SK16212000A3 - Homogeneous pharmaceutical compositions comprising abacavir, lamivudine and zidovudine - Google Patents

Abstract

A pharmaceutical composition comprising a homogeneous combination of abacavir, lamivudine, and zidovudine in an amount which achieves antiviral efficacy, a process for the preparation of such a composition, and a method of inhibiting human immunodeficiency virus (HIV) which comprises administering such a composition to an HIV infected patient is disclosed.

Description

Technical field

The present invention relates to novel pharmaceutical compositions combining the agents abacavir, lamivudine and zidovudine into a single homogeneous dosage form, useful in the treatment of diseases in mammals, including humans.

BACKGROUND OF THE INVENTION

Abacavir (also known as (1S, 4R) - cis -4- [2-amino-6- (cyclopropylamino) -9Hpurin-9-yl] -2-cyclopentene-1-methanol, 1592U89) and its antiviral uses, particularly against HIV infections, are described in European patent application no. 0,434,450th

(1S, 4R) - cis -4- [2-Amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol succinate is described in WO96 / 06844. (1S, 4R) - cis -4- [2-Amino-6- (cyclopropylamino) -9 H -purin-9-yl] -2-cyclopentene-1-methanol hemisulfate is described in WO98 / 52949. Abacavir is currently being tested clinically as an anti-HIV pharmaceutical.

Lamivudine (also known as EPIVIR ™ - Trade Name, 3TC ™, (2R, cis) -4-amino-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl) - (1H) -pyridin-2 -one, (-) - cis -1- [2- (hydroxymethyl) -1,3-oxathiolan-5-yl] cytosine) has shown antiviral activity against human immunodeficiency virus (HIV) and other viruses such as virus hepetitis B.

Lamivudine and its use against HIV are described in EP 0382526 and WO91 / 17159. Crystalline forms of lamivudine are described in WO92 / 21676. Combinations of lamivudine with other reverse transcriptase inhibitors, particularly zidovudine, are described in WO92 / 20344.

Zidovudine is known (also as 3'-azido-3'-deoxythymidine, RETROVIR ™) for the treatment of HIV and other viruses. Zidovudine is further described in U.S. Pat. 4,818,538, 4,828,838, 4,724,232, 4,833,130 and 4,837,208, all of which are incorporated herein by reference.

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The synergistic effect of the combination of abacavir, lamivudine and zidovudine is described in WO96 / 30025. However, there is no mention in this document of how to achieve homogeneity of the active ingredients when formulated as a single tablet.

The success of modern multi-agent HIV treatment often requires strict compliance with a comprehensive treatment regimen, which may require the administration of many different drugs administered at precise time intervals throughout the day, with careful attention to the diet. The patient's unwillingness to meet the treatment needs is a well-known problem accompanying such complex treatment regimens. See Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th edition, p. 1704-1705 (1996). The patient's unwillingness is a critical problem in the treatment of HIV, as unwillingness to submit to the treatment regimen may lead to the emergence of drug-resistant HIV strains.

The present invention addresses the problem of unwillingness by formulating multiple active ingredients into a single tablet. However, simply combining three drugs into one tablet could result in the tablet being too large to swallow without difficulty. In addition, the greater the amount of drug in the composition, the more excipients needed to compress the mixture into a tablet. Increased amounts of some excipients may have adverse effects on the properties of the tablet and may lead to problems such as dissolution, uniformity, hardness, and separation.

Separation is a major concern when attempting to formulate a single homogeneous tablet containing multiple active ingredients of different densities and particle sizes. Separation of the active ingredients in pharmaceutical powders and granules is a widely recognized problem, which may result in inconsistent dispersions of the active ingredients in final dosage forms. Some of the major factors contributing to separation are particle size, shape and density. Previous attempts to formulate tablets containing multiple drugs have been disrupted by such segregation problems. Although the blends were initially homogeneous, the active ingredients separated during material handling and prior to tablet compression.

Glidants are substances that have traditionally been used to improve the flow characteristics of granules and powders by reducing friction between particles. See

-3 ···································································· Lieberman, Lachman & Schwartz, Pharmaceutical Dosage Forms: Tablets, Vol 1, p. 177-178 (1989), which is incorporated herein by reference. Glidants are typically added to the pharmaceutical compositions immediately prior to compression of the tablets to facilitate flow of granular material into holes in the punch of the tablet press. Glidants 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, stearate z ™, starch, starch 1500, magnesium lauryl sulfate and magnesium oxide.

