HRP20000732A2 - Homogeneous pharmaceutical compositions comprising abacavir, lamivudine and zidovudine - Google Patents

Description

This invention relates to new pharmaceutical preparations that combine abacavir, lamivudine and zidovudine in the form of a single homogeneous dose useful in the treatment of diseases in mammals, including humans.

Abacavir (also known as (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, 1592U89) and its use as an antiviral substance, and especially in HIV infections, are described in European Patent Specification Number 0434450. Succinate salt (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2 -cyclopentene-1-methanol is described in WO96/06844. The hemisulfate salt of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol is described in WO98/52949. Currently, abacavir is being clinically investigated as an anti-HIV pharmaceutical agent.

Lamivudine (also known as EPIVIR™, 3TC™, (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, ( -)-cis-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine) shows proven antiviral activity against human immunodeficiency virus (HIV) and other viruses such as hepatitis B virus. Lamivudine and its use against HIV is described in EP 0382526 and WO91/17159. Lamivudine in its crystalline form is described in WO92/21676. Combinations of lamivudine with other reverse transcriptase inhibitors, particularly with zidovudine, are described in WO92/20344.

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

The synergistic effect of the combination of abacavir, lamivudine and zidovudine is described in WO96/30025. However, this document did not indicate how to achieve homogeneity of the three active ingredients when they are prepared in the form of a single tablet.

The success of modern multi-drug HIV treatments often requires strict adherence to a complex treatment regimen, which may require taking different drugs at specific times every day along with a careful diet. Patient non-adherence to a complex treatment regimen is a well-known problem with such treatments. See Goodman & Gilman, The Pharmacological Basis of Therapeutics, 9th ed., p. 1704-1705 (1996). Patient non-adherence is a critical problem in HIV treatment because, as a consequence, HIV resistance to combination drugs can occur.

This invention approaches the problem of non-adherence by preparing a single tablet containing several active ingredients. However, usually combining three drugs into one pill would result in a pill too large to swallow without effort. Furthermore, the greater the amount of drug in the preparation, the greater the amount of additional substances required to compress the mixture into a tablet. Increasing the amount of some excipients can also have the opposite effect on tablet properties and can lead to problems related to, for example, dissolution, content uniformity, firmness and disintegration.

Separation is a major problem when attempting to prepare a single, homogeneous tablet containing multiple active ingredients of different densities and particle sizes. Separation of active ingredients in pharmaceutical powders and granules is a well-known problem that can lead to inhomogeneous dispersions of active ingredients in final dosage forms. One of the main factors of separation is the size of the particles, their shape and density. Previous attempts to prepare tablets containing multiple drugs were prevented precisely because of the separation problem. Although the mixed mixtures were homogenous at the beginning, the active ingredients separated during further preparation and before compression into a tablet.

Slip agents are substances that are commonly used to improve the flow characteristics of granules and powders because they reduce friction between particles. See Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms: Tablets, Volume 1. Str. 177-178 (1989), incorporated herein by reference. Gliding agents are commonly added to the pharmaceutical formulation immediately prior to compression into a tablet to allow the granular material to flow into the openings of tableting machines. Lubricants include colloidal silica, asbestos-free talc, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metal stearate, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate and magnesium oxide.

Investigations into separation problems in pharmaceutical preparations have unexpectedly shown that glidants can be used to increase the homogeneity of the mixed mixture. The new compositions of this invention use glidants for their effect on the homogeneity of the active ingredients and to maintain the homogeneity of the ingredients during preparation prior to compression into a tablet.

Accordingly, the object of this invention is to provide a pharmaceutical preparation containing the active ingredients abacavir, lamivudine and zidovudine or their pharmaceutically acceptable derivatives in a sufficiently homogeneous form, and to provide a method for using such pharmaceutical preparations.

Another object of this invention is to enable a pharmaceutical preparation in the form of a tablet with a high drug content, while preserving the desirable properties of the tablets and their convenient size.

