MXPA99004025A - Pharmaceutical compositions containing lamivudine and zidovudine - Google Patents

Abstract

A pharmaceutical composition and a method of inhibiting human immunodeficiency virus (HIV) is disclosed which comprises administering to an HIV infected patient a homogenous combination of lamivudine, zidovudine and a pharmaceutical glidant in an amount which achieves antiviral efficacy.

Description

PHARMACEUTICAL COMPOSITIONS 'CONTAINING LAMIVUDINE AND ZIDOVUDINE FIELD OF THE INVENTION The present invention relates to novel pharmaceutical compositions, which combine the agents lamivudine and zidovudine in a single dosage form, useful in the treatment of diseases in mammals, including humans.

BACKGROUND OF THE INVENTION The present invention relates to novel pharmaceutical compositions that combine lamivudine and zidovudine agents in a single dosage form useful in the treatment of diseases in mammals, including humans. The present invention is particularly useful for treating viral infections, particularly retroviral infections, including human immunodeficiency virus (HIV) HIV causes a variety of clinical conditions, including acquired immunodeficiency syndrome (AIDS) and neurological disorders REF. 30084 chronic The recent advent of a variety of multiple drug treatment regimens has dramatically improved the treatment of patients infected with HIV. Prior to these multiple drug regimens, treatment was often limited to a single drug with limited effectiveness. Regimens of single drug treatment typically require long-term treatment increasing the incidence of undesirable side effects. In addition, single-drug therapies are particularly vulnerable to mutations in the HIV virus, leading to HIV variants resistant to the drug. The use of multiple drug therapies can lead to the development of HIV strains resistant to the drug, because a drug will usually cancel the mutations against the other drugs. Multiple drug therapies can still inhibit the reproduction of HIV viruses for a period of time sufficient to eliminate HIV from the body. The success of modern multiple drug treatments for HIV often requires strict adherence to a complete treatment regimen that may require the administration of many different drugs per day, "administered at precisely timed intervals with careful attention to diet. The patient who does not comply is a well-known problem that accompanies such complex treatment regimens, see Goodman &Gilman, The Pharmacological Basis of Therapeutics, 9th ed., Pp. 1704-1705 (1996), incorporated herein by reference. The patient who does not comply is a major problem in the treatment of HIV because such lack of compliance can lead to the emergence of HIV strains resistant to multiple drugs, two of the many compounds that are commonly included in drug treatment regimens. Multiple for HIV are zidovudine and lamivudine.Lamivudine (also known as 3TC ™) is a synthetic nucleoside analog, chemically known as (2R, cis) -4-amino-1- (2-hydroxymethyl-l, 3-oxathiolan-5-yl) - (1H) -pyrimidin-2-one. Lamivudine has also been referred to as (-) -2 ', 3'-dideoxy, 3' thiacytidine. Lamivudine has been shown to have antiviral activity against human immunodeficiency virus (HIV), and other viruses such as hepatitis B. Lamivudine is commercially available from Glaxo Wellcome Inc. under the EPIVIR ™ brand. Lamivudine and its use against HIV is described in EP 0382526 and W091 / 17159. The crystalline forms of lamivudine are described in W092 / 21676. Combinations of lamivudine with other inverted transcriptase inhibitors, in particular, zidovudine, are described in W092 / 20344. Zidovudine, chemically known as 3'-azido-3'-deoxythymidine, is a nucleoside analog of pyrimidine commercially available from Glaxo Wellcome Inc. under the trademark RETROVIR ™ for the treatment of HIV and other viruses. Zidovudine is further described in US Patents 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. In November 1995, the FDA granted accelerated approval for the use of lamivudine in combination with zidovudine for the first-line treatment of HIV infection in adults and children. Lamivudine exhibits unexpected advantages when used in combination with known inhibitors of HIV reproduction. In particular, lamivudine shows a synergistic antiviral effect when used in combination with zidovudine. In controlled clinical trials, combination therapy with lamivudine and zidovudine delayed the emergence of HIV mutations resistant to zidovudine. The segregation of active ingredients in pharmaceutical powders and granulations is a widely recognized problem that can result in an inconsistent dispersion of the active ingredients in final dosage forms. Some of the main factors that contribute to segregation are particle size, shape and density. Segregation is particularly problematic when it is intended to formulate a single homogeneous tablet containing the multiple active ingredients having different densities and different particle sizes. Previous attempts to formulate tablets containing lamivudine and zidovudine were prevented precisely by such segregation problems. Although the mixed combinations were initially homogeneous, the active ingredients were segregated during the handling of the material and before the compression of the tablet. Lubricants are substances that have traditionally been used to improve the flow characteristics of granulations and powders by reducing friction between particles. See Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms: Tablets, Volume 1, p. 177-178 (1989), incorporated herein by reference. Lubricants are typically added to the pharmaceutical compositions immediately prior to compression of the tablet to facilitate flow of the granular material into the die cavities of the tableting machines. Lubricants include: colloidal silicon dioxide, asbestos free talc, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metal stearates, calcium stearate , magnesium stearate, zinc stearate, stearowet C, starch, 1500 starch, magnesium lauryl sulfate, and magnesium oxide. Research into the problem of segregation in pharmaceutical compositions has surprisingly shown that lubricants can be used to increase and aid in the homogeneity of the mixed composition. The novel compositions of the present invention use lubricants to effect and maintain the homogeneity of the active ingredients during handling prior to compression of the tablet.