Surprisingly, research into the problem of separation in pharmaceutical compositions has shown that glidants can be used to enhance and promote the homogeneity of the mixed composition. The novel compositions of the present invention use glidants to affect and maintain the homogeneity of the active agents during handling prior to tablet compression.

SUMMARY OF THE INVENTION

The invention provides a pharmaceutical composition comprising the active ingredients abacavir, lamivudine and zidovudine, or a pharmaceutically acceptable derivative thereof, in a sufficiently homogenized form, and the use of such a pharmaceutical composition.

Further, the invention provides a pharmaceutical composition in the form of a high drug content tablet while maintaining the appropriate properties of the tablets and their appropriate size.

Further, the invention provides the use of glidants to reduce the separation of active ingredients in pharmaceutical compositions during material handling prior to tablet compression.

Further, the invention provides a pharmaceutical composition combining the active ingredients abacavir, lamivudine and zidovudine, or pharmaceutically acceptable derivatives thereof, with a pharmaceutically acceptable glidant, resulting in a composition characterized by a pharmaceutically acceptable degree of homogeneity.

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The invention further provides a pharmaceutical composition comprising abacavir or a pharmaceutically acceptable derivative thereof, lamivudine or a pharmaceutically acceptable derivative thereof, and zidovudine or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic and / or prophylactic ingredients.

Other therapeutic agents may include agents that are effective for treating viral infections or conditions associated with them, such as (1a, 2β, 3α) -9- [2,3-bis (hydroxymethyl) cyclobutyl] guanine, [(-) BHCG , SQ 34514]; oxetanocin-G, (3,4-bis (hydroxymethyl) -2-oxethanosylguanine); acyclic nucleosides (e.g., acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleoside phosphonates (e.g. (S) -1- (3-hydroxy-2-phosphonylmethoxypropyl) -cytosine, HPMPC or PMEA; ribonucleotide reductase inhibitors such as 2 5 - [(2-chloroanilino) thiocarbonyl] -thiocarbonohydrazone, 3'-azido-3'-deoxythymidine; other 2 ', 3'-dideoxynucleosides such as 2', 3'-dideoxycytidine, 2 ', 3'-dideoxyadenosine, 2'3'-dideoxyinosine, 2 ', 3'-didehydrogentymidine, protease inhibitors such as indinavir, ritonavir, nelfinavir; [3S [3R * (1R *, 2S *)]] - [3 - [[(4-aminophenyl) sulfonyl] - (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] tetrahydro-3-furanyl ester (141W94) oxathiolane nucleoside analogs such as cis-1- (2-hydroxymethyl) - 1,3-oxathiolan-5-yl) -5-fluorocytosine (FTC), 3'-deoxy-3'-fluoro-thymidine, 5-chloro-2 ', 3'-dideoxy-3'-fluorouridine, ribavirin, 9- [4-hydroxy-2 (hydroxymethyl) but-1-yl] guanine (H2G); tat inhibitors such as 7-chloro-5- (2-pyryl) -3H1,4-benzodiazepin-2- (H) -one (Ro5-3335), 7-chloro-1,3-dihydro-5- (1 / - (- pyrrol-2-yl) -3,71,4-benzodiazepin-2-amine (Ro24-7429); interferons such as α-interferon; renal excretion inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; pentoxifylline; N-acetylcysteine (NAC); Procysteine; α-trichosantín; phosphonomic acid; as well as immunomodulators such as interleukin II or thymosin; granular macrophage colonies stimulating factors; erythropoietin; soluble CD ₄ and genetically engineered derivatives thereof; non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (BI-RG587), loviride (α-APA) and delavuridine (BHAP) and phosphoric acid and NNRTI type

1,4-dihydro-2H-3,1-benzoxazin-2-one such as (-) - 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1- benzoxazin-2-one (L-743, 726 or DMP-266); and 9 9 9 9

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-5-quinoxaline NNRTIs such as isopropyl (2S) -7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1 (2H) quinoxaline carboxylate (HBY 1293); hydroxyurea; or inosine monophosphate dehydrogenase inhibitors such as mycophenolic acid or its esters.

Carriers must be pharmaceutically acceptable in the sense of being compatible with the other ingredients in the composition and not deleterious to the recipient of the pharmaceutical composition.

Further, the invention provides simplification of treatment regimens for HIV and other viruses in order to increase patient willingness to cooperate by providing a simplified dosage form containing pharmaceutically acceptable amounts of abacavir, lamivudine and zidovudine, or pharmaceutically acceptable derivatives thereof.