A further object of the present invention is to enable the beneficial use of slip agents in reducing the separation of active ingredients of pharmaceutical preparations during preparation prior to compression.

Furthermore, another object of this invention is to enable pharmaceutical preparations that combine the active ingredients abacavir, lamivudine and zidovudine or their pharmaceutically acceptable derivatives with a pharmaceutically acceptable glidant, thereby obtaining a mixture with a pharmaceutically acceptable measure of homogeneity.

Another object of the present invention is to provide a pharmaceutical composition containing abacavir or its pharmaceutically acceptable derivative, lamivudine or its pharmaceutically acceptable derivative and zidovudine or its pharmaceutically acceptable derivative together with one or more pharmaceutically acceptable carriers and optionally, other therapeutic and/or prophylactic substances. Other therapeutic agents may include substances effective in the treatment of viral infections or related conditions such as (1 alpha, 2 beta, 3 alpha)-9-[2,3-bi(hydroxymethyl)cyclobutyl]guanine [( -)BHCG, SQ-34514], oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetanosyl]guanine), acyclic nucleosides (eg acyclovir, valacyclovir, famciclovir, ganciclovir, penciclovir, acyclic nucleoside phosphonates (eg (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC) or PMEA, ribonucleotide reductase inhibitors such as 2-acetylpyridine 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'-didehydrothymidine, 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), analogues of oxathiolane nucleosides as which is cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3'-deoxy-3'-fluorothymidine, 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)-3H-1 ,4-benzodiazepine-2-(H)one (Ro5-3335), 7-chloro-1,3-dihydro-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepine-2-amine (Ro24-7429), interferons such as α-interferon, renal secretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole, pentoxifylline, N-acetylcysteine (NAC), procysteine, α-trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony-stimulating factors, erythropoietin, soluble CD4 and its genetically engineered derivatives, or non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (BI-RG-587), loviride (α-APA ) and delavuridine (BHAP), and phosphoformic acid, and 1,4-dihydro-2H-3,1-benzoxazin-2-one NNRTI k and which is (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266) and quinoxaline NNRTIs such as is isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3oxo-1(2H)-quinoxalinecarboxylate (HBY1293), hydroxyurea or inosine monophosphate dehydrogenase inhibitors such as mycophenolic acid or its esters.

The carrier(s) must be pharmaceutically acceptable in terms of its compatibility with the other ingredients of the formulation and must not be harmful to its recipients.

Another object of the present invention is to simplify the treatment regimen for HIV and other viruses in order to increase patient adherence to the regimen by providing a simpler dosage form containing pharmaceutically acceptable amounts of abacavir, lamivudine and zidovudine or pharmaceutically acceptable derivatives thereof.

In its first aspect, this invention provides a pharmaceutical composition containing:

a safe and therapeutically effective amount of abacavir or its pharmaceutically acceptable derivative;

a safe and therapeutically effective amount of lamivudine or its pharmaceutically acceptable derivative;

a safe and therapeutically effective amount of zidovudine or its pharmaceutically acceptable derivative;

a pharmaceutically acceptable carrier that is characterized by the homogeneity of the active ingredients.

In a further aspect, this invention provides a pharmaceutical preparation containing abacavir or its pharmaceutically acceptable derivative, lamivudine or its pharmaceutically acceptable derivative and zidovudine or its pharmaceutically acceptable derivative in an amount of about 30% to about 70% of the total weight of the preparation. It is convenient that the preparation is in the form of a tablet, where said tablet contains 30% to 60% of the amount of the drug, and it is suitable for it to be 40% to 60% of the amount of the drug.

As used herein, the term "safe and therapeutically effective amount" means an amount of a drug, compound, composition, product, or pharmaceutical substance sufficient to reduce, reverse, or treat a disease in humans or other mammals without causing severe damage to the mammalian tissue. to whom the medicine or pharmaceutical substance is given.

