WO2009037449A1

WO2009037449A1 - Solid pharmaceutical compositions comprising one or more herpes virus inhibitors and one or more reverse transcriptase inhibitors

Info

Publication number: WO2009037449A1
Application number: PCT/GB2008/003155
Authority: WO
Inventors: Amar Lulla; Geena Malhotra
Original assignee: Cipla Limited; Curtis, Philip, Anthony
Priority date: 2007-09-18
Filing date: 2008-09-18
Publication date: 2009-03-26

Abstract

A solid pharmaceutical composition comprising one or more herpes virus inhibitors, such as valaciclovir, and one or more reverse transcriptase inhibitors, such as tenofovir. Methods for making the compositions are also disclosed.

Description

SOLID PHARMACEUTICAL COMPOSITIONS COMPRISING ONE OR MORE HERPES VIRUS INHIBITORS AND ONE OR MORE REVERSE TRANSCRIPTASE INHIBITORS

Technical field:

5 The present invention relates to solid pharmaceutical compositions for prophylaxis and/or treatment of viral infections and a process for manufacturing the same thereof.

Background and Prior Art:

10 Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-I) encodes at least three enzymes which are required for viral replication: Reverse transcriptase (RT), Protease (Prt), and Integrase (Int). Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity

15 and development of resistant strains have limited their usefulness. Human immunodeficiency virus type 1 (HIV-I) protease (Prt) is essential for viral replication and is an effective target for approved antiviral drugs. The HIV Prt cleaves the viral Gag and Gag-Pol polyproteins to produce viral structural proteins (pi 7, p24, p7 and p6) and the three viral enzymes. Combination therapy with RT inhibitors has proven to be highly effective in suppressing

20 viral replication to unquantifiable levels for a sustained period of time. Also, combination therapies with RT and Prt inhibitors (PI) have shown synergistic effects in suppressing HIV replication. Unfortunately, a high percentage, typically 30 to 50% of patients currently fail combination therapy due to the development of drug resistance, non-compliance with complicated dosing regimens, pharmacokinetic interactions, toxicity, and lack of potency.

25 Therefore, there is a need for new HIV-I inhibitors that are active against mutant HIV strains, have distinct resistance profiles, fewer side effects, less complicated dosing schedules, and are orally active. In particular, there is a need for a less onerous dosage regimen, such as once per day oral dosing, optimally with as few pills as possible.

30 Human immunodeficiency virus (HIV) causes an infection for which researchers have long sought effective antiviral agents. Patients infected with HIV experience a variable but progressive decline in immune function resulting in clinically apparent opportunistic infections and other diseases. Studies have shown that the long term prognosis in HIV infected patients is dictated by the blood cell level of HIV DNA present at the initiation of infection. As the DNA form is a relatively long lived, mostly host cell DNA integrated form of the virus, this high HIV DNA load suggests that patients who have a larger HIV DNA reservoir do worse clinically that do those with lower levels of HIV DNA.

HIV is an RNA retrovirus, that upon successful infection of a host cell, reverse transcribes its genomic RNA into DNA, which then, in a double stranded form, integrates into susceptible host cells. The major targets for infection in vivo are the CD4 expressing T cells and macrophages. Whereas T cells, upon activation of the HIV DNA into an infectious RNA form, generally get killed, the virus expressing macrophages don't die after infection and likely serve as the long term HW DNA reservoir in vivo.

At least one study on the HIV reservoir has provided half life estimates of 4 years for infected blood macrophages and less than 2 years for infected T cells. Both values help explain the reason for the failure of highly active antiretroviral therapy (HAART) to clear the virus in vivo. More recently, studies on the HIV DNA sequence in vivo showed that in HIV plasma viral load negative subjects on HAART HIV replication continued to occur in vivo within macrophages but not T cells. Therefore, the longest lived reservoir of HIV in vivo is the macrophage. Considering that HAART only keeps new cells from becoming infected with HIV, any cell already containing HIV DNA would be resistant to drug effects. It is therefore no surprise that upon discontinuation of HAART most HIV infected patients rapidly develop high HIV plasma viral loads because the reservoir initiates new rounds of primary infection, presumably in part because of the infected macrophage reservoir. Therefore, in order to impact the HIV reservoir, a drug must be able to kill the infected macrophages and have a less toxic effect on normal macrophages.