DESCRIPTION OF THE INVENTION Therefore, an object of the present invention is to provide a pharmaceutical formulation that combines the active ingredients lamivudine and zidovudine, or pharmaceutically acceptable derivatives thereof, in a sufficiently homogenized form, and a method for using this pharmaceutical formulation. . A further object of the present invention is to use lubricants to reduce the segregation of the active ingredients in pharmaceutical compositions during handling of the precompressed material. A still further object of the present invention is to provide a pharmaceutical formulation that combines the active ingredients lamivudine and zidovudine, or pharmaceutically acceptable derivatives thereof, with a pharmaceutically acceptable lubricant, resulting in a mixture characterized by a measure of pharmaceutically homogeneity acceptable. Another object of the present invention is to provide a pharmaceutical formulation comprising zidovudine, or a pharmaceutically acceptable derivative thereof, and lamivudine, or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and / or prophylactic ingredients. The carriers must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Still another object of the present invention is to simplify treatment regimens for HIV and other viruses in order to increase patient compliance by providing a simplified dosage form containing pharmaceutically acceptable amounts of lamivudine and zidovudine or pharmaceutically acceptable derivatives thereof. . Those additional objects and objects will be apparent from the following description of the invention. In a first aspect, the present invention provides a pharmaceutical composition comprising: a) a safe therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof; b) a safe therapeutically effective amount of zidovudine or a pharmaceutically acceptable derivative thereof; and c) a pharmaceutically acceptable lubricant thereof. The phrase "a safe and therapeutically effective amount" as used herein, means a "" sufficient amount of a drug, compound, composition, product or pharmaceutical agent to kill or reverse or treat a disease in a human or other mammal without severely damaging the tissues of the mammal to which the drug or pharmaceutical agent is administered. The phrase "pharmaceutically acceptable derivatives", as used herein, means any salt, solvate, ester or salt of such pharmaceutically acceptable ester, or any other compound which, after being administered to the recipient, is capable of providing (directly or indirectly) the intended active ingredient or any active metabolite or residue thereof. The phrase "safe and effective amount" as used herein, is that amount of an agent that is required to perform the function that is sought by the researcher or physician without severely damaging the tissues of the mammal to which the agent is administered. In a second or alternative aspect, the present invention provides a method for treating, reversing, reducing or inhibiting retroviral infections, in particular HIV infections, in a mammal, in particular a human, which method comprises administering to said mammal a safe amount and effective of a composition according to the invention. In a further or alternative aspect, the present invention provides the combined use of lamivudine, or a pharmaceutically acceptable derivative thereof, zidovudine, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable lubricant in the manufacture of a medicament for the treatment of a retroviral infection, in particular an HIV infection. It should be appreciated by those skilled in the art that the reference here to "treatment" extends to both prophylaxis and treatment of an established disease, infection or its symptoms. The compositions of the present invention employ a safe and therapeutically effective amount of 3 '-azido-3' -deoxythymidine (zidovudine) and its pharmaceutically acceptable salts, solvates and derivatives thereof, with a safe and therapeutically effective amount of (-) 2 ', 3' -dideoxy, 3 '-thiacytidine (lamivudine) and its pharmaceutically acceptable salts, solvates or derivatives thereof, together with a safe and effective amount of a pharmaceutically acceptable lubricant to maintain the homogeneity of the compositions prior to compression of the tablet. Typically, the particle size of the two active ingredients will be different. The pharmaceutical formulation is homogeneous in the sense that the active ingredients are substantially uniformly dispersed in all or part of the finished formulation, which includes lamivudine, zidovudine and the lubricant. For example, in the case of a compressed tablet coated with a film, the active ingredients are dispersed evenly throughout the core of the tablet. The compositions of the present invention may optionally employ a safe and effective amount of a diluent, a safe and effective amount of a disintegrant, and a safe and effective amount of a lubricant or any other safe and effective amounts of excipients commonly used in the technique. Lamivudine (also known as 3TC ™) known chemically as (2R, cis) -4-amino-1- (2-hydroxymethyl-1,3-oxathiolan-5-yl) - (1H) -pyrimidin-2-one and also known as (-) -2 ', 3'-dideoxy, 3' thiacytidine, is a synthetic nucleoside analog with antiviral activity against the human immunodeficiency virus (HIV). In vitro studies have shown that, intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite (L-TP). The main mode of