As used herein, the term "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt, solvate, ester, or salt of such an ester, or any substance which, when administered to a recipient, is capable of providing (directly or indirectly) the desired active ingredient or any which its active metabolite or residue.

As used herein, the term "pharmaceutically acceptable derivative of abacavir" means any pharmaceutically acceptable salt, solvate, ester, or salt of such an ester of abacavir or any substance which, when administered to a recipient, is capable of delivering (directly or indirectly) abacavir or any its antiviral active metabolite or residue.

As used herein, the term "pharmaceutically acceptable derivative of lamivudine" refers to any pharmaceutically acceptable salt, solvate, ester, or salt of such an ester of lamivudine or any substance which, when administered to a recipient, is capable of delivering (directly or indirectly) lamivudine or any its antiviral active metabolite or residue.

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

As used herein, the term "homogeneous" means that the active ingredients are reliably equally dispersed within that part of the finished tablet in which they are found (for example, in the case of a film-coated tablet, the active ingredients are equally dispersed in the core of the tablet). The homogeneity of the active ingredients in the tablet can be determined by measuring the uniformity of the drug.

As used herein, the term "safe and effective amount" means that the amount of a substance required to achieve an effect has been determined by the investigator or physician without causing severe damage to the tissue of the mammal to which the substance is administered.

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

Lamivudine is preferably substantially purified from its (+)-enantiomer. As used herein, the term "substantially purified" means that the mass ratio (w/w) of (+)-enantiomer to lamivudine is less than about 10%. It is preferable that this ratio is less than about 5%.

In a further aspect, the present invention provides a method for treating, reversing, alleviating or inhibiting retrovirus infection, particularly HIV infection, in mammals, particularly humans. This method involves administering to said mammal a safe and effective amount of a composition of the present invention.

In its next aspect, this invention enables the combined use of abacavir or its pharmaceutically acceptable derivative, lamivudine or its pharmaceutically acceptable derivative and zidovudine or its pharmaceutically acceptable derivative and a pharmaceutically acceptable lubricant in the production of medication for the treatment of retrovirus infection, especially HIV infection. Experts in the field will appreciate that the term "treatment" used here includes both prophylaxis and treatment of already established diseases, infections or their symptoms.

The preparations of this invention use a safe and therapeutically effective amount of (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol ( abacavir) or its pharmaceutically acceptable derivatives, 3'-azido-3'-deoxythymidine (zidovudine) or its pharmaceutically acceptable derivatives and (-)-cis-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (lamivudine) or its pharmaceutically acceptable derivatives together with a safe and effective amount of a pharmaceutically acceptable glidant, to preserve the homogeneity of the preparation before compression into a tablet. It is usual that the particle size and shape of the three active ingredients will be different. The pharmaceutical preparation is homogeneous in the sense that the active ingredients, which include abacavir, lamivudine, zidovudine and a sliding agent, are reliably equally dispersed within the part of the finished tablet in which they are found. For example, if the tablet is coated with a film, the active ingredients are equally dispersed in the core of the tablet.

Abacavir can be prepared by methods described in European Patent Specification Number 0434450 or in WO95/21161, incorporated herein by reference. The succinate salt of compound 1592U89 can be prepared as described in WO96/06844, herein incorporated by reference. The hemisulfate salt of compound 1592U89 can be prepared as described in WO98/52949, herein incorporated by reference. Preferred salts of abacavir include succinate and hemisulfate salts.

Lanivudine can be prepared by methods described, inter alia, in WO92/20669 or in WO95/29174, incorporated herein by reference.

Zidovudine can be prepared by methods described in United States Patent No. 5,011,829, incorporated herein by reference.

The compositions of the present invention may optionally use a safe and effective amount of diluent, a safe and effective amount of disintegrant, a safe and effective amount of lubricant, or a safe and effective amount of any other field-use additive.