The present invention provides a pharmaceutical composition comprising:

(i) a safe and therapeutically effective amount of abacavir or a pharmaceutically acceptable derivative thereof;

ii) a safe and therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof;

iii) a safe and therapeutically effective amount of zidovudine or a pharmaceutically acceptable derivative thereof;

iv) a pharmaceutically acceptable glidant, wherein the active ingredients are homogeneous.

In a preferred embodiment, the pharmaceutical composition comprises abacavir or a pharmaceutically acceptable derivative thereof, lamuvidine or a pharmaceutically acceptable derivative thereof, and zidovudine or a pharmaceutically acceptable derivative thereof in an amount of from about 30% to about 70% by weight of the total composition. The pharmaceutical composition may preferably be in the form of a tablet, wherein the tablet has a 30% to 60% drug loading, preferably a 40% to 60% drug loading.

The term "safe and therapeutically effective amount" as used herein means an amount of a drug, compound, mixture, product or pharmaceutical agent sufficient to ameliorate or reverse or cure the disease in a human or other mammal without seriously damaging the mammalian cells into which the drug is administered. or the pharmaceutical agent is administered.

The term "pharmaceutically acceptable derivative of abacavir" as used herein means any pharmaceutically acceptable salt, solvate, ester or salt thereof.

-6 ··· ······························ An ester or any other compound which, when administered to a recipient, is capable of providing (directly or indirectly) abacavir or any antiviral active metabolite or residue.

The term "pharmaceutically acceptable derivative of lamivudine" as used herein means any pharmaceutically acceptable salt, solvate, ester or salt of such an ester or any other compound which, when administered to a recipient, is capable of providing (directly or indirectly) lamivudine or any antiviral active metabolite. or the rest.

As used herein, the term "pharmaceutically acceptable zidovudine derivative" means any pharmaceutically acceptable salt, solvate, ester or salt of such an ester or any other compound which, when administered to a recipient, is capable of providing (directly or indirectly) zidovudine or any antiviral active metabolite, or Rest.

The term "homogeneous" as used herein means that the active ingredients are substantially uniformly dispersed in the portion of the final tablet containing them (for example, in the case of compressed film coated tablets, the active ingredients are uniformly dispersed in the tablet core). The homogeneity of the active ingredients in the tablet can be determined by measuring drug uniformity.

The term "safe and effective amount" as used herein means the amount of agent required to perform the function sought by the researcher or physician without seriously damaging the tissue of the mammal to which the agent is administered.

As used herein, the term "drug loading" refers to the ratio of drug to total tablet weight.

Lamivudine is preferably provided substantially free of the corresponding (+) enantiomer. The term "substantially free" as used herein means that less than 10% by weight of the (+) enantiomer is present relative to the amount of lamivudine. Preferably less than about 5% by weight of the (+) enantiomer is present based on the amount of lamivudine.

Further, the invention provides a method of treating, reversing, reducing or inhibiting retroviral infections and in particular HIV infections in a mammal, and in particular a human, comprising administering to said mammal a safe and effective amount of a composition of the invention.

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Further, the invention provides the combined use of abacavir or a pharmaceutically acceptable derivative thereof, lamuvidine or a pharmaceutically acceptable derivative thereof, and zidovudine or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable glidant for the manufacture of a medicament for the treatment of retroviral infections, particularly HIV infections.

Those of skill in the art will appreciate that the reference made herein to treatment is extended to both prophylaxis and treatment of a established disease, infection, or symptom thereof.

The compositions of the present invention use safe and therapeutically effective amounts of (-) - (1S, 4R) -4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol ( abacavir) or a pharmaceutically acceptable derivative thereof, 3'-azido-3'-deoxythymidine (zidovudine) or a pharmaceutically acceptable derivative thereof, and (-) - cis -1- [2- (hydroxymethyl) -1,3-oxathiolane- 5-yl] cytosine (lamivudine) or a pharmaceutically acceptable derivative thereof, together with a safe and effective amount of a pharmaceutically acceptable glidant for the homogeneity of the compositions prior to tablet compression. The particle size and shape of the three active agents will typically be different. The pharmaceutical composition is homogeneous in the sense that the active ingredients are substantially uniformly dispersed in that portion of the final composition which includes abacavir, lamivudine, zidovudine and a glidant. For example, in the case of film-coated tablets, the active ingredients are uniformly dispersed in the tablet core.