action of L-TP is the inhibition of inverted transcription via the termination of the viral DNA chain. L-TP also inhibits the activities of the DNA polymerase that depend on the RNA and DNA of the retroviral inverted transcriptase. The enantiomers of 2 ', 3' -dideoxy, 3'-thiacytidine are equipotent against HIV; however, the (-) enantiomer (lamivudine) has considerably lower cytotoxicity than the (+) enantiomer. Particularly, the enantiomer (-) (lamivudine), (-) 2 'r 3' -dideoxy, 3 'thiacytidine, is provided substantially free of the (+) enantiomer, ie approximately 10% w / w of the enantiomer is present (+), particularly not more than 5%, and more particularly less than 1% by weight / weight. The methods for the preparation of lamivudine are described inter alia, WO 92/20669 and WO 95/29174 both incorporated herein by reference. The phrase "pharmaceutically acceptable derivative of lamivudine" as used herein, means any salt, solvate, ester or salt of such ester, lamivudine, or any other pharmaceutically acceptable compound which, upon administration to the recipient, is capable of providing ( directly or indirectly) lamivudine or any metabolite or antivirally active residue thereof. Zidovudine, chemically known as 3'-azido-3 '-deoxythymidine, is also a nucleoside analog of primidine. Intracellularly, zidovudine is converted enzymatically to zidovudine triphosphate. Zidovudine triphosphate interferes with DNA polymerase (inverted transcriptase), which depends on the viral RNA of HIV and thus inhibits viral reproduction. The phrase "pharmaceutically acceptable derivative of zidovudine" as used herein, means any salt, solvate, ester or salt of such an ester, of zidovudine, or any other pharmaceutically acceptable compound which, after being administered to the recipient, is capable of to provide (directly or indirectly) zidovudine or any metabolite or antivirally active residue thereof. Methods for the preparation of zidovudine are described in U.S. Patent No. 5,011,829, incorporated herein by reference. Lubricants are substances which have traditionally been used to improve the flow characteristics of granulations and dusts producing friction between particles. See, 4 Remington, The Science & Pracfice of Pharmacy, p. 1619, 19th. ed. (1995) and see Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms: Tablets, Volume 1, p. 177-178 (1989), both of which are incorporated herein by reference. Improving flow characteristics helps reduce tabletting and malfunction and minimizes the weight variation of the tablet. Lubricants are typically added to the pharmaceutical compositions just prior to compressing the tablet to facilitate the flow of the granular material into the cavities of the tableting die. A commonly used lubricant is silicon dioxide (SiO2), also known as colloidal silica, fuming silicon dioxide, fuming silica, light anhydrous silicic acid, or silicic anhydride. Silicon dioxide is sold under the AEROSIL ™ and CAB-O-SIL ™ brands. Other lubricants include asbestos-free talcum, sodium silicate alumina, 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, or magnesium oxide. The ability of lubricants to improve flow characteristics depends on: (i) their chemical characteristics in relation to the chemical characteristics of the other ingredients of the composition, and; (ii) the physical characteristics, such as the size, shape and distribution of the lubricants and the other components of the granulation or pulverized composition, such as the moisture content and temperature of the composition. The investigation into the problem of the segregation of the active ingredient in the pharmaceutical compositions, powders and granules led the present inventors to the surprising discovery that the lubricants can be used to reduce, the segregation of the active ingredients and thus improve the homogeneity of pharmaceutical compositions, powder and granules. The present invention employs from 0.5% to approximately . 0% lubricant. Below approximately 0. 05% the homogeneity can not be enough and with quantities greater than 10.0% no additional homogeneity is gained. Silicon dioxide is a preferred lubricant because it is relatively "inert." A preferred form of silicon dioxide is fuming colloidal silicon dioxide, which is submicroscopic fumed silica. This is a light amorphous powder, not sandy. Particularly from about 0.05% to about 1.0% of colloidal silicon dioxide is used because below about 0.05% homogeneity can not be sufficient and with amounts greater than 1.0% no additional homogeneity is gained. Where lubricants are used to improve the flow characteristics, it is typically added to the composition immediately before compression during the lubrication step. See, Remington, The Science &; Practice of Pharmacy, p. 1619, 19th ed. (1995) incorporated herein by reference. However, the present invention makes use of lubricants in the initial mixture to improve and maintain homogeneity during handling before compression. The invention is preferably presented as a pharmaceutical formulation suitable for oral administration. Such formulations may conveniently be presented as discrete units, such as tablets, dragees, or any other form suitable for oral administration and compatible with the compositions of the present invention, each containing a predetermined amount of the active ingredients. A particularly suitable formulation is a tablet made by dry compression. Such formulations may contain safe