The compositions according to this invention may contain from 0 to about 2% of magnesium stearate; from about 0.05 to about 5% glidant, from 0 to about 5% starch sodium glycolate and from about 20 to about 50% microcrystalline cellulose.

Slip agents are substances that are commonly used to improve the flow characteristics of granules and powders because they reduce friction between particles. See Remington, The Science & Practice of Pharmacy, p. 1619, 19th ed. (1995) and Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms: Tablets, Volume 1. Str. 177-178 (1989), incorporated herein by reference. Improving flow characteristics helps reduce tableting machine clogging and tablet malfunction, and minimizes variation in tablet weight. Gliding agents are usually added to pharmaceutical preparations immediately before compression into a tablet in order to facilitate the flow of the granular material into the openings of the machine and tableting. Silicon dioxide (SiO2), also known as colloidal silica, fumed silica, fumed silica, light silicic acid anhydride or silicon anhydride can be used for the compositions of this invention. Silica is sold under the trade names AEROSIL™ and CAB-O-SIL™. Other glidants that can be used in the compositions of this 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 silicon dioxide in combination with microcrystalline cellulose or ProSolve™.

The ability of slip agents to improve flow characteristics depends on:

their chemical properties in relation to the chemical properties of other ingredients of the preparation and:

physical properties such as the size, shape and distribution of the sliding agent and other ingredients of granulates and powders, as well as the content of the wetting agent and the temperature of the preparation.

The investigation of the problem of separation of active ingredients in pharmaceutical preparations, powders and granules led the researchers of this invention to the unexpected discovery that sliding agents can be used to reduce the separation of active ingredients, and thus improve the homogeneity of pharmaceutical preparations, powders and granules. In this invention, from about 0.05% to about 5% of the glidant is used. Below a value of about 0.05%, the homogeneity may be insufficient, while at values higher than about 5%, no more homogeneity is obtained.

Silica may be a preferred glidant because it is relatively inert. A preferred form of silica may be fumed colloidal silica, which is submicroscopic fumed silica. It is a light, fine amorphous powder. In particular, from about 0.05% to about 1% of silica is used, because below a value of about 0.05% the homogeneity may be insufficient, while at values higher than about 1% no more homogeneity is obtained. Magnesium stearate may be a preferred glidant.

It is common practice for slip agents, when used to improve flow characteristics, to be added to the formulation during the lubricant addition stage just prior to compression. See Remington, The Science & Practice of Pharmacy, p. 1619, 19th ed. (1995), given here as a reference. However, this invention uses glidants in the initial mixture to improve and maintain homogeneity during preparation and prior to compression. A further glidant may be added during the lubricant addition stage immediately prior to compression in order to improve the properties of the formulation, as is known in the pharmaceutical formulation art.

It is preferable that the pharmaceutical composition according to this invention be prepared in a form suitable for oral use. Usually, such preparations are prepared in the form of individual units, such as tablets, caplets, capsules or any other form suitable for oral use and compatible with the preparations according to this invention, which contain a predetermined amount of active ingredients. Preparations that can be prepared by direct tableting or granulation are particularly suitable. Such compositions may contain a safe and effective amount of common additives such as binders, fillers, lubricants or diluents. The tablets may be coated by any method known to one skilled in the art which does not affect the release properties or other physical or chemical properties of the tablets of this invention. Tablet coating is described and shown in Remington, The Science & Practice of Pharmacy, 19th ed. (1995), given here as a reference. If necessary, the preparations described above can be modified by any method known to the expert in the field, in order to achieve a prolonged release of the active ingredients. The preparations may also contain a safe and effective amount of other active ingredients such as antimicrobial substances or preservatives.