The epidemiologic and biologic studies support a strong association between herpes simplex virus type 2 (HS V-2) and infection with human immunodeficiency virus type 1 (HIV-I) wherein a meta analysis of prospective observational studies showed that patients who were seropositive for HS V-2 had three times the risk of acquiring HIV-I, as compared with those who were seronegative for the virus. It is estimated that HSV-2 acts as a facilitator for genital HIV-I RNA through various mechanism including:

(a) Local influx of activated CD4+ lymphocytes in HS V-infected lesions, (b) Transactivation of the HIV-I tat protein and long terminal repeat genes by HSV-2 proteins.

This could result in greater HIV-I replication at the genital mucosal level and possibly also at the systemic level. In fact, symptomatic HSV-2 reactivation has been associated with transient increases in plasma HIV-I RNA levels.

US20070078187 discloses methods for treating viral infections by using polyamine analogs thereby reducing the viral load in the subject.

WO2006135933 discloses a triple drug pharmaceutical product wherein the composition is a two component layered dosage form for treatment against HIV strains.

EP 1802315 discloses method of treating viral infections by administering a pharmaceutical composition comprising a combination of elvucitabine and a second active agent (for example, an immunomodulatory compound, an anti- viral agent, or a combination)

For the above cited reasons, there still remains a need for a pharmaceutical composition which will provide suitable measures for prophylaxis, not only against herpes virus infection, but also against the related infections caused by the HIV strains.

It has been surprisingly found that a pharmaceutical composition comprising a combination of two or more antiviral agents of different mechanism, without compromising on the stability and the compatibility between the agents and using simpler manufacturing process, acts in the prophylaxis and /or treatment of the viral infections. Objects of the Invention:

It is an object of the present invention is to provide a solid pharmaceutical composition for prophylaxis and/or treatment of viral infections.

Another object of the present invention is to provide a solid pharmaceutical composition in a single unit dosage with better patient compliance.

Still another object of the present invention is to provide a stable solid pharmaceutical composition which does not lead to any incompatibilities between the actives and the formulation.

Yet another object of the present invention is to provide a solid pharmaceutical composition with ease of manufacture.

Summary of the Invention:

According to one aspect of the present invention there is provided a solid pharmaceutical composition comprising one or more herpes virus inhibitors or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more reverse transcriptase inhibitors or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs in therapeutic amounts and pharmaceutically acceptable excipients.

The compositions according to each aspect of the invention may be provided in a form for simultaneous, sequential or separate administration.

Advantageously the compositions according to the invention are provided as a single unit dosage form. Advantageously also, the reverse transcriptase inhibitor is a nucleotide reverse transcriptase inhibitor.

According to still another aspect of the present invention there is provided a process of manufacturing the solid pharmaceutical compositions according to the invention.

According to yet another aspect of the present invention there is provided a combination composition for prophylaxis and/or treatment of viral infections thereof.

Detailed description of the invention:

As discussed above, the present invention relates to a solid pharmaceutical composition wherein the inventors have surprisingly found that, a combination of one or more herpes virus inhibitors and one or more reverse transcriptase inhibitors in therapeutic amounts in single unit dosage form which will not only act against herpes virus infection, but also against the related infections caused by the HIV strains.

The inventors have found that preferably, by combination of nucleotide reverse transcriptase inhibitors with herpes virus inhibitors, there is decrease in the plasma HIV-I RNA levels which is associated with symptomatic HSV-2 reactivation.