and effective amounts of conventional excipients such as binding agents, fillers, lubricants or disintegrants. The tablets may also be coated in accordance with any method known to those skilled in the art that would not interfere with the release properties of the tablets or the other physical or chemical characteristics of the present invention. The coating of tablets is best outlined in Remington, The Science & Practice of Pharmacy, 19th ed. (1995), incorporated herein by reference. When desired, the above formulations can also be modified by any method known to those skilled in the art to achieve sustained release of the active ingredients. The formulations may also include a safe and effective amount of other active ingredients, such as antimicrobial agents or preservatives. These compositions of the present invention are suitable for administration to humans or other mammals particularly via the oral route of administration. However, other routes such as those used by physicians and other experts in the technique of administration of pharmaceutical dosages such as Pharmacists and Nurses are not excluded. One such method could be to crush a solid dosage form, mix it with a suitable vehicle for administration and administer it rectally as an enema. Other administration routes may be included: topical and inhalation. It should be appreciated by those skilled in the art that the amount of active ingredients that are required to be used in the treatment will vary in accordance with a variety of factors, including the nature of the condition being treated and the age and condition of the patient, and finally it will be at the discretion of the doctor, veterinarian or person to the health care that provides the care. In general, however, the currently recommended oral dose of lamivudine for adults and adolescents is 150 mg twice daily given in combination with zidovudine. For adults with low body weights (less than 50 kg or 110 Ib) the currently recommended oral dose of lamivudine is 2 mg / kg twice daily given in combination with zidovudine. The recommended oral dose of lamivudine in pediatric patients from 3 months to 12 years of age is 4 mg / kg twice daily, up to a maximum of 150 mg twice daily given in combination with zidovudine. In general, the currently recommended oral dose of zidovudine is 600 mg per day divided into doses in combination with other antiretroviral agents. The recommended oral dose in pediatric patients from 3 months to 12 years of age is 180 mg / m2 every 6 hours or 720 mg / m2; per day without exceeding 200 mg every 6 hours. The compositions of the present invention allow patients to be freed to a large extent from multiple dose administration regimens and facilitate the necessary diligence required to remember times and complex daily dosing schedules. By combining lamivudine and zidovudine in a single dosage form, the desired daily dose can be presented in a single dose or as divided doses., particularly as divided doses, administered at appropriate intervals, for example, two, three, four or more sub-doses per day, particularly two sub-doses per day. The compositions of the present invention allow convenient administration of two separate compounds in a unit dosage form containing, for example, from about 15 to about 1000 mg of lamivudine, particularly from about 100 to about 500 mg of lamivudine. and more particularly 150 mg of lamivudine, and from about 30 to 1000 mg of zidovudine, particularly from about 200 mg to about 500 mg of zidovudine and more particularly 300 mg of zidovudine per unit dosage form. The composition of the present invention can be used in combination with other pharmaceutical formulations as a component of a multiple drug treatment regimen. The compositions of the present invention may also be packaged as articles of manufacture comprising a safe and therapeutically effective amount of lamivudine, or a pharmaceutically acceptable derivative thereof.; a safe and therapeutically effective amount of zidovudine, or a pharmaceutically acceptable derivative thereof and a safe and effective amount of a pharmaceutically acceptable lubricant. Any of the various methods known to those skilled in the art for packaging tablets, dragees, or other solid dosage forms suitable for oral administration, which do not degrade the components of the present invention, are useful for use in packaging. Tablets, dragees, or other solid dosage forms suitable for oral administration can be packaged and contained in various packaging materials, particularly glass and plastic bottles, also including packaging in unit dose ampoules. The packaging material may also have a label and information related to the pharmaceutical composition printed thereon. Additionally, a manufacturing item may contain a brochure, report, notification, pamphlet or sheet that contains product information. This form of pharmaceutical information is known in the pharmaceutical industry as "package inserts". A package insert can be attached or included with a pharmaceutical article of manufacture. The package insert and any article of manufacture mark provides information related to the pharmaceutical composition The information and labeling provides various forms of information used by health care professionals and patients, which describe the composition, its doses and various other parameters required by regulatory agencies such as the Food and Drug Administration of the United States.