The compositions according to the present invention are particularly suitable for oral administration to humans or other mammals. However, other methods of administration that can be determined by physicians or other persons skilled in the field of administering pharmaceutical doses, such as pharmacists or nurses, are not excluded. One such procedure would be to crush the solid dose and mix it with a suitable vehicle and take it 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 treatment will vary depending on a number of factors, including the nature of the condition being treated, and the age and condition of the patient, and will be within the sole discretion of the responsible physician, veterinarian or other healthcare worker.

However, generally speaking, a suitable dose of abacavir for administration to humans in 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 per day, and most preferably in the range of 5 to 60 mg per kilogram of body weight per day.

Currently, the recommended oral dose of lamivudine for adults and adolescents is 150 mg twice daily, taken in combination with zidovudine. For adults with a low body weight (less than 50 kg or 110 Ib), the currently recommended oral dose of lamivudine is 2 mg/kg twice daily, taken in combination with zidovudine. The recommended oral dose of lamivudine for pediatric patients aged 3 months to 12 years is 4 mg/kg twice a day, up to a maximum of 150 mg taken twice a day in combination with zidovudine.

In general, the currently recommended oral dose of zidovudine is 600 mg per day taken in divided doses in combination with other antiretroviral agents. The recommended oral dose for pediatric patients aged 3 months to 12 years is 180 mg/m2 every 6 hours or 720 mg/m2 per day, but not to exceed 200 mg every 6 hours.

The preparations according to the present invention give patients more freedom in medical regimens with a larger number of drugs and make it easier to remember complex daily schedules and times of administration. By combining abacavir, lamivudine and zidovudine in a single dose, the preferred daily dose can be given as a single dose or as a multiple dose, and especially as a multiple dose, taken at convenient intervals, for example two, three, four or more smaller dose per day, especially if it is taken in the form of two smaller doses per day.

The preparations according to the present invention enable the administration of three separate compounds in the form of a single dose containing, for example, from about 15 to about 1200 mg of abacavir, and especially from about 100 to about 600 mg of abacavir, and most preferably about 350 mg of abacavir, from about 15 to about 1000 mg lamivudine, and especially from about 100 to about 500 mg lamivudine, and most preferably 150 mg lamivudine and from about 30 to 1000 mg zidovudine, and especially from about 200 mg to about 500 mg zidovudine, and especially 300 mg zidovudine per unit dose.

The composition of the present invention can be used in combination with other pharmaceutical compositions as one component of a multidrug treatment regimen.

The preparations according to the present invention can be packaged in the form of a product of manufacture containing 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, and a safe and therapeutically effective amount of zidovudine or a pharmaceutically acceptable derivative thereof and a safe and an effective amount of a pharmaceutically acceptable glidant.

Any method known to one skilled in the art of packaging tablets, caplets, or other solid dosage forms suitable for oral use, which does not diminish the effect of the compounds of this invention may be used for packaging. Tablets, caplets or other solid dosage forms suitable for oral use can be packaged or contained in different packaging materials, especially in glass or plastic bottles, and also in single-dose blister packs. Labels and information related to the pharmaceutical preparation may be printed on the packaging material. In addition, the production product may also contain a brochure, report, notice, propaganda material or leaflets containing information about the product. These forms of pharmaceutical notices are called "package inserts" in the pharmaceutical industry. The package insert can be attached to or located in the pharmaceutical product of manufacture. Package inserts and any other industrial labeling products provide information about the pharmaceutical preparation. Data and labels provide various forms of information used by health professionals or patients, and describe the composition, dosage and various other parameters that must be listed in accordance with the requirements of responsible institutions such as the United States Food and Drug Agencies.

Preparations according to this invention can be prepared using procedures and techniques suitable for the physical and chemical properties of the preparation, which are commonly used by experts in the field of preparation of oral dosage forms using direct tableting or granulation processes. Remington, The Science & Practice of Pharmacy, p. 1615-1623, 1625-1648 and other usable parts, 19th ed. (1995).

The compositions of this invention, in their methodological aspect, are administered to humans or other mammals in a safe and effective amount as described herein. The safe and effective amount will vary depending on the species and size of the treated mammal and the desired results of the treatment.