Abacavir can be prepared as described in European patent application no. No. 0434450 or WO95 / 21161, incorporated herein by reference. The 159U89 succinate salt may be prepared as described in WO96 / 06844, incorporated herein by reference. 159U89 hemisulfate can be prepared as described in WO98 / 52949, incorporated herein by reference. Preferred abacavir salts include succinate and hemisulphate.

Methods for preparing lamuvidine are described, inter alia, in WO92 / 20669 and WO95 / 29174, incorporated herein by reference.

Methods for preparing zidovudine are described in U.S. Pat. No. 5,011,829, incorporated herein by reference.

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The compositions of the invention may optionally use a safe and effective amount of a solvent, a safe and effective amount of a disintegrant, a safe and effective amount of excipients commonly used in the art.

compositions of the present invention may comprise 0 to about 2% magnesium stearate, 0.05 to about 5% glidant, 0 to about 5% sodium starch glycolate and about 20% to 50% microcrystalline cellulose.

Glidants are substances that have traditionally been used to improve the flow characteristics of granules and powders by reducing friction between particles. See Remington: The Science & Practice in Pharmacy, p. 1619, 19th edition (1995) and Lieberman, Lachman & Schwartz: Pharmaceutical Dosage Forms: Tablets, Vol. 1, p. 177-178 (1989), which are incorporated herein by reference. Improved flow characteristics help to reduce clogging and breakdown of the tablet press and minimize tablet weight differences. Glidants are typically added to the pharmaceutical compositions just prior to compression of the tablets to facilitate flow of granular material into holes in the punch of the tablet press. Silica (SiO 2), also referred to as colloidal silica, fumed silica, fumed silica, weakly anhydrous silica or silicic anhydride may be used in the compositions of the present invention. Silicon dioxide is sold under the trade names AEROSIL ™ and CAB-O-SIL ™. Other glidants that may be used in the compositions of the present invention include 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, Stearowet C ™, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, colloidal silica in conjunction with Pro Solve ™ microcrystalline cellulose.

The ability of glidants to improve flow characteristics depends on: (i) their chemical characteristics depending on the chemical characteristics of the other constituents of the formulation; and · · ······· · · 9 9 9 9 «« 9 9 9 9 9 9 9

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(9ii) physical characteristics such as size, shape and distribution of glidants and other components of the granular or powder composition as well as the moisture content and temperature of the composition.

Investigating the problem of the separation of active ingredients in pharmaceutical compositions, powders and granules has led the inventors to the surprising finding that glidants can be used to reduce the separation of active ingredients and thereby improve the homogeneity of the pharmaceutical compositions, powders and granules. The present invention uses from 0.05% to about 5.0% glidant, at levels less than 0.05% homogeneity may not be sufficient, and at levels greater than 5.0% no additional homogeneity is achieved.

Silica may be a preferred glidant due to its relative inertness. A preferred form of silica may be fumed colloidal silica, which is a submicroscopic fumed silica gel. It is a light, non-granular amorphous powder.

In particular, colloidal silicon dioxide is used at about 0.05 to about 1.0%, since at less than 0.05% homogeneity may not be sufficient and at an amount above 1.0% no additional homogeneity is obtained. The preferred glidant may be magnesium stearate.

When glidants are used to improve flow characteristics, they are typically added to the composition immediately prior to compression during the lubrication step. See Remington, The Science & Practice of Pharmacy, p. 1619, 19th edition (1995), incorporated herein by reference. However, the present invention uses glidants in the starting mixture to improve and maintain homogeneity during handling prior to compression. An additional glidant may be added to the mixture immediately prior to compression during the lubrication step to improve the flow characteristics of the composition as known in the pharmaceutical compositions.

The invention is preferably presented as a pharmaceutical composition suitable for oral administration. Such compositions may preferably be presented as discrete units such as tablets, layered tablets (having a hard, soluble outer layer and core), capsules, or any other form suitable for oral administration and compatible with the compositions of the invention containing a predetermined amount of active ingredients. A particularly suitable composition may be

-10 ··············································· 99 99 99 99 99 999 prepared by direct compression or by a granulation process. Such compositions may contain safe and effective amounts of conventional excipients such as binding agents, fillers, lubricants, or disintegrants. The tablets may also be coated by any method known to those of ordinary skill in the art that would not interfere with the tablet-release properties or other physical or chemical characteristics of the present invention. Tablet coating is further described and illustrated by Remington in The Science & Practice of Pharmacy, 19th Edition (1995), incorporated herein by reference. If desired, the above compositions may also be altered by any method known to those skilled in the art to achieve sustained release of the active ingredients. The compositions may also comprise a safe and effective amount of other active ingredients such as antimicrobial agents or preservatives.

