HRP980264A2 - Antiviral combinations - Google Patents

Description

This invention relates to therapeutic combinations of (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol (1592U89) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), which have anti-HIV activity. This invention also relates to pharmaceutical preparations containing the mentioned combinations, and to their use in the treatment of HIV infections, including infections with HIV mutants that carry resistance to nucleoside and/or non-nucleoside inhibitors.

Therapeutic agent 1592U89 (European specification EPO434450) is a promising HIV chemotherapeutic candidate (International Conference on Antiviral Research, April 23, 1995) that shows strong activity against human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AEDS), small toxicity and excellent brain penetration, which is significant for the treatment of AIDS and HIV-related central nervous system conditions such as AIDS insanity complex.

An attractive target for HIV inhibition is the virally encoded enzyme, reverse transcriptase (RT), which acts at the beginning of the viral replication cycle. Reverse transcriptase contains polymerase and ribonuclease components that are responsible for transcription of viral RNA in double-stranded DNA before integration with the gene in the cell. Reverse transcriptase inhibitors such as zidovudine didanosine, zalcitabine, and 1592U89 are all nucleosides that rely on cellular kinases to convert them to triphosphates, which are slow inhibitors of the natural substrate for RT. An attractive alternative strategy is the use of suitable non-nucleoside reverse transcriptase inhibitors.

Non-nucleoid reverse transcriptase inhibitors synthesized to date include HEPT, TIBO derivatives, atevirdine, L-ofloxacin, L-697,639, L-697-661, nevirapine (BI-RG-587), loviride (α-APA), delavuridine (BHAP ), phosphonoformic acid, benzodiazepines, dipyridodiazinones, 2-pyridones, bis(heteroaryl)piperazines, 6-substituted pyrimidines, imidazopyridazines, 1,4-dihydro-2H-3,1-benzoxazin-2-ones, such as (-)- 6-Chloro-4-cyclopropylethylyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266), and quinoxalines, such as isopropyl (2S)-7 - fluoro-3,4-dihydro-2-ethyl-3-oxo-1-(2H)-quinoxalinecarboxylate (HBY 1293), HBY 097, or MKC442.

It was found that combining 1592U89 and non-nucleoid reverse transcriptase inhibitors achieves a synergistic anti-HIV effect. It is a characteristic of this invention that the application of such a drug combination will provide one or more of the following effects: synergistic antiviral effects, more complex viral suppression, viral suppression over a longer period, limiting the appearance of drug-resistant HIV mutants, and/or enabling better management of drug-related toxicities.

According to one aspect of the invention, a combination comprising 1592U89, or a physiologically functional derivative thereof, and a non-nucleoid reverse transcriptase inhibitor is provided.

Another feature of the present invention is a combination comprising 1592U89, an NNRTI, and a secondary reverse transcriptase inhibitor, for example lamivudine. The ratios of the components of such combinations will most often be the same as the ratios of the relevant compounds in the double combinations of the invention.

In a further aspect of this invention, a combination containing 1592U89, an NNRTI, and an HIV protease inhibitor is presented. The ratios of the components of such combinations will most often be the same as the ratios of the relevant compounds in the double combinations of the invention.

Examples of protease inhibitor compounds include those described in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/16501, WO 95/16688, WO/US94/13085, WO/US94/12562, US 93/59038, EP 541168, WO 94/14436, WO 95/09843, WO 95/32185, WO 94/15906, WO 94/15608, WO 94/04492, WO 92/08701, WO 95/32185, and US Pat. 5,256,783, especially (S)-N-((.alpha.S)-((1R)-2-((3S, 4αS, 8αS)-3-(tert-butylcarbamoyl) octahydro-2-(1H)- isoquinolyl)-1-hydroxyethyl)phenethyl)-2-quinaldaminosuccinimide monomethanesulfonate (saquinavir), N-(2(R)-hydroxy-1(S)indanyl)- 2(R)-(phenylmethyl)-4-(S)- pentanamide (indinavir), 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis (phenylmethyl )-2,4,7,12-tetraazatridecan-13-onic acid, 5-thiazolylmethyl ester (ritonavir), (N-(1,1-dimethyl) decahydro-2-[2-hydroxy-3-[(3-hydroxy- 2-methylbenzoyl) monomethanesulfonate (nelfinavir), and related compounds.

