (eg Magnesium), ammonium and NX4 + (wherein the parent is (: 1-4 alkyl) and other appropriate base salts. _ The physiologically acceptable salts of amines or amine groups include organic carboxylic acids such as acetic acid, lactic acid, tartaric acid , Malic acid, isethionic acid, lactobionic acid and succinic acid, organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluic acid, and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, and Salts of aminosulfonic acid, etc. Physiologically acceptable salts of hydroxy compounds ζ 0 This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) Packing-U * (Please read the note on the back first (Fill in this page again)

, TT 1230610 A7 B7 V. Description of the invention (5) Including the combination of the anion of the compound with appropriate cations such as Na +, NH4 + and NX4 + (where X is Cp4 alkyl). (Please read the notes on the back before filling this page) As a therapeutic application, 1592U89, the salts of azidothymidine and 3TC will be physiologically acceptable, that is, they will be derived from physiologically acceptable acids or Alkali salts. However, salts that are not physiologically acceptable acids or bases may find use, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the invention. The preferred salt of 1592U89 is succinate. The combination of 1592U89 or a physiologically functional derivative thereof, azide thorax or a physiologically functional derivative thereof and 3 T C or a physiologically functional derivative thereof may hereinafter mean a combination according to the present invention. The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs has printed the present invention to provide a combination according to the present invention for treatment, particularly for the treatment and / or prevention of HIV infections that include HIV mutant infections resistant to nuclear tritium inhibitors. In particular, azide chest falcon, 3TC, FTC, ddl, ddC or D4T or a combination thereof and non-nuclear inhibitors, WNevirapine (BI-RG-587), Loviride (a -APA) and Delavuridine (BHAP). Furthermore, the combination according to the present invention is particularly beneficial for the treatment of AIDS and related clinical conditions, such as AIDS-related syndrome (ARC), progressive comprehensive lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, and AIDS dementia AIDS-related neurological conditions of the complex, AHDS-related neurological conditions such as multiple scleroderma or tropical lower paresis, and anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients. According to another aspect, the present invention provides a method for treating or preventing infection.-Paper size suitable for household use (CNS) A4 size (210X297 mm) 1230610 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (6) For example, in mammals including humans, a method or method of affecting HIV infection, which includes the use of a therapeutically effective amount of 1592U89, azido thorax and 3TC (or, selective replacement with FTC) 3TC) or any combination of its physiologically functional derivatives. It will be recognized that the compounds of the combination may be administered simultaneously in the same or different pharmaceutical formulations or sequentially. When administered sequentially, the delay in administering the second and third active elements should not cause the combination of active elements to lose the advantage of synergistic therapeutic effects. It will also be understood that 1592U89, azide chest falcon, and 3TC (or, 3TC is selectively replaced with FTC) 'or any of its physiologically functional derivatives, whether presented simultaneously or sequentially, can be used individually or with The compound is applied in the form of any combination thereof. 1592U89, azide chest falcon and 3TC (or alternatively 3TC for FTC) are preferably administered simultaneously or sequentially in the form of separate pharmaceutical formulations, and are best administered simultaneously. The invention also provides the use of 1592U8 9 in mass production of medicaments for simultaneous or sequential administration of azidothora and 3TC (or, selective replacement of 3TC with FTC), respectively for HIV infection and related as described above Treatment and / or prevention of clinical conditions. 1592U89, azide chest falcon or 3TC (or, optionally, 3 T C replaced with FTC), or any combination thereof, to be recognized can be used in mass production of the above-mentioned agents. 