The compositions of the present invention are suitable for administration to humans or other mammals, in particular by the oral route of administration.

However, other modes of administration used by physicians and other experts in the art of administering pharmaceutical doses such as pharmacists and nurses are not excluded in advance. One such method may be crushing the solid dosage form, mixing it in an environment suitable for administration, and administering rectally as an enema. Other routes of administration may include topical administration and inhalation.

Those skilled in the art will appreciate that the amount of active ingredients required for use in therapy will vary depending on a number of factors including the nature of the condition to be treated and the age and condition of the patient and will ultimately be at the discretion of the attending physician, veterinarian or general practitioner.

In general, however, a suitable dosage of abacavir for human administration for the treatment of HIV infection 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 per day, and most preferably in the range of 5 to 60 mg per kilogram of body weight per day.

The usual recommended dose of lamivudine for adults and adolescents is 150 mg, given twice daily in combination with zidovudine. For adults ····································

-11 with low body weights (less than 50 kg) is the usual recommended oral dose of lamivudine 2 mg / kg, given twice daily in combination with zidovudine.

The recommended oral dose of lamivudine in pediatric patients 3 months to 12 years of age is 4 mg / kg given twice daily up to a maximum dose of 150 mg given twice daily in combination with zidovudine.

The usual recommended oral dose of zidovudine is generally 600 mg per day in single doses in combination with other antiretroviral agents. The recommended oral dose in pediatric patients 3 months to 12 years of age is 180 mg / m ² body surface area every 6 hours or 720 mg / m ² body surface area daily and should not exceed 200 mg every 6 hours.

The compositions of the present invention provide patients with greater freedom from multiple dose treatment regimens and facilitate the required endurance required to memorize the complex of daily dosing times and schedules. By combining abacavir, lamivudine and zidovudine into a single dosage form, the desired daily doses may be presented in a single dose or as divided doses, particularly as divided doses, administered at appropriate time intervals, for example as two, three, four or more smaller doses per day and as two divided smaller doses per day.

the compositions of the present invention preferably allow the administration of three separate compounds in a unit dosage form containing, for example, about 15 to 1200 mg of abacavir, in particular about 100 to 600 mg of abacavir, and in particular about 350 mg of abacavir; about 15 to 1000 mg of lamivudine, especially about 100 to 500 mg of lamivudine, and especially about 150 mg of lamivudine; and about 30 to 1000 mg zidovudine, especially about 200 to 500 mg zidovudine, and especially about 300 mg zidovudine.

The composition of the invention may be used in combination with other pharmaceutical compositions as a component of the treatment regimen of multi-component drugs.

The compositions of the present invention may also be packaged as articles comprising a safe and therapeutically effective amount of abacavir or a pharmaceutically acceptable derivative thereof; a safe and therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof; safe and curative 9 9 9 9 9 • • • • • • • • • • • • • • • • • • · ········ ·· ··· ·· ·· ·· ··

-12 an effective amount of zidovudine or a pharmaceutically acceptable derivative thereof; and a safe and effective amount of a pharmaceutically acceptable glidant.

Any of a variety of methods known to those skilled in the art of packaging tablets, layered tablets, or other solid dosage forms suitable for oral administration that will not degrade the components of the present invention are suitable for use in packaging. Tablets, layered tablets or other solid dosage forms suitable for oral administration may be packaged in and contained in various packaging materials, in particular glass and plastic vials, including blister packs of single doses. The packaging material may also have a label and information related to the pharmaceutical composition printed thereon. In addition, the product may contain a brochure, report, notice, folding box or leaflet containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as a 'package leaflet'. The package insert may be attached to or inserted into a pharmaceutical article of manufacture. The package leaflet and any marking of the article of manufacture provide information concerning the pharmaceutical composition. Information and labeling provide various forms of information used by healthcare professionals, describing the device, its dosage, and various other parameters required by regulatory agencies such as the United States Food and Drug Agencies.

The compositions of the present invention may be formulated using methods appropriate to the physical and chemical characteristics of the compositions and commonly used by those skilled in the art to prepare oral dosage forms using direct compression or granulation techniques. Remington: The Science & Practice of Pharmacy, p. 1615-1623, 1625-1648, and other suitable sections, 19th edition (1995).