Another aspect of the present invention is a combination comprising 1592U89, a second reverse transcriptase inhibitor, for example, lamivudine, an NNRTI, and an HIV protease inhibitor. The ratios of the compounds of such combinations will most often be the same as the ratios of the relevant compounds in the double or triple combinations of the invention.

As used herein, the term "physiologically functional derivative" includes any physiologically acceptable solvate, salt, ether, ester, salt of such ester, or solvates of any such salt, ether, or ester, of 1592U89 or NNRTI(s); or any other compound which, after introduction into the recipient, is capable of providing (directly or indirectly) such a compound or its antiviral active metabolite.

Preferred esters according to the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl portion of the carboxylic acid portion is an ester grouping selected from normal or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1 -C alkyl, or C 10 alkoxy), or amino; (2) sulfonate esters, such alkyl- or aralkylsulfonyl (for example, methanesulfonal); (3) amino acid esters (for example, L-valyl or L-isoleucyl); and (4) phosphonate esters. In such esters, unless otherwise specified, any alkyl moiety present preferably contains from 1 to 18 carbon atoms, especially from 1 to 6 carbon atoms, more precisely from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters preferably contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters preferably contains a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.

Preferred derivatives of 159U89 are mono-, di-, and tri-phosphate esters of (1R,4S)-9-[4-(hydroxymethyl)-2-cyclopenten)-1-yl]guanine (carbovir).

Examples of physiologically acceptable salts of 1592U89 or NNRTI(s) and physiologically acceptable derivatives thereof include salts derived from a suitable base, such as alkali metal (for example sodium), alkaline earth metal (for example magnesium), ammonium and NX4+ (where X is C1- 4 alkyl). Physiologically acceptable salts of hydrogen atoms or amino groups include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic, and succinic acids, organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic, and p-toluenesulfonic acids, and inorganic acids. , such as hydrochloric, sulfuric, phosphoric and sulfamic acid. Physiologically acceptable salts of hydroxy group compounds include the anion of said compound in combination with a suitable cation such as Na+, NH4+ and NX4+ (where X is a C1-4 alkyl group).

For therapeutic use, salts of 1592U89 or NNRTI(s) will be physiologically acceptable, i.e. they will be salts derived from physiologically acceptable salts or bases. However, salts of acids or bases that are not physiologically acceptable can also be used, for example in obtaining or purifying a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of this invention.

Preferred salts of 1592U89 are the succinate salt and the hemisulfate salt.

Combinations of 1592U89 or a physiologically functional derivative thereof, and NNRTI(s) or a physiologically functional derivative thereof, including combinations of one or more reverse transcriptase inhibitors, or physiologically functional derivatives thereof, and one or more HIV protease inhibitors, or physiologically functional derivatives thereof, may further be referred to as combinations according to the invention.

This invention further provides combinations according to the invention for use in the treatment of HIV infection, including infections with HIV mutants that carry resistance to nucleoside inhibitors, especially zidovidin, lamivudine, ddl, ddC or d4T or combinations thereof, and HIV inhibitors of HIV ptotease. Furthermore, the combinations according to the invention are particularly useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions such as AIDS insanity complex, multiple sclerosis or tropical paraparesis, and also 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 the treatment of HIV infection in an infected animal, for example a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a combination of 1592U89, or a physiologically functional derivative thereof, and at least one NNRTI or a physiologically functional derivative thereof , or other combinations according to the invention.

Reference to treatment here includes prophylaxis as well as treatment of established infections or symptoms.

It should be noted that the compounds of the combination can be administered simultaneously, in the same or different pharmaceutical formulations, or sequentially. If it is introduced sequentially, the delay in introducing the second and following active ingredient must not be such that the gain of the synergistic therapeutic effect of the combination of active ingredients is lost.