The compositions of the present invention can be formulated using methods and techniques suitable for the physical and chemical characteristics of the compositions that are commonly employed by those skilled in the art to prepare oral dosage forms using a dry pressure granulation. Remington, The Science & Practice of Pharmacy, p. 1615-1623, 1625-1648, and other applicable sections, 19th edition (1995). The compositions of the present invention in their method aspect are administered to a human or other mammal in a safe and effective amount as described herein. These safe and effective amounts will vary according to the type and size of the mammal being treated and the desired results of the treatment.

EXAMPLES The following examples best describe and demonstrate the particular embodiments within the scope of the present invention. The examples will be for illustration only and should not be construed as limitations on the many variations that are possible without departing from the spirit and scope of the invention.

Example I Ingredients Amount (mg Zidovudine 300.00 lamivudine 150.00 microcrystalline cellulose NF 269.63 sodium starch glycollate NF 22.50 colloidal silicon dioxide NF 2.25 magnesium stearate 5.63 10 Example II Preparation The amounts of the present example of i c; The manufacturing process was based on a batch of typical size of 400 kg and can be adjusted depending on the size of the batch. First, the components are weighed from the bulk containers in the following quantities: 20 Ingredient Amount (mg) Zidovudine 160.00 Lamivudine 80.00 Microcrystalline cellulose NF 143.80 25 sodium starch glycollate NF 12.00 colloidal silicon dioxide NF 1.20 magnesium stearate 3.00 The components are then sieved using a Russell-SIV equipped with 14 mesh (1.4mm aperture) or an equivalent screen and mesh, and deposited in a stainless steel mixing vessel. Zidovudine, lamivudine, microcrystalline cellulose NF, sodium starch glycolate NF, and colloidal silicon dioxide NF were mixed for 20 minutes using a suitable mixer, such as a Matcon-Buls barrel type mixer, a V mixer or equivalent. The magnesium stearate is then added to the mixture and is continuously mixed for about 2 minutes. The lubricated mixture is then compressed using a suitable rotary tablet press, typically a Courtoy R-190, R-200 or equivalent. Process controls are applied to the weight and hardness of the tablet at appropriate intervals through compression and the necessary adjustments are made to the tablet press. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the contents of the following are claimed as property.

Claims (22)

1. A pharmaceutical composition, characterized in that it comprises: i) a safe and therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof; ii) a safe and therapeutically effective amount of zidovudine or a pharmaceutically acceptable derivative thereof; and iii) a pharmaceutically acceptable lubricant; wherein the pharmaceutically acceptable lubricant is present in an amount of 0.05% to about 10.0% by weight.