The compositions of the present invention are administered to a human or other mammal in a safe and effective amount as described herein. These safe and effective amounts will vary depending upon the type and size of the mammal to be treated and the desired treatment results.

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DETAILED DESCRIPTION OF THE INVENTION

The following examples further describe and show a specific embodiment within the scope of the present invention. The examples are given by way of illustration only and are not to be construed as limiting the number of possible variants within the scope of the invention.

Example 1

Preparation of (1S, 4R) - cis -4- [2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol hemisulphate

A stirred mixture of water (25 mL) and isopropanol (IPA) (100 mL) was heated to 45-55 ° C and then the (1S, 4R) -cis-4- [2-amino-6- ( cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol (WO 98/06844) (50 g) and washed with IPA (12.5 mL). The mixture was heated to reflux of approximately 30 minutes to give a clear solution and then the mixture was cooled to 65-75 ° C. A solution of concentrated sulfuric acid (6.07 g) in water (12.5 ml) was then added. Then a mixture of IPA (37.5 mL) and water (12.5 mL) was added and the solution was cooled to 45-55 ° C, during which time the mixture was seeded with the original (1S, 4R) cis-4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol. After stirring at this temperature range for about 1 hour to allow crystallization, additional IPA (300 mL) was added while maintaining the temperature of the mixture at 45-55 ° C. The suspension was then cooled to 0-5 ° C over 2 hours, the product was then filtered, washed with IPA (2 x 75 mL) and dried under vacuum at 40-45 ° C to give the title compound as a pale yellow-brown powder ( 34.3 g, 90% purity), m.p. 224-225 ° C (dec.).

¹ H NMR (DMSO-d 6): δ 10.76 (br m, 1, purine NH), 8.53 (vbr m, 1, NH), 7.80 (s, 1, purine CH), 6.67 (br m, 1, NH ₂ ), 6.13 (m, 1, = CH), 5.87 (m, 1, = CH), 5.40 (m, 1, NCH), 3.45 (d J = 5.8 Hz, 2, OCH ₂ ), 2.96 (br m, 1, cyclopropyl CH), 2.87 (m, 1, CH), 2.67-2.57 (m, 1, CH), 1.65-1.55 (m, 1, CH), 0.84-0.64 (m, 4.2 x ₂ cyclopropyl).

-14Example 2

Directly compressed tablet for triple combination tablets, containing abacavir, lamivudine and zidovudine · · »» »» »» »» »» »» »» ·· · · a aaa ·· aa aa

component Quantity (mg) Percent abacavir hemisulphate 351.0 * 26.0 zidovudine 300.0 22.2 lamivudine 150.0 11.1 microcrystalline cellulose 466.9 34.6 sodium starch glycolate, non - flammable 64.5 4.8 colloidal silicon dioxide, non - flammable 4.07 0.3 magnesium stearate, non - flammable 13.6 1.0 total tablet weight 1350.0

* equivalent of 300 mg abacavir free base

Batch production method

The amounts according to this production example refer to a typical batch size of 400 kg and may be varied depending on the batch size.

The ingredients are first weighed from the batch containers in the following quantities:

Additive Quantity

abacavir hemisulphate 104.00 zidovudine 88.88 Lamivudine 44,44 Microcrystalline cellulose, non - flammable 145.48 sodium starch glycolate, non - flammable 12,00 colloidal silicon dioxide, non - flammable 1.20 magnesium stearate, non - flammable 4.00

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The ingredients are then screened using a Russell-SIV screen supplemented with mesh # 1. 14 (1.4 mm holes) or the corresponding screen and mesh and are placed in a stainless steel mixing container.

Abacavir, zidovudine, lamivudine, non-flammable microcrystalline cellulose, non-flammable sodium starch glycolate, and non-flammable colloidal silica are mixed for 20 minutes using a suitable mixer such as a Matcon-Buls, V-mixer or equivalent types. Magnesium stearate is then added to the mixture and stirring is continued for about 2 minutes.

The lubricated mixture is then compressed using a suitable rotary tablet press, typically Courtoy R-190, R-200 or the like. An internal control process is used for the weight of the tablets and their hardness and appropriate intervals during compression and adjustment of the tabletting pressure are made as required.