It should be understood that the compounds of the combination or any physiologically functional derivatives thereof, presented simultaneously or sequentially, may be administered singly or in multiplets, or in any combination thereof. 1592U89 and NNRTI(s) are preferably administered simultaneously or sequentially in separate pharmaceutical formulations, most preferably simultaneously.

The present invention also provides for the use of 1592U89 in the manufacture of a medicament for administration simultaneously or sequentially with at least one NNRTI for the treatment and/or prophylaxis of HIV infections and the previously described associated clinical conditions. It should be noted that 1592U89 and at least one NNRTI can be used in the production of the above drug.

The synergistic effects of the combination of 1592U89 and NNRTI or any of their physiologically functional derivatives can be seen through a ratio, for example, of 1 to 10 : 1 to 20 (by weight), preferably 1 to 5 : 1 to 10 (by weight), especially 1 to 2 : 1 to 3 (by mass). Conventional ratios of 1592U89 to NNRTI include 1:1,1:1,5,1:2,1:3, and 1:4.

The synergistic effects of the combination of 1592U89, an NNRTI and an HIV protease inhibitor or any physiologically functional derivative thereof can be seen through a ratio of, for example, from 1 to 10 : 1 to 20 : 1 to 20 (by mass), preferably 1 to 5 : 1 to 10 : 1 to 10 (by mass), especially 1 to 2 : 1 to 3:1 to 3 (by mass). Suitable ratios of 1592U89:NNRTI:HIV protease inhibitor include 1:1:1.5,1:1.5:2,1:2:3 and 1:3:4.

Any suitable compound may be used in combination in that amount at which it exhibits antiviral activity when used alone.

The amount of the combination of 1592U89 and one or more NNRTIs that should be effective as an anti-HIV agent can, of course, be changed, which is solely within the competence of the Physician. Factors considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition, and the nature and severity of the disease being treated.

In general, a suitable dose of 1592U89 for administration to a human for the treatment of HIV injection may be in the range of 0.1 to 120 mg per kilogram of body weight of the recipient per day, preferably in the range of 3 to 90 mg per kilogram of body weight, and most preferably in the range of 5 to 60 mg per kilogram of body weight per day.

In general, a suitable dose of an NNRTI for human administration may be in the range of 1 to 100 mg per kilogram of body weight per day, preferably in the range of 3 to 70 mg per kilogram of body weight per day, and most preferably in the range of 5 to 60 mg per kilogram of body weight. Daily.

In general, a suitable dose of the protease inhibitor for human administration may be in the range of 5 to 100 mg per kilogram of body weight per day, preferably in the range of 8 to 70 mg per kilogram of body weight per day, and most preferably in the range of 8 to 50 mg per kilogram of body weight Daily.

Unless otherwise indicated, all weights of active ingredients are calculated under the appropriate conditions of use of the medicine. In the case of a physiologically active derivative of 1592U89 or an NNRTI, or any of its solvates, the figures may be proportionally increased. The desired dose may preferably be presented as 1, 2, 3, 4, 5, 6 or more subdoses administered at convenient intervals throughout the day. These subdoses may be administered as unit dosage forms, for example containing from 1 to 1500 mg, preferably from 5 to 1000 mg, and most preferably from 10 to 700 mg of active ingredient per unit dosage form. Alternatively, if the recipient's condition so requires, the dose may be administered as a continuous infusion.

The components of the combination which can be referred to as active ingredients can be suitably administered as therapy to an animal, eg a mammal including a human.

If it is possible to introduce the active ingredients of the combination as a raw chemical, it is preferable that it is in the form of a pharmaceutical formulation. Pharmaceutical formulations according to the present invention contain the combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The carrier(s) must be acceptable in the sense that it is compatible with the other ingredients of the formula, and that it is not harmful to its recipient. When the individual components of the combination are administered separately, they can generally be presented as a pharmaceutical formulation. References herein to pharmaceutical formulations refer, unless otherwise stated, to formulations or combinations, or components thereof.