The pharmaceutical composition of the present invention comprises one or more herpes virus inhibitor agent or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and one or more reverse transcriptase inhibitor (most preferably a nucleotide reverse transcriptase inhibitor) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Said composition is advantageously in the form of single unit dosage. Said composition may also comprise one or more pharmaceutically acceptable excipients, as in case of a conventional dosage form, comprising diluents or fillers, binders, disintegrants, surfactants, glidants, lubricants, polymers and the like.

Further, the pharmaceutical composition may contain uncoated or coated particles comprising the active substance wherein the particles contain either only the herpes virus inhibitor or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof or only the reverse transcriptase inhibitor (preferably the nucleotide reverse transcriptase inhibitor) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Alternatively both the actives may be provided as coated or uncoated in the pharmaceutical composition.

A person skilled in the art will understand that the pharmaceutical composition of the present invention can be administered through oral dosage i.e. in the form of solid oral dosage such as tablets, capsules, granules, powders, pellets and the like.

As discussed above, the pharmaceutical composition according to the present invention comprises a herpes virus inhibitor which may be, but is not limited to, acyclovir, valaciclovir, penciclovir, ganciclovir, famciclovir and the possible pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.

According to a preferred embodiment, the pharmaceutical composition comprises valaciclovir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. The quantity of the herpes virus inhibitor to be used in the formulation preferably ranges from about 5% to about 50% by weight of the formulation. The pharmaceutical composition according to the present invention comprises a reverse transcriptase inhibitor which may be, but is not limited to tenofovir, adefovir, lamivudine, emtricitabine, abacavir, stavudine, zidovudine or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Most preferably, the pharmaceutical composition comprises nucleotide reverse transcriptase inhibitors such as tenofovir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.

The quantity of the reverse transcriptase inhibitor to be used in the formulation preferably ranges from about 5% to about 50% by weight of the formulation.

As noted above the herpes virus inhibitor may be provided in the form of a salt or other forms. Valaciclovir or a salt thereof is the preferred herpes virus inhibitor. The preferred salt form is the hydrochloride, i.e., valaciclovir hydrochloride.

Further, as noted above, the reverse transcriptase inhibitor may be provided in the form of salt or other forms. Tenofovir or a salt thereof is the preferred reverse transcriptase inhibitor. The most preferred reverse transcriptase inhibitor is tenofovir disoproxil fumarate.

The pharmaceutical composition according to the invention may include more than one herpes virus inhibitor and/or more than one reverse transcriptase inhibitor. It is particularly preferred that a second reverse transcriptase inhibitor is provided, which is preferably lamivudine.

As discussed above, the pharmaceutically acceptable excipients comprising diluents or the fillers which may include, but are not limited to, microcrystalline cellulose, powdered cellulose, sugar compressible, lactose, fructose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, starch, pregelatmised starch and mixtures thereof. Preferably, the diluent used in the formulation is starch and lactose. The diluent is preferably present in a quantity ranging from 5% to 30% by weight of the formulation.

Examples of binders or binding agents, according to the present invention, may include, but are not limited to methyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), starch, polyvinyl pyrrolidone (PVP), gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, tragacanth, sodium alginate and equivalents thereof. Preferably, the binder used in the formulation is starch. The binder is preferably present in a quantity ranging from 1% to 15% by weight of formulation.

Examples of the disintegrants, according to the present invention, may include, but are not limited to hydroxypropyl cellulose (HPC), low density HPC, carboxymethyl cellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium, crospovidone, starch, crystalline cellulose, sodium starch glycollate, hydroxypropyl starch and equivalents thereof. Preferably, the disintegrant used in the formulation is croscarmellose sodium. The disintegrant is preferably present in a quantity ranging from 1% to 10% by weight of the formulation.

Examples of suitable glidants and lubricants, according to the present invention, may include, but are not limited to stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, microcrystalline cellulose, colloidal silicon dioxide and equivalents thereof. Preferably, the glidants and lubricants used in the formulation are present in a quantity ranging from 0.1% to 5% each by weight of the formulation.

