FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"SOLID PHARMACEUTICAL COMPOSITION
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

Technical field:
The present invention relates to a solid pharmaceutical composition for prophylaxis and/or treatment of viral infections and a process for manufacturing the same thereof.
Background and Prior Art:
Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) 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 and development of resistant strains have limited their usefulness. Human immunodeficiency virus type 1 (HIV-1) 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 (p17, p24, p7 and p6) and the three viral enzymes. Combination therapy with RT inhibitors has proven to be highly effective in suppressing 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. Therefore, there is a need for new HIV-1 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.
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 HIV 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's 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 (HSV-2) and infection with human immunodeficiency virus type 1 (HIV-1) wherein a meta analysis of prospective observational studies showed that patients who were seropositive for HSV-2 had three times the risk of acquiring HIV-1, as compared with those who were seronegative for the virus.

It is estimated that HSV-2 acts as a facilitator for genital HIV-1 RNA through various mechanism including:
(a) Local influx of activated CD4+ lymphocytes in HSV-infected lesions,
(b) Transactivation of the HIV-1 tat protein and long terminal repeat genes by HSV-2 proteins.
This could result in greater HIV-1 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-1 RNA levels.
US Pat. No. 20070078187 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.
EP1802315 discloses method of treating viral infections by administering a pharmaceutical composition comprising a combination of elvucitabine and a second active agent (for eg. an immunomodulatory compound, an anti-viral agent, or a combination)
For the above cited reasons, there still remains a need of 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.
Object of the Invention:
The 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 inhibitor agents 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 inhibitor agents 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. According to one aspect of the present invention there is provided a solid pharmaceutical composition comprising one or more herpes virus inhibitor agents 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 nucleotide reverse transcriptase inhibitor agents 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.

According to other aspect of the present invention there is provided a solid pharmaceutical combination comprising one or more herpes virus inhibitor agents 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 inhibitor agents or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs in therapeutic amounts in a single unit dosage form.
According to other aspect of the present invention there is provided a solid pharmaceutical combination comprising one or more herpes virus inhibitor agents 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 nucleotide reverse transcriptase inhibitor agents or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs in therapeutic amounts in a single unit dosage form.
According to still another aspect of the present invention there is provided a process of manufacturing the solid pharmaceutical composition thereof.
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 inhibitor agent and one or more reverse transcriptase inhibitor agent 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-1 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 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 in the form of single unit dosage. Said composition comprises 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 either only the 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 or only 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, or both the actives may be coated or uncoated in the pharmaceutical composition.

It will be acknowledged to a person skilled in the art 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 herpes virus inhibitor agent which include, but are 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 to be used in the formulation ranges from about 5% to about 50% by weight of the formulation.
The pharmaceutical composition according to the present invention comprises nucleotide reverse transcriptase inhibitor agents which includes, but are not limited to tenofovir, adefovir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Preferably, the pharmaceutical composition comprises tenofovir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and the quantity to be used in the formulation ranges from about 5% to about 50% by weight of the formulation.
As discussed above, the pharmaceutically acceptable excipients comprising diluents or the fillers which includes, but are not limited to, microcrystalline cellulose, powdered cellulose, sugar compressible, lactose, fructose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, starch, pregelatinised

starch and mixtures thereof. Preferably, the diluent used in the formulation is starch and lactose and can be added in a quantity ranging from 5% to 30% by weight of the formulation.
Examples of binders or binding agents, according to the present invention, which includes, but are not limited to methyl cellulose, hydroxylpropyl cellulose (HPC), hydroxylpropyl 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 and can be added in a quantity ranging from 1% to 15% by weight of formulation.
Examples of the disintegrants, according to the present invention, which includes, but are not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium, crospovidone, starch, crystalline cellulose, sodium starch glycollate, hydroxylpropyl starch and equivalents thereof. Preferably, the disintegrant used in the formulation is croscarmellose sodium and can be added in a quantity ranging from 1% to 10% by weight of the formulation.
Examples of suitable glidants and lubricants, according to the present invention, which includes, 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 can be added in a quantity ranging from 0.1% to 5% each by weight of the formulation.
Alternatively, the composition, in accordance with the present invention, may further comprise surfactants which includes, but are not limited to one or more of polysorbates, castor oil and derivatives, and sodium lauryl sulphate (SLS) and can be added in a quantity ranging from 0.5% to 10% by weight of the formulation.
According to a preferred embodiment, the said composition can be film coated with a ready colour mix system.

The said composition can be manufactured by processes 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.
According to a preferred embodiment, the pharmaceutical composition of the present invention is processed by wet granulation of first active wherein the diluent and the first active are sifted and dried. Then, binder solution is prepared by dissolving the binding agent in purified water and straining. Granulation is carried out by spraying of the binder solution to the above first dry mixture of the ingredients, after which the formed granules are dried, sifted through the mesh and milled. After unloading, the second active is, similarly, processed by wet granulation wherein the diluent, disintegrant and the second active are sifted and dried. Then, binder solution is prepared by dissolving the binding agent in purified water and straining. Granulation is carried out by spraying of the binder solution to the above second dry mixture of the ingredients, after which the formed granules are dried, sifted through the mesh and milled. Further, both the granules as obtained above are mixed thoroughly and blended with the glidants and lubricants and finally compressed into tablets. The tablets thus obtained via the process are then 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 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.
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 are sifted and dried. Then, binder solution is prepared by dissolving the binding agent in purified water and straining. Granulation is carried out by spraying of the binder solution to the above first dry mixture of the ingredients, after which the formed granules are dried, sifted through the mesh and milled. After unloading, the granules obtained are then blended with the glidants and lubricants and compressed into tablets. The second active is, similarly, processed by wet granulation wherein the diluent, disintegrant and the second active are sifted and dried. Then, binder solution is prepared by first dissolving the surfactant in purified water and then dissolving the binding agent and straining. Granulation is carried out by spraying of the binder solution to the above dry mixture of the ingredients, after which the formed granules are dried, sifted through the mesh and milled. The granules are then 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 is then 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 suspension made of ready colour mix system.
It will be well 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.
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.

S. No Ingredients Qty / Tab (mg)
Dry mix I
1. Valaciclovir hydrochloride equivalent to 500mg valaciclovir 622.67
2. Starch USP 107.78
Binder Solution I
3. Starch USP 6.00
4. Purified water q. s.
Dry Mix II
5. Tenofovir disoproxil fumarate equivalent to 300mg of tenofovir 304.70
6. Lactose 200M 154.8
7. Croscarmellose sodium 20.00
8. Corn Starch 30.00
Binder solution II
9. Corn Starch 15.00
10. Tween 80 3.00
11. Purified water q. s.
Lubrication
12. Microcrystalline cellulose 97.00
13. Magnesium stearate 5.50
Coating
12. Opadry colour 5.00
13. Purified Water q.s.
TOTAL 1367
Process:
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.
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.