The combination of 1592U89 and one or more NNRTIs, or any physiologically functional derivative thereof, may be conventionally presented as a pharmaceutical formulation in dosage unit form. A suitable unit dosage formulation contains the active ingredients in amounts of about 50 mg to 3 mg of each ingredient, for example 100 mg to 2 g.

It is also possible to combine any two active ingredients in unit dosage form for simultaneous or sequential administration with a third active ingredient, for example a typical unit dosage may contain 50 mg to 3 g each of 1592U89 and one or more NNRTIs, preferably 100 mg to 2 g each of 1592U89 and one or more NNRTIs.

As a further characteristic of this invention, a unit dosage form is presented that contains at least two active ingredients selected from 1592U89 and one or more NNRTIs, or any of their physiologically functional derivatives and their pharmaceutically acceptable carrier.

Pharmaceutical formulations are often prescribed to a patient in "patient packs" that contain the entire course of treatment in a single package, usually a drug pack. Patient packs have an advantage over traditional prescriptions, where the pharmacist divides the required pharmaceutical dose for the patient from one large dose, so that the patient always has access to the required dose in the patient pack, which is normally lacking in traditional prescriptions. It has been shown that the content of a particular package improves compliance with the doctor's instructions, which generally leads to more successful patient treatment.

It should be understood that the administration of the combination of the invention by means of a single patient package, or a patient package of each formulation, containing within a particular package an instruction for the correct application of the invention is a desirable additional feature of this invention.

According to a further aspect of the invention, a multiple, for example double or triple, package containing at least one active ingredient 1592U89 and one or more NNRTI(s) of the combination of the invention and inserted information containing instructions for applying the combination of the invention is provided.

According to a further aspect, the invention provides a package for a patient containing for separate administration the compound 1592U89 or its physiologically functional derivative together with at least one NNRTI or its physiologically functional derivative.

Formulations include those suitable for oral, nasal, topical (including transdermal, buccal, and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. The formulations may conveniently be presented in dosage unit form and may be prepared by procedures well known in the art of pharmacy. Such procedures represent the next characteristic of this invention, and include the phase of introduction by combining the active ingredients with a carrier that forms one or more ingredients of the drug. In general, the formulations are obtained with uniform and ultimate delivery by combining the active ingredients with liquid carriers or finally divided solid carriers or both, with final shaping of the product if necessary.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, containers or tablets each containing a predetermined 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 can also be presented as a large pill, electuary or paste.

The tablet can be made with compression or pressing, optionally with one or more drug ingredients. Compressed tablets can be obtained by compressing the active ingredients in a free liquid form such as powder or granules in a suitable machine, optionally mixed with a binder (i.e. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrator (i.e. sodium starch glycolate , cross-linked povidone, cross-linked sodium carboxymethyl cellulose), active surface or dispersing agent. Pressed tablets may be obtained by pressing a mixture of the 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 slow or controlled release of the active ingredients using, for example, hydroxypropylethyl cellulose in variable proportions to provide the desired release profile. Tablets can optionally be made with an enteric coating, to allow release in parts of the gut other than the stomach.

Formulations suitable for oral administration include pills containing the active ingredients on a fragrance basis, usually sucrose or acacia or tragacanth; lozenges containing active ingredients on an inert base such as gelatin and glycerin, or sucrose or acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base containing, for example, coconut butter or a salcilate.

It can also be delivered to a specific location using a transdermal iontophoretic device.

Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations, which in addition to the active ingredient contain suitable carriers known in the art.

Pharmaceutical formulations suitable for rectal administration, where the carrier is solid, are most preferably presented as unit dose suppositories. Suitable carriers include coconut butter and other materials commonly used in the art. Suppositories may conveniently be formed by mixing the active combination with the softened or melted carrier(s), followed by cooling and molding.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of a particular recipient; both aqueous and non-aqueous sterile suspensions which may include suspending agents and solidifying agents; and liposomes or other microparticle systems that are designed for targeted attachment to blood components or one or more organs. Formulations can be presented as unit dose or multi-dose sealed containers, for example ampoules and vials, which can be stored in a freeze-dried (lyophilized) state which preparation requires the simple addition of a sterile liquid vehicle, for example water for injection, immediately before administration . Extemporaneous injection solutions and suspensions can be obtained from sterile powders, granules and tablets, of the type described earlier.