Example 3

Wet formulation for triple combination tablets containing abacavir, lamivudine and zidovudine

component Quantity (mg) Percent abacavir hemisulphate 351.0 * 34.0 zidovudine 300.0 29.0 lamivudine 150.0 14.5 colloidal silicon dioxide, non - flammable 3.1 0.3 Microcrystalline cellulose, non - flammable 160.0 15.5 povidone, US pharmacopoeia 32.0 3.1 sodium starch glycolate, non - flammable 32.0 3.1 magnesium stearate, non - flammable 8.0 0.8 purified water, US Pharmacopoeia as needed total tablet weight 1,036.1

* equivalent of 300 mg abacavir free base

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Method of production

The ingredients are weighed and screened using a Russell-SIV screen supplemented with mesh # 1. 30 or corresponding sieve and mesh and are placed in a stainless steel mixing container.

Abacavir, zidovudine, microcrystalline cellulose, sodium starch glycolate and colloidal silica are mixed for 1 to 5 minutes using a suitable granulator / mixer such as Spectrum SP or Fielder PMA or similar equipment. A 10-20% (w / w) solution of povidone in water is then prepared and added to the granulation of the powder. If desired, additional water may be added during the granulation. The granules are dried using a microwave drying in a granulator such as Spectrum SP or the like, or dried using a fluid bed dryer such as UniGlatt or Aeromatic MP or Aeromatic Stea-1 or the like. The dried granules are ground using a Comill or Fitzmili mill or the like. Lamivudine is added to the milled granules and blended for 15 minutes using a suitable blender, such as a Matcon-Buls, V-blender or the like. Magnesium stearate is then added to the mixture and stirring is continued for about 2 minutes.

The lubricated mixture is then compressed using a suitable rotary press typically of Manesty Beta or Fette or Courtoy or the like. An internal control process is used for the weight of the tablets and their hardness and appropriate intervals during compression and adjustment of the tabletting pressure are made as required.

Example 4

Direct compression formulation for triple combination tablets containing abacavir, lamivudine and zidovudine

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Ingredients and composition of zbacavir / lamivudine / zidovudine tablets

component quality theoretical amount / dose Unit (mg) % (w / w) abacavir sulfate Glaxo Wellcome 351,001 ¹ 26.0 lamivudine Glaxo Wellcome 150.00 11.1 zidovudine Glaxo Wellcome 300.00 22.2 microcrystalline cellulose fireproof 464.25 34.4 sodium starch glycolate nonflammable 64.50 4.8 magnesium stearate nonflammable 20.25 1.5 total weight core tablets 1350,00 100% Opadry ^R Green 03B11434 Glaxo Wellcome 29.70 2.2% target purified water ² US Pharmacopoeia as needed

¹ amount corresponding to 300 mg abacavir per tablet based on a factor of 1.17 ² removed during processing

Method of production

The ingredients are first weighed from the batch containers and then sieved using a Russell-SIV sieve, supplemented with mesh # 1. 14 (1.4 mm holes) or the corresponding screen and mesh and are placed in a stainless steel mixing container.

The abacavir, zidovudine, lamivudine, non-flammable microcrystalline cellulose, non-flammable sodium starch glycolate, and non-flammable colloidal silica are mixed for 20 minutes using a suitable mixer, such as a Matcon-Buls, Mixer or equivalent types. Magnesium stearate is then added to the mixture and stirring is continued for about 2 minutes.

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The lubricated mixture is then compressed using a suitable rotary tablet press, typically a Courtoy R-190, R-200 or the like. An internal control process is used for the weight of the tablets and their hardness and appropriate intervals during compression and adjustment of the tabletting pressure are made as required.

A patent application including this disclosure and claims may be used as a basis for priority to any subsequent patent application. The claims of such a subsequent patent application may be directed to any feature or combination of features described herein. They may take the form of a claim relating to a product, composition, method of manufacture or use and may include, by way of example and without limitation, one or more of the following claims.

Claims (27)