EXAMPLES

The following examples further describe and illustrate particular embodiments within the scope of this invention. The examples are given by way of illustration only and no limitations can be made from them, as numerous variations are possible without departing from the spirit and scope of the present invention.

Example 1

Preparation of the hemisulfate salt of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol

A mixture of water (25 ml) and isopropanol (IPA) (100 ml) was stirred and heated to 45 to 55° C, and succinate salt (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino) was added. -9H-purin-9-yl]-2-cyclopenten-1-methanol (WO 96/06844) (50 g) and washed with IPA (12.5 ml). The mixture was heated under reflux for about 0.5 hours, and the resulting transparent solution was cooled to 65 to 75° C., and a solution of concentrated sulfuric acid (6.07 g) and water (12.5 ml) was added. A mixture of IPA (37.5 ml) and water (12.5 ml) was added to the solution, and the solution was cooled to 45 to 55° C, and then a germ of the original hemisulfate salt (1S,4R)-cis- was added to the solution. 4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-methanol. During 1 hour, the solution was stirred in the specified temperature range to achieve crystallization, and IPA (300 ml) was added while maintaining the temperature of the mixture in the range of 45 to 55° C. The suspension was cooled to 0 to 5° C for 2 hours, and the product was filtered, washed with IPA (2 x 75 ml) and dried in vacuo at 40 to 45° C, and the title compound was obtained as a light yellowish brown powder (34.3 g, 90%); m.p. 224-225° C (decomp.);

1H-NMR (DMSO-d6)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, NH2), 6.13(m, 1, = CH), 5.87(m, 1, = CH), 5.40(m, 1, NCH), 3.45(d, J = 5.8Hz,2, OCH2), 2.96(br, m, 1 CH from cyclopropyl), 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 CH2 from cyclopropyl).

Example 2

Preparation of a tablet containing a combination of abacavir, lamivudine and zidovudine by direct tableting process

[image] *Equivalent to 300 mg of abacavir free base

Bulk preparation process

The quantities in this production example were based on a typical batch size of 400 kg and may vary depending on the production batch size.

The ingredients were first weighed out of their containers in the following amounts:

[image]

The ingredients were then sieved using a Russell-SIV screen equipped with 14 mesh (1.4 mm mesh) or equivalent screen and stored in a stainless steel mixer tank.

Abacavir, zidovudine, lamivudine, microcrystalline cellulose NF, starch sodium glycolate NF and colloidal silica NF were mixed for 20 minutes using a suitable mixer such as a Matcon-Buls bin-type mixer, V-mixer or similar. Magnesium stearate was then added, and mixing was continued for approximately 2 minutes.

The mixture to which the lubricant was added was then compressed using a suitable rotary tablet press, usually Courtoy R-190, R-200 or similar. At appropriate intervals during the compression process, controls were applied for tablet mass and firmness, and pressure corrections were also made when necessary.

Example 3

Preparation of a tablet containing a combination of abacavir, lamivudine and zidovudine by wet granulation process

[image] *Equivalent to 300 mg of abacavir free base

Preparation process

The ingredients were weighed and sieved using a Russell-SIV screen fitted with 30 mesh or an equivalent screen and stored in a stainless steel mixer container.

Abacavir, zidovudine, microcrystalline cellulose, starch sodium glycolate, and colloidal silica are mixed for 1-5 minutes using a suitable granulator/mixer, such as a Spectrum SP or Fielder PMA or similar. An aqueous solution of providone with a mass ratio of 10-20% m/m was prepared and added to granulate the powder. If necessary, more water can be added during granulation. The granulate is then dried using microwave drying in a granulator such as Spectrum SP or similar, or dried using a fluidizing device such as UniGlatt or Aeromatic MP or Aeromatic Stea-1 or similar. The dried granulate was milled using a Comill or Fitzmill or the like. Lamivudine was added to the milled granules and mixed for 15 minutes using a suitable mixer such as a Matcon-Buls bin-type mixer or V-mixer or similar. Magnesium stearate was then added to the mixture, and mixing was continued for approximately 2 minutes.