Preferred unit dosage formulations are those containing a daily dose or oral daily subdoses of the active ingredients, as noted earlier, or suitable fractions thereof.

It should be understood that the ingredients of the above-mentioned formulations of this invention may additionally include other conventional agents in the known art, which depends on the type of formulation in question, for example those suitable for oral administration may include such additional agents as sweeteners , hardeners and fragrances.

Combinations of the compounds of this invention can be obtained in a conventional manner.

1592U89 can be obtained with the process described in European specification EPO434450, PCT application PCT/GB/4500225, PCT/GB95/02014, US patent no. 5,034,394 or GB9709945.1 all of which are incorporated herein by reference.

NNRTIs can be obtained by any process known to those skilled in the art, for example by the processes described in EPA 0509398, EP429987, US Pat. 5,366,972, EP482481, EP667348, US patent no. 5,571,912, US patent no. 5,532,358, WO 94/02155, EP582455, WO 95/20389, WO 91/09849, EP507861, US patent no. 5,563,142, WO 95/28398, WO 92/00952, EP538301, and US Patent No. 5,556,886, all of which are incorporated herein by reference.

HIV protease inhibitors can be obtained by any method known to those skilled in the art, for example by the methods described in WO 94/05639, WO 95/24385, WO 94/13629, WO 92/1650, WO/16688, WO/US94/13085, WO /US94/12562, USA 93/59038, EP 541168, WO 94/14436, WO 95/09843, WO 95/32185, WO 94/15906, WO 94/15608, WO 94/04492, WO 92/08701, WO 95 /32185, and US patent no. 5,256,783, all of which are incorporated herein by reference.

The following examples are intended for illustration only, and do not limit the scope of the invention in any way. "Active ingredient" means 1592U89, NNRTI(s), HIV protease inhibitor(s), or their multiplets, or a physiologically functional derivative of any of the aforementioned compounds.

Examples: Tablet formulation

The following formulations A, B and C were obtained by wet granulation of the ingredients with povidone solution, followed by the addition of magnesium stearate and compression.

Formulation A

mg/tablet

Active ingredient 250

LactoseB.P. 210

PovidonB.P. 15

Sodium starch glycolate 20

Magnesium stearate 5

----------------------------------

500

Formulation B

mg/tablet

Active ingredient 250

LactoseB.P. 200

Avicel PH 101 60

PovidonB.P. 15

Sodium starch glycolate 20

Magnesium stearate 5

-----------------------------

500

Formulation C

mg/tablet

Active ingredient 250

LactoseB.P. 200

Starch 50

Povidone 5

Magnesium stearate 4

-----------------------------

359

The following formulations, D and E, were obtained by following compression of the mixed ingredients. In formulation E, the lactose is of the direct compression type (Daily Crest-"Zeparox").

Formulation D

mg/tablet

Active ingredient 250

Pregelatinized starch NF15 150

-----------------------------

400

Formulation E

mg/tablet

Active ingredient 250

Lactose B.P. 150

Avicel 100

------------------------------

500

Formulation F (controlled release formulation)

The formulation is obtained by wet granulation of the ingredients with a povidone solution, followed by the addition of magnesium stearate and compression.

mg/tablet

Active ingredient 500

Hydroxypropylmethylcellulose (Methocel K4M Premium) 112

Lactose B.P. 53

PovidonB.P. 28

Magnesium stearate 7

----------------------------

700

The drug is released over a period of about 6-8 hours and is complete after 12 hours.

Example 2: Capsule formulation

Formulation A

The capsule formulation was obtained by mixing the ingredients of formulation D in example 1 above, and filling into two-part solid gelatin capsules. Formulation B (infra) was obtained in a similar way.

Formulation B

mg/capsule

Active ingredient 250

Lactose B.P. 143

Sodium starch glycolate 25

Magnesium stearate 2

------------------------------

420

Formulation C

mg/capsule

Active ingredient 250

Macrogel 4000 B.P. 350

----------------------------------

600

Formulation C capsules are obtained by melting Macrogel 4000 B.P., dispersing the active ingredient into the melt and filling into two-part hard gelatin capsules.