The composition, in accordance with the present invention, may further comprise a surfactant, which may include, but is not limited to one or more of polysorbates, castor oil and derivatives, and sodium lauryl sulphate (SLS). The surfactant may be present in a quantity ranging from 0.5% to 10% by weight of the formulation.

According to a preferred embodiment, the composition can be film coated, for example with a ready colour mix system. The composition can be manufactured by processes known to a person skilled in the art, which include, but are not limited to granulation (e.g. dry granulation, wet granulation, hot granulation), direct compression, fluidized bed granulation, extrusion, and solvent evaporation and are not intended to limit the scope of the invention.

In an yet another preferred embodiment of the invention, the composition may be prepared by a hot granulation process. The process is preferably carried out using an extruder. Each ingredient i. e. the actives and/or excipients may be exposed to the extruder to produce dried granules, which may then be further processed into tablets. Advantageously, unlike the conventional wet granulation, there is no separate drying stage required in this process. In an alternative embodiment, according to the present invention, the composition may be processed, in such a way that one active (with one or more optional excipients), or more than one of the actives (each with one or more optional excipients) or all the actives (each with one or more optional excipients) are prepared by hot granulation.

According to a preferred embodiment, the pharmaceutical composition of the present invention may be processed by wet granulation of first active wherein the diluent and the first active are sifted and dried. Then, binder solution may be prepared by dissolving the binding agent in purified water and straining. Granulation may be carried out by spraying of the binder solution to the above first dry mixture of the ingredients, after which the formed granules may be dried, sifted through the mesh and milled. After unloading, the second active may be, similarly, processed by wet granulation wherein the diluent, disintegrant and the second active are sifted and dried. Then, binder solution may be prepared by dissolving the binding agent in purified water and straining. Granulation may be carried out by spraying of the binder solution to the above second dry mixture of the ingredients, after which the formed granules may be dried, sifted through the mesh and milled. Further, both the granules as obtained above may be mixed thoroughly and blended with the glidants and lubricants and finally compressed into tablets. The tablets thus obtained via the process may then be sprayed with a coating, which is preferably a suspension made of ready colour mix system.

Alternatively, after compression into tablets, they can be further seal coated and then sprayed with a coating, which is preferably suspension made of ready colour mix system. Still, alternatively, the pharmaceutical composition, according to the present invention, may comprise two or more components in a single solid dosage unit wherein each of the active may be present in each component. The component may form multiple layers and the process for such an invention may involve the techniques known to a person skilled in the art which includes, but are not limited to wet granulation, direct compression, fluidized bed granulation, extrusion, and solvent evaporation and are not intended to limit the scope of the invention. Thus, the invention envisages the possibility that the pharmaceutical composition comprises a bilayered tablet, with the herpes virus inhibitor present only in one layer and the reverse transcriptase inhibitor present only in the other layer. The pharmaceutical composition may comprise more than two layers. For example, if a second reverse transcriptase inhibitor is present, such as lamivudine, is present, it may be formulated in a separate layer of a trilayer tablet. Alternatively, the pharmaceutical composition may comprise a herpes virus inhibitor in one layer and the second reverse transcriptase may be present in the same layer comprising first reverse transcriptase inhibitor, to give a bilayer tablet.

According to preferred embodiment, the pharmaceutical composition of the present invention is processed by wet granulation of both the actives as discussed above wherein the diluent and the first active may be sifted and dried. Then, binder solution may be prepared by dissolving the binding agent in purified water and straining. Granulation may be carried out by spraying of the binder solution to the above first dry mixture of the ingredients, after which the formed granules may be dried, sifted through the mesh and milled. After unloading, the granules obtained may then be blended with the glidants and lubricants and compressed into tablets. The second active may be, similarly, processed by wet granulation wherein the diluent, disintegrant and the second active may be sifted and dried. Then, binder solution may be prepared by first dissolving the surfactant in purified water and then dissolving the binding agent and straining. Granulation may be carried out by spraying of the binder solution to the above dry mixture of the ingredients, after which the formed granules may be dried, sifted through the mesh and milled. The granules may then be laid in the die cavity followed by the above tablet and compressed to form a multilayer tablet. Finally, the multi layer tablet thus obtained via the process may then be sprayed with a coating suspension made of ready colour mix system.