Then the mixture to which the lubricant has been added is compressed using a suitable rotary tablet press, commonly used is Manesty Beta or Fette or Courtoy or similar. At appropriate intervals during the compression process, controls were applied for tablet mass and firmness, and pressure corrections were also made when necessary.

Example 4

Preparation of a tablet containing a combination of abacavir, lamivudine and zidovudine by direct tableting process

Compounds and preparations in tablets containing abacavir, lamivudine and zidovudine

[image] Notice:

1Equivalent to 300 mg of abacavir per tablet based on a factor of 1.17.

2Removed during the procedure.

Preparation process

The ingredients were first removed from the container and sieved using a Russell-SIV sieve equipped with 14 mesh (1.4 mm mesh) or equivalent sieve and stored in a stainless steel mixer container.

Abacavir, zidovudine, lamivudine, microcrystalline cellulose NF, and sodium starch glycolate NF were mixed for 20 minutes using a suitable mixer such as a Matcon-Buls bin-type mixer, V-mixer or similar. Magnesium stearate was then added, and mixing was continued for approximately 2 minutes.

The mixture to which the lubricant has been added is then compressed using a suitable rotary tablet press, usually Courtoy R-190, R-200 or similar. At appropriate intervals during the compression process, controls were applied for tablet mass and firmness, and pressure corrections were also made when necessary.

An application of which these descriptions and requirements form part may be used as the basis of priority in terms of any subsequent application. The requirements of such subsequent applications may relate to any feature described herein or to a combination thereof. These may take the form of a claim for a product, preparation, process or use and may include, by way of example and without limitation, one or more of the following claims.

Claims (27)