1592U89, the synergistic effect of the combination of azide thorax and 3TC (or 3TC selective replacement with FTC) 'or any of their physiologically functional derivatives can be seen at a ratio, such as 1 to 20: 1 to 10 (weight ratio), 1 to 10: 1 to 10: 1 to 5 weight ratio is preferred, especially 1 to 3: 1 to 3: 1 to 2 (weight-9-this paper size applies to China National Standard (CNS) 8-4 specifications (210X297 public director) (Please read the notes on the back before filling out this page) Binding and ordering 1230610 A7 B7 ___ V. Description of the invention (7) ratio). Each compound will conveniently be employed in combination in the amount that exhibits antiviral activity when used alone. 1592U89, the combination of azidothymidine and 3TC (or, selective replacement of 3TC with FTC) is effective as an anti-HI V agent. The amount required will, of course, be different and ultimately determined by the doctor. Factors to be considered include the route of administration and the nature of the mash, the animal's weight, age and general condition, and the severity of the disease to be treated. In general, a suitable dose of 1592U89 for administration to humans for the treatment of HIV infection will be in the range of 0.1 to 100 mg per kg of body weight of a recipient per day, and within the range of 0.5 to 50 mg per kg of body weight per day. It is preferred and the range of 7 to 30 milligrams per kilogram of body weight per day is optimal. Generally speaking, a suitable dosage of azidothymidine will be in the range of 3 to 120 mg per kg of body weight per day, preferably in the range of 6 to 90 mg per kg of body weight per day and 10 to 30 mg per kg of body weight per day It is printed in the best park. It is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). For 3TC, the appropriate daily dose will be about 0.1 per kilogram of recipient's body weight per day. In the range of about 120 mg per day, a range of 0.5 to 75 mg per kg of body weight per day is preferred, and in the range of 1 to 40 mg per kg of body weight per day is optimal, such as 5 to 10 mg per kg of body per day. . In terms of FTC, a suitable daily dose will be in the range of about 0.1 to about 120 mg per kg of body weight of the recipient per day, preferably in the range of 0.5 to 75 mg per kg of body weight per day, and 1 to per kg of body weight per day. The best size is 40 grams, such as 5 to 10 milligrams per kilogram of body weight per day. -10- This paper size is suitable for financial and family standards ^^ Called 44 specifications (2 offering 297 mm) 1230610 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Printing A7 ~-~ -____ B7 V. Invention-〆 Unless otherwise specified It means that the total weight of the active ingredient is calculated based on the drug itself. In 1592U89, examples of physiologically functional derivatives of azide thorax or 3TC (or, with FTC selectivity 3 T C) 'or any of its solvents will increase proportionally. The desired dose is presented in two, three, four, five, six or more sub-dose forms administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage form. For example, the parent unit dosage form contains from 1 to 15 mg, preferably from 5 to 15 mg, and the most active ingredient is from 10 to 700 mg. Alternatively, when the condition of another person is so required, the dose may be administered by continuous infusion. A combination of ingredients, which may be referred to as an active ingredient, may be administered to an animal ' such as a human mammal for conventional treatment. Although the active ingredients of the combination may be administered in the form of a crude chemical agent, it is preferred that the kernel is presented in the form of a pharmaceutical wither. The pharmaceutical formulation according to the present invention includes a combination according to the present invention with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The carrier (class) must be acceptable in the sense that it is compatible with the other elements of the formulation and not harmful to its recipients. When the individual ingredients of a combination are administered separately, they are usually presented individually in the form of a pharmaceutical formulation. References to formulations below, unless otherwise indicated, mean formulations that include a combination or its ingredients. 1592U89, the combination of azide chest falcon with 3TC (or, optionally 3TC with FTC) or any physiologically functional derivative can be conveniently presented as a single-dose pharmaceutical formulation. A convenient single-dose formulation includes the active elements each from 50 mg to 3 g, for example from 0.00 mg to 2 g