Alternatively, after compression into tablets, they can be further seal coated and then sprayed with a coating, for example a suspension made of ready colour mix system.

It will be appreciated by a person skilled in the art, that alternatively, the pharmaceutical composition according to the present invention may be further processed with rate retardant polymers to produce modified release dosage form.

The present invention further provides for a method of treatment and/or prophylaxis of the viral infections and other related disorders by administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a mammal in need thereof in a suitable therapeutic regimen.

Reference will now be made to the following examples, which are for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.

Examples

Example 1

Procedure:

1. Valaciclovir hydrochloride and starch were sifted, mixed and granulated with starch paste.

2. Tenofovir disoproxil fumarate, lactose 200M, croscarmellose sodium and corn starch were sifted, mixed and granulated with starch paste with tween 80.

3. The granules obtained in (1) and (2) were mixed together and blended with microcrystalline cellulose and magnesium stearate. 4. The blend obtained in (3) was then compressed into tablets and finally coated.

Example 2

Procedure:

1. Valaciclovir hydrochloride and corn starch were co-sifted to form a premix which was further dry mixed along with Tenofovir DF, Lamivudine, microcrystalline cellulose and croscarmellose sodium.

2. Binder solution was prepared and the above mixture was granulated.

3. The granules obtained above were mixed with microcrystalline cellulose and croscarmellose sodium and lubricated with magnesium stearate, and compressed into tablet and finally film coated.

Example 3

Sr. Ingredients Mg/tab

Procedure:

1. Tenofovir DF, croscarmellose sodium and microcrystalline cellulose were dry mixed and granulated using starch paste.

2. Lamivudine, sodium starch glycollate and microcrystalline cellulose were dry mixed and granulated using starch paste.

3. Similarly, Valaciclovir HCl and corn starch were dry mixed and granulated using starch paste.

4. Granules obtained from step 1, 2 and 3 were mixed together and lubricated using croscarmellose sodium, microcrystalline cellulose, and magnesium stearate followed by compression into tablets.

5. Tablets obtained above were finally film coated with Opadry II YS-I- 7003 white.

Example 4

Procedure:

1. Tenofovir DF, Lamivudine, croscarmellose sodium and microcrystalline cellulose were dry mixed to form a premix which was granulated using starch paste.

2. Granules obtained were lubricated using croscarmellose sodium, microcrystalline cellulose, and magnesium stearate.

3. Valaciclovir HCl and corn starch were dry mixed and granulated using starch paste.

4. Granules were lubricated using microcrystalline cellulose and magnesium stearate.

5. Granules obtained in step 2 and step 4 were compressed into bilayer tablet followed by film coating with Opadry II YS- 1-7003 white

Example 5

Procedure:

2. Valaciclovir HCl and corn starch were dry mixed and granulated using starch paste.

3. Granules obtained in step 1 and step 2 were lubricated using microcrystalline cellulose, croscarmellose sodium and magnesium stearate followed by compressing into tablet.

4. The tablet obtained above were finally film coated with Opadry II YS-1-7003 white.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.

It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a diluent" includes a single diluent as well as two or more different diluents, reference to a "disintegrant" refers to a single disintegrant or combination of two or more disintegrants, and the like.

Claims

CLAIMS:

1. A solid pharmaceutical composition comprising one or more herpes virus inhibitors or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more reverse transcriptase inhibitors or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs in therapeutic amounts and pharmaceutically acceptable excipients, for simultaneous, sequential or separate administration.

2. A composition according to claim 1, which is provided as a single unit dosage form.

3. A composition according to claim 1 or 2, wherein the reverse transcriptase inhibitor is a nucleotide reverse transcriptase inhibitor.