Formulation D

mg/capsule

Active ingredient 250

Lecithin 100

Peanut oil 100

---------------------------------

450

Formulation D capsules obtained by dispersing the active ingredient in lecithin and peanut oil and filling the dispersion into soft, elastic gelatin capsules.

Formulation E

mg/capsule

Active ingredient 150.0

Vitamin E TPGS 400.0

Polyethylene glycol 400 NF 200.5

Propylene glycol USP 39.5

Four (4) kilograms (kg) of Vitamin E TPGS (obtained from Eastman Chemical Co.) were heated at 50°C until melting. To the melted vitamin E TPGS, 2.005 kg of polyethylene glycol 400 (PEG400) (small aldehyde, <10 ppm, obtained from Union Carbide or Dow Chemical Co.) heated to 50°C was added and mixed until a homogeneous solution was formed. The resulting solution was heated to 65°C. 1.5 kg of the active ingredient was dissolved in a molten solution of vitamin E TPGS and PEG400. 0.395 kg of propylene glycol was added at room temperature and mixed until a homogeneous solution was formed. The solution was cooled to 28-35°C. The solution was then depleted. The mixture is preferably encapsulated at 28-35°C by filling a weight equivalent to 150 mg of volatile matter-free compound into size 12 oblong, opaque white soft gelatin capsules using a capsule filling machine. The capsule liners are dried to a constant fill moisture of 3-6% water, and the liner hardness is 7-10 Newtons, and placed in a suitable container.

Formulation F (controlled release capsule)

The following controlled release capsule formulation was obtained by ejecting ingredients a, b, and c using an ejector, followed by spheronization of the ejected ingredients and drying. The dried pellets are then coated with a controlled release membrane (d) and filled into a two-piece, hard gelatin capsule.

mg/capsule

(a) Active ingredient 250

(b) Microcrystalline cellulose 125

(c) LactoseB.P. 125

(d) Ethyl cellulose 13

-------------------------

513

Example 3: Injectable formulation

Formulation A

mg

Active ingredient 200

Hydrochloric acid solution 0.1M or

Sodium hydroxide solution) 1M q.s. at pH 4.0 to 7.0

Sterile water 10 ml

The active ingredient is dissolved mostly with water (35°C - 40°C) and the pH is adjusted between 4.0 and 7.0 with hydrochloric acid or sodium hydroxide, as appropriate. The batch was then made up to full volume with water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with a sterile cap and seal.

Formulation B

Active ingredient 125 mg

Sterile without pyrogen, pH 7 phosphate buffer, q.s. 25 ml

Example 4: Intramuscular injection

Active ingredient 200 mg

Benzyl alcohol 0.10 g

Glycofurol75 1.45 g

Water for injection q.s. 3.00 ml

The active ingredient is dissolved in glucofurol. Then benzyl alcohol was added and dissolved, and the water was made up to 3 ml. The mixture was then filtered through a sterile micropore filter and sealed in a sterile 3 ml amber glass vial (type 1).

Example 5: Syrup

Active ingredient 250 mg

Sorbitol solution 1.50 g

Glycerol 2.00 g

Sodium benzoate 0.005 g

Fragrance, peach 17.42.3169 0.0125 ml

Purified water q.s. 5.00 ml

The active ingredient is dissolved in a mixture of glycerol and mostly purified with water. Then an aqueous solution of sodium hydroxide was added to the solution, followed by the addition of a sorbitol solution and finally the smell. The volume was topped up with purified water and mixed well.

Example 6: Suppository

mg/capsule suppository

Active ingredient 250

Hard fat, B.P. (Witepsol Hl5-Dynamite Nobel) 1770

------------------------------

in 2020

One fifth of Witepsol Hl5 is melted in a metal vessel with steam at 45°C maximum. The active ingredient was sieved through a 200 μm sieve and added to the molten base with stirring, using a Silverson device with a cutting knife attached, until a uniform dispersion was achieved. Keeping the mixture at 45°C, the remaining Witepsol H15 was added to the suspension and mixed to ensure a homogeneous mixture. The entire suspension was passed through a 250 μm stainless steel screen, with continuous stirring, and allowed to cool to 45°C. At a temperature of 38°C to 40°C, 2.02 g of the mixture was filled into suitable 2 ml plastic molds. The suppositories were allowed to cool to room temperature.