2. A pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable lubricant is selected from the group consisting of: silicon dioxide, colloidal silicon dioxide, fuming silicon dioxide, sodium aluminosilicate, calcium silicate, powdered cellulose, cellulose microcrystalline, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, talc free of asbestos, metal stearates, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate , or magnesium oxide.

3. The pharmaceutical composition according to claim 2, characterized in that the pharmaceutically acceptable lubricant is fumed silicon dioxide.

4. The pharmaceutical composition according to any of claims 1 to 3, characterized in that the amount of lamivudine is from about 15 to about 1500 mg per unit dosage form.

5. The pharmaceutical composition according to claim 4, characterized in that the amount of lamivudine is from about 100 to about 500 mg per unit dosage form.

6. The pharmaceutical composition according to claim 5, characterized in that the amount of lamivudine is 150 mg per unit dosage form.

7. The pharmaceutical composition according to any of claims 1 to 6, characterized in that the amount of zidovudine is from about 30 to about 1000 mg per unit dosage form.

8. The pharmaceutical composition according to claim 7, characterized in that the amount of zidovudine is from about 200 to about 500 mg per unit dosage form.

9. The pharmaceutical composition according to claim 8, characterized in that the amount of zidovudine is 300 mg per unit dosage form.

10. The pharmaceutical composition according to any of claims 1 to 9, characterized in that the lamivudine is provided substantially free of the corresponding (+) enantiomer.

11. The pharmaceutical composition according to any of claims 1 to 9, characterized in that the (+) enantiomer is present in an amount of not more than about 5% w / w of the amount of lamivudine.

12. The pharmaceutical composition according to any of claims 1 to 11, characterized in that the composition is covered with a pharmaceutically acceptable lubricant.

13. A method for increasing and maintaining the homogeneity of a pharmaceutical composition, characterized in that it includes a safe and effective amount of a pharmaceutically acceptable lubricant.

14. The method according to claim 13, for increasing and maintaining the homogeneity of a pharmaceutical composition including a safe and effective amount of a pharmaceutically acceptable lubricant, characterized in that the lubricant is selected from the group consisting of: silicon dioxide, silicon dioxide colloidal, fuming silicon dioxide, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, talc free of asbestos, metal stearates, calcium stearate, stearate of magnesium, zinc stearate, stearowet C, starch, 1500 starch, magnesium lauryl sulfate, or magnesium oxide.

15. The method according to claim 14, for increasing and maintaining the homogeneity of a pharmaceutical composition comprising a safe and effective amount of a pharmaceutically acceptable lubricant, characterized in that the lubricant is selected from the group consisting of: fuming silicon dioxide, colloidal silicon, or fuming colloidal silicon dioxide.

16. A method for treating, reversing, reducing or inhibiting retroviral infections characterized in that it administers a safe and effective amount of a composition according to any of claims 1 to 12.

17. The method for treating, reversing, reducing or inhibiting retroviral infections according to claim 16, characterized in that the retrovirus is an immunodeficiency virus, including HIV.

18. The use of "lamivudine or a pharmaceutically acceptable derivative thereof, zidovudine or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable lubricant in the manufacture of a medicament for the treatment of a retroviral infection, wherein the pharmaceutically acceptable lubricant is present in an amount of 0.05% to about 10.0% by weight.

19. A manufacturing article characterized in that it comprises: i) a packaging material; and ii) a pharmaceutical composition contained within the packaging material, comprising: a) a safe and therapeutically effective amount of lamivudine or a pharmaceutically acceptable derivative thereof; b) a safe and therapeutically effective amount of zidovudine or a pharmaceutically acceptable derivative thereof; and c) a pharmaceutically acceptable lubricant; wherein the pharmaceutically acceptable lubricant is present in an amount of 0.05% to about 10.0% by weight.

20. An article of manufacture according to claim 19, characterized in that it additionally comprises a brochure containing information about the product.

21. A manufacturing article according to claim 19 or claim 20, characterized in that the packaging material is a unit dose blister pack.

22. A process for the preparation of a pharmaceutical composition as claimed in claims 1-12, characterized in that the process comprises mixing lamivudine or a pharmaceutically acceptable derivative thereof, zidovudine or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable lubricant.