4. A composition according to any preceding claim, wherein the herpes virus inhibitor is selected from acyclovir, valaciclovir, penciclovir, ganciclovir, famciclovir or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.

5. A composition according to any preceding claim, wherein the herpes virus inhibitor is present in the composition in an amount from about 5% to about 50% by weight.

6. A composition according to any preceding claim, wherein the reverse transcriptase inhibitor is selected from tenofovir, adefovir, lamivudine, emtricitabine, abacavir, stavudine, zidovudine or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.

7. A composition according to any preceding claim, wherein the reverse transcriptase inhibitor is present in the composition in an amount from about 5% to about 50% by weight.

8. A composition according to any preceding claim, wherein the herpes virus inhibitor is 5 valaciclovir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and the reverse transcriptase inhibitor is tenofovir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, 10 pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.

9. A composition according to any preceding claim, wherein the herpes virus inhibitor is valaciclovir hydrochloride, and the reverse transcriptase inhibitor is tenofovir disoproxil

15 fumarate.

10. A composition according to any preceding claim, further comprising a second reverse transcriptase inhibitor or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative,

20 pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof.

11. A composition according to claim 10, wherein the second reverse transcriptase inhibitor is lamivudine or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative,

25 pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof.

12. A composition according to any preceding claim, wherein the herpes virus inhibitor is provided in the composition in the form of particles.

30 13. A composition according to any preceding claim, wherein the reverse transcriptase inhibitor is provided in the composition in the form of particles.

14. A composition according to claim 13, wherein the particles containing the herpes virus inhibitor do not contain the reverse transcriptase inhibitor and vice versa.

15. A multilayer tablet dosage form incorporating a solid pharmaceutical composition 5 according to any preceding claim, said dosage form comprising multiple layers, wherein the or each herpes virus inhibitor is in one of the layers, but not in the or each other layer, and one or more reverse transcriptase inhibitors is disposed the or each other layer, but not in said one layer.

10 16. A multilayer tablet dosage form according to claim 15, wherein there are two layers.

17. A multilayer tablet dosage form according to claim 15, wherein there are three layers.

18. A process for preparing a pharmaceutical composition as defined in any one of claims 15 1 to 14, comprising producing granules containing at least one of the or each herpes virus inhibitor and one or more optional pharmaceutically acceptable excipients; producing granules containing at least one of the or each reverse transcriptase inhibitor and one or more optional pharmaceutically acceptable excipients; and forming a solid tablet dosage form by combining the granules containing the herpes virus inhibitor and the reverse transcriptase 20 inhibitor.

19. A process according to claim 18, wherein the granules containing at least one of the or each herpes virus inhibitor are produced by a wet granulation process.

25 20. A process according to claim 18 or 19, wherein the granules containing at least one of the or each reverse transcriptase inhibitor are produced by a wet granulation process.

21. A process according to claim 16, wherein the granules containing at least one of the or each herpes virus inhibitor are produced by a hot granulation process.

30

22. A process according to claim 16 or 19, wherein the granules containing at least one of the or each reverse transcriptase inhibitor are produced by a hot granulation process.

23. A process according to claim 21 or 22, wherein the granules containing the herpes virus inhibitor, and/or the granules containing the reverse transcriptase inhibitor are prepared in which the or each inhibitor, together with the or each optional pharmaceutically acceptable

5 excipient, is exposed to an extruder to produce the granules in a dried form.

24. A process according to any one of claims 18 to 23, wherein the granules containing the or each herpes virus inhibitor are formed into a first layer, and the granules containing the or each reverse transcriptase are formed into a second layer, and said layers are combined to

10 form a bilayer tablet.

25. A solid pharmaceutical composition according to any one of claims 1 to 14, for use in the treatment and/or prophylaxis of one or more viral infections or related disorders.

15 26. A method of treatment and/or prophylaxis of one or more viral infections or related disorders, comprising administering a therapeutically effective amount of a solid pharmaceutical composition according to any one of claims 1 to 14 to a patient in need thereof.