--------- Installation-> _ (Please read the precautions on the back before filling this page) Order Φ

• I —i-I! 23〇61〇

V. Description of the invention (μ The formulations of the present invention suitable for oral administration can be presented in separate unit forms, such as capsules, caplets, caeget or lozenges respectively containing the previously determined active ingredients; in powder or granule form; in solution or in Aqueous solution or = suspension in aqueous solution; or liquid emulsion in oil winter water or water-in-oil liquid emulsion. Active ingredients can also be presented in the form of pills, tinctures or pastes. Lozenges can be compressed by Or a mold, optionally prepared with one or more auxiliary elements. Pressed tablets can be formed into powders or granules by pressing the active elements in a free-flowing form in a suitable machine, optionally with a binder (Such as polyvinylpyrrolidone, gelatin, hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium glycolate, crosslinked Povidone, crosslinked carboxymethyl Cellulose sodium), surfactant or dispersant are mixed to prepare. Casting pastilles can be prepared by powder compound moistened with inert liquid diluent. Scale preparation in a suitable machine. Lozenges can be optionally coated or scored and can be manufactured to provide slow or controlled release of the active ingredients used therein, for example, different proportions of trimethoprim Methylcellulose to provide the desired release sample g. The bonding agent can optionally be provided in an enteric coating form to obtain separate release in the intestines outside the stomach. Consumption by employees of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed C— * i (please read the notes on the back before filling out this page) I · Suitable formulations for oral application include sugar vortex, which contains active ingredients in a flavored base, usually sucrose And gum arabic or reed sugar; soft lozenges containing active ingredients in an inert base, such as gelatin and glycerol, or sucrose and gum arabic; and mouthwashes containing active ingredients in a suitable liquid carrier. Recipes for rectal administration may contain a suitable substrate-14- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1230610 A7 —— a _ ___5Z_ 一 _ V. Description of the invention (12) " " s The main form of the agent is that the matrix includes, for example, cocoa butter or salicylate. Local administration can also be performed by percutaneous iontophoresis. Suitable for use in Formulations for vaginal administration can be presented in the form of uterine condoms, stoppers, cream gels, pastes, foams or spray formulations, which contain active ingredients other than those known in the art as suitable vehicles. Suitable for rectal administration Pharmaceutical formulations, in which the carrier is a solid, mostly in the form of a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in this technology. Suppositories can be conveniently combined with softening by active combination Or molten carrier (class) is mixed and then cooled and shaped in the mold ^. ≪ Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain anti- Oxidants, buffers, bacteriostats and solvents that promote the formulation to be isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and Thickening agents, and valves designed to said plastid or calibration compound to blood components or one or more organ < microparticles other systems. The formulation can be in the form of unit_dose or compound_dose, such as ampoules and vials, such as ampoules and vials, which can be presented and stored in a freeze-dry environment. It only needs to be added with a sterile liquid carrier just before use. In water for injection. Temporary injection solutions and suspensions can be prepared from the same sterile powders, granules, and lozenges as described above. A preferred unit dose formulation is an active ingredient comprising a daily dose or a sub-dose, as described above, or an appropriate administerer thereof. It should be understood that in addition to the elements specifically mentioned above, considering the doubtful formulation < type, the formulation of the present invention may include other traditional C in this technology-f Please read the notes on the back before filling this page } 1T. D -15-1230610 A7 B7 V. Description of the invention (13) Medicinal agents, for example, suitable for oral administration may include further agents such as sweeteners, thickeners and flavoring agents. The compounds in the combination according to the invention can be obtained in a conventional manner. Azide breastcatchers can be prepared, for example, as described in U.S. Patent No. 4,724,232, which is incorporated herein by reference. Azide breast thighs are also available from Aldrich Chemical Co., Milwaukee, W1 53233, USA. 1592U89 can be prepared via the European specification EPO434450 or PCT application PCT / GB / 4500225, which is incorporated herein by reference, as described. The method used to prepare 3TC is described in International Patent Application No. W091 / 17159, which is incorporated herein by reference. The method used to prepare the FTC is described in International Patent Application No. W092 / 14743, which is incorporated herein by reference. The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. "• Active ingredient" means 1592U89, azidothymidine, 3TC (or, 3TC is selectively replaced by FTC), or a complex or a physiologically functional derivative of any of the foregoing compounds. Example 1: Formulation of lozenges The Consumer Cooperatives of the Central Standards Bureau of the Ministry of Material Economy printed the following formulations A, B and C, which were prepared by wet granulation of the elements and polyvinylpyrrolidone solution, followed by adding magnesium stearate and pressing.

Formulation A

Active element lactose B. P (please read the notes on the back before filling this page) mg / ingot 250 2 10 -16- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1230610 A7 B7 Description of the invention (14) polyvinylpyrrolidone B. P. 15 sodium starch glycolate 20 magnesium stearate 5 500 formulation B mg / bond active element 250 lactose BP 150 Avicel pH 101 60 polyvinylpyrrolidone B · P. 15 glycolic acid Sodium Starch 20 Magnesium Stearate 5 500 Formulation C mg / Hinge Active Element 250 Lactose BP 200 Starch 50 Polyacetone Biloxone 5 Magnesium Stearate 4 359 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

The following formulations, D and E, are made by directly pressing the mixed elements # Dairy Crest- " Zeparox, formulation D -17 in formulation E- This paper size applies Chinese national standards ( CNS) A4 specification (210X297 mm) 1230610 A7 B7 Description of the invention (15) mg / tablet active element 250 former gelatinized starch NF1 5 150 400 Formulation E mg / tablet active element 250 lactose BP 150 Avi c el 100 500 1 襞—— # I (Please read the notes on the back before filling in this page} Formulation F (Controlled release 詷 compound) This formulation is made by wet knees with elements and povidone solution ^, collar granulation and then add Preparation of magnesium stearate and compression. Mg / tablet active ingredient 500 hydroxypropyl methylcellulose 112 (Methocel K4M Premium) lactose B: P. 53 polyvinylpyrrolidone B. P. 28 magnesium stearate Ί 700 drug The release occurred for a period of about 6 to 8 hours and was completely released after ί hours. Example 2: Capsule Preparation-18- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 1 ---- -Order Printed by the Consumers 'Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs f / 4 1230610 A7 B7 V. Description of the Invention (16) Modified A printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A capsule formulation was prepared by mixing the formulation in Example 1 above D Zhiyao is prepared by filling into two hard gelatin capsules. Formulation B (below) is prepared in a similar manner. Formulation B mg / capsule active element 250 lactose B. P. 143 sodium starch glycolate 25 Magnesium stearate 2 420 碉 Compound C mg / capsule active element 250 Macrogel 4000 BP 3 50 6 00 Capsules of Formula C are prepared by melting Macrogel 4000 BP, dispersing the active elements in the marginal solution and filling the melt It is prepared by adding two parts of hard gelatin capsules. Formulation D mg / capsule active element 250 egg vat fat 100 esoteric oil 100 4 5 0 (Please read the precautions on the back before filling out this page} -19-