1. Pharmaceutical preparation, characterized in that it contains: i) a safe and therapeutically effective amount of abacavir or its pharmaceutically acceptable derivative; ii) a safe and therapeutically effective amount of lamivudine or its pharmaceutically acceptable derivative; iii) a safe and therapeutically effective amount of zidovudine or its pharmaceutically acceptable derivative; and iv) a pharmaceutically acceptable lubricant which is magnesium stearate; where said abacavir, lamivudine and zidovudine are present in an amount of 30% to 70% of the total mass of the preparation and said sliding agent is present in an amount of 0.05% to 5.0% of the total mass of the preparation. 2. Pharmaceutical preparation according to claim 1, characterized in that said abacavir, lamivudine and zidovudine are present in an amount of 40% to 60% of the total weight of the preparation and said magnesium stearate is present in an amount of 1.5% of the total weight of the preparation. 3. Pharmaceutical preparation according to claim 1, characterized in that the amount of abacavir is from about 15 to about 1200 mg per unit dosage form. 4. Pharmaceutical preparation according to claim 1, characterized in that the amount of abacavir is from about 100 to about 600 mg per unit dosage form. 5. Pharmaceutical preparation according to claim 1, characterized in that the amount of abacavir is 300 mg per unit dosage form. 6. Pharmaceutical preparation according to any of claims 1 to 5, characterized in that the pharmaceutically acceptable derivative of abacavir is a hemisulfate salt. 7. Pharmaceutical preparation according to claim 1, characterized in that the amount of lamivudine is from about 15 to about 1000 mg per unit dosage form. 8. Pharmaceutical preparation according to claim 7, characterized in that the amount of lamivudine is from about 100 to about 500 mg per unit dosage form. 9. Pharmaceutical preparation according to claim 8, characterized in that the amount of lamivudine is 150 mg per unit dosage form. 10. Pharmaceutical preparation according to claim 1, characterized in that the amount of zidovudine is from about 30 to about 1000 mg per unit dosage form. 11. Pharmaceutical preparation according to claim 10, characterized in that the amount of zidovudine is from about 200 to about 500 mg per unit dosage form. 12. Pharmaceutical preparation according to claim 11, characterized in that the amount of zidovudine is 300 mg per unit dosage form. 13. A pharmaceutical composition according to any one of claims 1 to 12, characterized in that the lamivudine provided is substantially pure from the corresponding (+)-enantiomer. 14. A pharmaceutical composition according to any one of claims 1 to 12, characterized in that the lamivudine is provided so that the corresponding (+)-enantiomer is present in an amount not greater than about 5% w/w of the amount of lamivudine. 15. Pharmaceutical preparation according to any of claims 1 to 14, characterized in that it contains: Abacavir sulfate 26% m/m; Lamivudine 11.1% m/m; Zidovudine 22.2% m/m; Microcrystalline cellulose 34.4% m/m; Starch sodium glycolate 4.8% m/m; and Magnesium stearate 1.5% m/m. 16. Pharmaceutical preparation according to claim 1, characterized in that it contains: Abacavir sulfate 351.00 mg; Lamivudine 150.00 mg; Zidovudine 300.00 mg; Microcrystalline cellulose 464.25 mg; Starch sodium glycolate 64.50 mg; and Magnesium stearate 20.25 mg. 17. A pharmaceutical preparation according to any one of claims 1 to 16, characterized in that the preparation is coated with a pharmaceutically acceptable envelope. 18. Pharmaceutical preparation according to any of claims 1 to 17, characterized in that it additionally contains a protease inhibitor. 19. Pharmaceutical preparation according to claim 18, characterized in that said protease inhibitor is selected from the group consisting of indinavir, ritonavir, nelfinavir and [3S-[3R*(1R*,2S*)]]-[3[[(4- aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furanyl ester. 20. A method for treating, reversing, reducing or inhibiting retroviral infections, characterized in that it comprises administering a safe and effective amount of the preparation according to any of claims 1 to 19. 21. A method for treating, reversing, reducing or inhibiting retroviral infections according to claim 20, characterized in that the retrovirus is an immunodeficiency virus, including HIV. 22. The use of abacavir or its pharmaceutically acceptable derivative, lamivudine or its pharmaceutically acceptable derivative, zidovudine or its pharmaceutically acceptable derivative and a pharmaceutically acceptable sliding agent which is magnesium stearate, indicated that they are used in the production of medicines for the treatment of retroviral infections. 23. Product of production, indicated by the fact that it contains: i) packaging material; and ii) pharmaceutical preparation, placed in packaging material, containing: a) a safe and therapeutically effective amount of abacavir or its pharmaceutically acceptable derivative; b) a safe and therapeutically effective amount of lamivudine or its pharmaceutically acceptable derivative; c) a safe and therapeutically effective amount of zidovudine or its pharmaceutically acceptable derivative; and d) pharmaceutically acceptable lubricant, which is magnesium stearate; where said abacavir, lamivudine and zidovudine are present in an amount of 30% to 70% of the total mass of the preparation and said sliding agent is present in an amount of 0.05% to 5.0% of the total mass of the preparation; and where the active ingredients are homogeneously dispersed in the pharmaceutical preparation. 24. The product of production according to claim 23, characterized by the fact that it additionally contains a brochure with information about the product. 25. The production product according to claim 23 or claim 24, characterized in that the packaging material is a unit dose blister pack. 26. The process of preparing a pharmaceutical preparation according to any of claims 1-14, characterized in that the process consists of mixing abacavir or its pharmaceutically acceptable derivative, lamivudine or its pharmaceutically acceptable derivative, zidovudine or its pharmaceutically acceptable derivative and a pharmaceutically acceptable sliding agent which is magnesium stearate. 27. The process according to claim 26, characterized in that a pharmaceutically acceptable sliding agent is included in the first mixing phase during the preparation process.