A pharmaceutical composition comprising: (i) a safe and therapeutically effective amount of abacavir or a pharmaceutically acceptable derivative thereof; ii) a safe and therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof; iii) a safe and therapeutically effective amount of zidovudine or a pharmaceutically acceptable derivative thereof; iv) a pharmaceutically acceptable glidant which is magnesium stearate, wherein said abacavir, lamivudine and zidovudine components are present in an amount of 30 to 70% of the total weight of the composition and said glidant is present in an amount of 0.05 to 5.0 % of the total weight of the composition. Pharmaceutical composition according to claim 1, characterized in that the components abacavir, lamivudine and zidovudine are present in an amount of 40 to 60% of the total weight of the composition and magnesium stearate is present in an amount of 1.5% of the total weight of the composition. The pharmaceutical composition according to claim 1, wherein the amount of abacavir is 15 to 1200 mg per unit dosage form. The pharmaceutical composition according to claim 1, wherein the amount of abacavir is 100 to 600 mg per unit dosage form. Pharmaceutical composition according to claim 4, characterized in that the amount of abacavir is 300 mg per unit dosage form. A pharmaceutical composition according to any one of claims 1 to 5 wherein the pharmaceutically acceptable derivative of abacavir is its hemisulfate. · · ···· · · ···· · · • • • • • • • • • · • • · · · • • • • • • • • • • • · • · · · · · · · · · · · · · · The pharmaceutical composition according to claim 1, wherein the amount of lamivudine is 15 to 1000 mg per unit dosage form. Pharmaceutical composition according to claim 7, characterized in that the amount of lamivudine is 100 to 500 mg per unit dosage form. The pharmaceutical composition according to claim 8, wherein the amount of lamivudine is 150 mg per unit dosage form. 10. The pharmaceutical composition of claim 1 wherein the amount of zidovudine is 30 to 1000 mg per unit dosage form. The pharmaceutical composition of claim 10, wherein the amount of zidovudine is 200-500 mg per unit dosage form. The pharmaceutical composition of claim 11, wherein the amount of zidovudine is 300 mg per unit dosage form. A pharmaceutical composition according to any one of claims 1 to 12, wherein the lamivudine is substantially free of the corresponding (+) - enantiomer. The pharmaceutical composition of any one of claims 1 to 12, wherein the lamivudine is provided such that the corresponding (+) enantiomer is present in an amount not exceeding about 5% by weight of lamivudine. Pharmaceutical composition according to any one of claims 1 to 14, characterized in that it comprises abacavir sulfate 26% by weight. lamivudine 11.1 wt. % zidovudine 22.2 wt. -21 ········································ Microcrystalline cellulose Sodium starch glycolate Magnesium stearate 34.4 wt. 4.8 wt. and 1.5 wt. 16. A pharmaceutical composition according to claim 1 comprising: abacavir sulfate 351.00 mg lamivudine 150.00 mg zidovudine 300.00 mg microcrystalline cellulose 464.25 mg sodium starch glycolate 64.50 mg and magnesium stearate 20.25 mg. The pharmaceutical composition according to any one of claims 1 to 16, wherein the composition is coated with a pharmaceutically acceptable coating. A pharmaceutical composition according to any one of claims 1 to 17 comprising a protease inhibitor. 19. The pharmaceutical composition of claim 18, wherein the protease inhibitor is selected from the group consisting of indinavir, ritonavir, nelfinavir, and [3 S- [3 R * (1 R *, 2 S *)]] - [3 - [[(4-aminophenyl) sulfonyl] - (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] tetrahydro-3-furanyl ester. 20. A method of producing a pharmaceutical composition according to any one of claims 1 to 14, wherein the method comprises admixing abacavir or a pharmaceutically acceptable derivative thereof, lamivudine or a pharmaceutically acceptable derivative thereof, zidovudine or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable glidant which is magnesium stearate. -22 ······································· · t 21. The method of claim 20 wherein the pharmaceutically acceptable glidant is incorporated into the first stage of mixing in the manufacture of the composition. A pharmaceutical composition according to any one of claims 1 to 19 for the treatment, reversal, reduction or inhibition of retroviral infections. The pharmaceutical composition of claim 22, wherein the retroviral disease is an immunodeficiency virus, including HIV. Use of abacavir or a pharmaceutically acceptable derivative thereof, lamivudine or a pharmaceutically acceptable derivative thereof, zidovudine or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable glidant such as magnesium stearate, for the manufacture of a medicament for the treatment of retroviral infections. 25. A product comprising: (i) packaging material; and (ii) a pharmaceutical composition contained in the packaging material, comprising: (a) a safe and therapeutically effective amount of abacavir or a pharmaceutically acceptable derivative thereof; (b) a safe and therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof; c) a safe and therapeutically effective amount of zidovudine or a pharmaceutically acceptable derivative thereof; d) a pharmaceutically acceptable glidant, which is magnesium stearate, wherein the components abacavir, lamivudine and zidovudine are present in an amount of 30 to 70% of the total weight of the composition and said glidant is present in an amount of 0.05 to 5.0% the total weight of the composition. An article according to claim 25, comprising a brochure containing article information. -23 ·· ···· ·· ···· ·· 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 Product according to claim 25 or 26, characterized in that the packaging material is a unit dose packaging blister.