Cf I This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1230610 A7 B7 V. Description of the invention (17) The capsule of formulation D is prepared by dispersing the active elements in lecithin and peanut oil and filling the dispersion. Prepared in soft, elastic gelatin capsules. Formulation E (Controlled release capsules, the following controlled release capsules are extruded using an extruder to squeeze out the elements a, b and c, followed by spheronization and drying of the extrudate. The dried precipitate is then released using release The control film (d) is covered and filled into a two-piece type, hard gelatin capsule. Mg / capsule (a) Active ingredient 25 0 (b) Microcrystalline cellulose 125 (c) Lactose B · P. 125 (d ) Ethyl Cellulose 13-Pack-W 4 (Please read the notes on the back before filling this page) 1Τ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 5 13 Example 3: Injectable Formulation Formulation A mg Active ingredient 200 0.1 M hydrochloric acid solution or 0.1 M sodium hydroxide solution qs to pH 4.0 to 7.0 Sterile water volume is made up to 10 ml Active ingredient is dissolved in most water (3 5-40 ° C) and the pH is using hydrochloric acid Or sodium hydroxide is adjusted to be between 4.0 and 7.0. The batch is then replenished with water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sterile Sealed and hermetically sealed. -20- This paper size applies to Chinese national standards (CNS) Α4 specification (210 × 297 mm) 1230610 A7

Please read the notes on the back first

I

t

Packing 1230610 A7 B7 V. Description of the invention (19) 250 Active element hard fat, BP (Witepsol 1770 H15-Dynamit Nobel) 2020 One-fifth of Witepsol HI 5 is melted in the shallowest of the steam jacket at the highest 45 ° C Intraday. The active ingredient was transferred through a 200 micron screen and stirred to the melted matrix using a Silverson equipped with a cutting head until a smooth dispersion was obtained. While maintaining the mixture at 45 ° C, the remaining Witepsol H1 5 was added to the suspension and stirred to ensure uniform mixing. The entire suspension was passed through a 250 micron stainless steel sieve and, with continuous stirring, was allowed to cool to 40 ° C. At a temperature of 38 ° (: to 40 ° (:), 2.02 grams of the mixture is filled into a suitable, 2 ml plastic mold. The suppository is allowed to cool to room temperature. Mg / uterine condom active element 250 anhydrous glucose 380 horses Bell potato palace powder 363 Magnesium stearate 7 1000 Example 7: Printed by the Consumer Cooperatives of the Central Standards Bureau of the Uterine Intramenstrual Dripping Department (Please read the precautions on the back before filling this page) The above elements are directly mixed and passed The mixture was directly pressed to prepare a uterine condom. Biological test results Spikes and trough plasma levels -22- This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 1230610 A7 B7 V. Description of the invention (20) ) Spikes and troughs in micromolar concentrations used in this study were derived from clinically measured spikes and trough plasma levels. These are intended to reflect the solids achieved in patients when each drug is used as the therapeutic dose of a single agent Spike and trough plasma levels. Drug spike level (ju M) Trough level (ju M) Azide chest ridge 5 0.4 3TC 9 0.7 1592U89 3.5 0.1 FTC 10 0.5 alone or Combined antiviral activity anti-HIV test. Human T-cell lymphotropic virus type 1-transformed cell line MT4 was grown and, unless otherwise indicated, 10 times the amount required to cause a 50% reduction in MT4 cell growth (10X TCID50, 2X104 plaque forming units / cells) were infected with HIV-1 virus strain 3B or virus strain MN (Advanced Biotechnologies Inc., Columbia, Maryland). Cells imitating the control infection were also prepared. After 1 hour incubation Cells were pipetted into 96-well culture plates at 1 × 104 cells / well. These wells contained different concentrations of azidothymidine, as well as 3TC of spike and trough plasma levels (or, 3TC was selectively replaced with FTC), and As shown in Table 1, 1592U89. Infected T-lymphoid embryonic cells were cultured for 5 days to promote HIV-1 dominated growth inhibition. Then 28 microliters of phosphate-buffered saline (PBS) was used. A 5% Nonidet P-40 (Sigma) -treated culture plate and 60 microliters of specimens were transferred to a 96-well culture plate (Idexx Corp.) at the bottom of the paper. The culture plate was placed in an automatic analyzer (Idexx Screen Machine). In which it breaks propidium by -23 -This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) One pack-«(* (Please read the precautions on the back before filling this page)