Example 7: Pessaries

mg/pessary

Active ingredient 250

Dextrose Anhydrate 380

Potato starch 363

Magnesium stearate 7

-----------------------------

1000

The above ingredients were mixed directly, and the pessaries were obtained by direct compression of the resulting mixture.

Any patent application of which this description and claims form a part may be used as a basis for priority over any subsequent application. The claims of such subsequent application may be directed to any characteristic or combination of characteristics described herein. These may take the form of product, preparation, process or application requirements, and may include, by way of example and without limitation, one or more of the following requirements.

Claims (22)

1. Combination characterized by containing (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol and an inhibitor of non- nucleoside reverse transcriptase. 2. A combination characterized in that it contains (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol and a compound selected from nevirapine, loviride, delavuridine, DMP-266, HBV-1293 and MKC 442. 3. Combination characterized by containing (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol or its physiological functional derivative and nevirapine or its physiologically functional derivative. 4. Combination characterized by containing (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-pyrin-9-yl]-2-cyclopenten-1-methanol or its physiological functional derivative and loviride or its physiologically functional derivative. 5. Combination characterized by containing (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol or its physiological functional derivative and delavuridine or its physiologically functional derivative. 6. Combination characterized by containing (-)-(1S,4R)-4-[2-amino-6-(caminopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol or its physiological functional derivative and DMP-266 or a physiologically functional derivative thereof. 7. Combination characterized by containing (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol or its physiological functional derivative and HBV-1293 or a physiologically functional derivative thereof. 8. Combination characterized by containing (-)-(1S,4R)-4-[2-amino-6-cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol or its physiologically functional derivative, non-nucleoside reverse transcriptase inhibitor or physiologically functional derivative thereof, reverse transcriptase inhibitor or physiologically functional derivative thereof. 9. Combination characterized by containing (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol or its physiologically functional derivative, a non-nucleoside reverse transcriptase inhibitor or a physiologically functional derivative thereof, an HIV protease inhibitor or a physiologically functional derivative thereof. 10. The combination according to any one of claims 1 to 9, characterized in that it is used in medical therapy. 11. Pharmaceutical formulation, characterized in that it contains the combination according to any one of claims 1 to 9 together with one or more pharmaceutically acceptable carriers. 12. The formulation according to claim 11, characterized in that it is in the form of a dosage unit. 13. A method for treating HIV infection in an infected animal, characterized in that it comprises treating said animal with a therapeutically effective amount of a combination as defined in any one of claims 1 to 9. 14. The method according to claim 13, characterized in that at least two of the components in combination are used simultaneously. 15. The method according to claim 13, characterized in that at least two of the components in the combination are introduced sequentially. 16. The method according to claim 13, characterized in that the combination is introduced as one combined formulation. 17. The method according to any one of claims 13 to 16, characterized in that said animal is a human. 18. Application of (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol, characterized by the fact that it is used in the production a drug for administration, either simultaneously or sequentially, with one or more non-nucleoside reverse transcriptase inhibitors for the treatment and/or prophylaxis of HIV infection. 19. Application according to claim 18, characterized in that it is used for the treatment of HIV infection resistant to nucleoside reverse transcriptase inhibitors or HIV protease inhibitors. 20. Use as claimed in claim 18 or 19, characterized in that it is used in the treatment of AIDS. 21. Use as claimed in claim 18 or 19, characterized in that it is used in the treatment of AIDS related conditions or AIDS madness complex. 22. Package for the patient, characterized in that it contains at least one active ingredient selected from (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol and one or more NNRTIs selected from nevirapine, loviride, delavuridine, DMP-266, HBY-1293 and MKC 442.