1T Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs C / 1230610 A7 B7 V. Description of Invention (21) Into each well, perform a series of cleanings and measure the fluorescence (E) produced. Fluorescence has been shown to be directly related to cell number, which allows the quantification of HIV-1-dominated cytopathic effect (CPE). Uninfected cells were determined to have 0% CPE and infected untreated cells were determined to have 100% CPE. The percentage of inhibition of HIV-1 against CPE and IC95s (95 ° / 0 inhibitory concentration) was measured. Figure 1 illustrates the results of the combination and combination of 3TC and 1592U89 with respect to the azide breastcatcher and 3TC. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -24- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

12306ID A8 B8 II No. 8, 51,058,007 patent application plus Chinese patent application scope amendment (89 丨 〖〗 ^ 六, application scope of patent dagger 7 L A kind of treatment and / or prevention of HIV infection A pharmaceutical composition comprising (IS, 4R) -cis-amino-6- (cyclopropylamino) _9Η_purinedongyl] -2-cyclopentene-; μmethanol or a physiologically functional derivative thereof, Azathymidine or its physiologically functional derivatives and (2R, cis) glacial amino] _ (2_Cyclomethyl-1,3-oxothiophene_5_yl) _ (1Η) · pyrimidone Or a physiologically functional derivative thereof; wherein (IS, 4R) -cis-4- [2-amino-6- (cyclopropylamino) -9Η_ thyme-9-yl] -2-cyclopentazone -1-Methanol or its physiologically functional derivative ·· Azide breast function or its physiologically functional derivative: (2R, cis) -4-amino group (2-methyl-1,3-oxosulfanyl) The ratio of Wuyi-5-yl)-(1Η) -ρ Miyodo-2-one or its physiologically functional derivative is 1 to 20: 2 to 20: 1 to 1% by weight. 2 · —Species Pharmaceutical composition for the treatment and / or prevention of HIV infection, comprising (IS, 4R) -cis-bucket [2-amino groups (cyclopropylamino) -9 H-Purinyl] -2-cyclopentene small methanol or its physiologically functional derivative, azidothorax or its physiologically functional derivative, and (2R, cis) -cetyl-5_fluoro small (2 -Hydroxymethyl_1, j-oxothiopent-5-yl)-(ih) -bite-2 · one or a physiologically functional derivative thereof; wherein (IS, 4R) -cis-4- [ 2-amino-6- (cyclopropylamino) -9Η-purine_ 9-yl] -2-cyclopentene- 丨 -methanol or its physiologically functional derivative: azidothorax or its physiological function Derivatives: (2R, cis) -4-amino group, printed by the Central Laboratories of the Ministry of Economic Affairs of the Central Bureau of Standards and Consumers Cooperatives-丨, 3-oxothiopent-5-yl)-(1Η) The ratio of -ρ dense bite-2-one 1 or its physiologically functional derivative is 1 to 20 ··· to 20 ··· 1 to 10 by weight. 3. The pharmaceutical composition according to item 1 of the scope of patent application, combined with one or more pharmaceutically acceptable carriers. 4. The pharmaceutical composition according to item 3 of the scope of patent application, which is in unit dose. ^ This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 1230610 A8 B8 C8 D8. 5. A patient component comprising at least one active ingredient selected from the group consisting of (4,) cis-aminobenzyl (cyclopropylamino) -9H-thyrin-9-yl], 2iridium pentamidine-i Methanol, azidothymidine, and (2R, cis) _4_aminomonophenyl (2-¾ylmethyl), 3 · oxothiophene_5_yl hih) "pyrimidin_2_one, and 〇 王 # Information insert for use instructions of two active ingredients combined together 6. Kinds of components for patients, including at least one active ingredient, selected from (IS '4R) _cis_4 · [2_amino group _6_ (Cyclopropylamino) _State_Thrynyl] 2cyclopentene-fluorene_methanol, azidothymidine and (2r, cis) _4 · amino · 5 · fluoro-1- (2- Hydroxymethyl'3_oxothiophene_5_ylη1η) _pyrimidinone, and a message insert containing instructions for use in which all three active ingredients are combined together. Printed on the paper by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs China National Standard (CNS) Α4 specification (210 × 297 mm)