Pharmaceutical Composition of Tenofovir Disoproxil Oxalate

Field of the Invention:

The present invention relates to a pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil oxalate. The composition may further comprise other additives for the preparation of the composition.

Background of the Invention:

Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors, which block reverse transcriptase, an enzyme crucial to viral production in HIV-infected people. Tenofovir inhibits the activity of HIV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Specifically, the drugs are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA chain. However, unlike the natural deoxynucleotides substrates, NRTIs and NtRTIs (nucleoside/tide reverse transcriptase inhibitors) lack a 3'-hydroxyl group on the deoxyribose moiety. As a result, following incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide cannot form the next 5'-3' phosphodiester bond needed to extend the DNA chain. Thus, when an NRTI or NtRTI is incorporated, viral DNA synthesis is halted, a process known as chain termination. All NRTIs and NtRTIs are classified as competitive substrate inhibitors.

Tenofovir, marketed by Gilead Sciences under the trade name Viread® in the form of tenofovir disoproxil fumarate (also known as Tenofovir DF, Tenofovir disoproxil, TDF, Bis-POC-PMPA,9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy Jpropyl]adenine fumarate (1 :1). It is also marketed in combination with other antiretroviral agents.

US Pat Nos. 5,935,946, 5,922,695, 5,977,089, 6,043,230, 6,069,249 disclose tenofovir, tenofovir disoproxil and tenofovir disoproxil fumarate.

Further, US Pat No. 8049009 discloses Tenofovir disoproxil hemifumarate and it method of preparation.
US patent application no. 2011/0009368 discloses various solid forms of tenofovir disoproxil. It discloses a solid form of Tenofovir disoproxil and an organic acid selected from the group consisting of succinic acid, tartaric acid, saccharic acid, citric acid, salicylic acid. WO 2010/142761 discloses succinate of tenofovir disoproxil and various dosage forms containing succinate of tenofovir disoproxil.

The present invention relates to a pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil oxalate. The composition may further comprise other additives for the preparation of the composition.

Summary of the Invention:

One embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the active agent is present in an amount of more than 35% by weight based on the total weight of the pharmaceutical composition.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the active agent is present in an amount of more than 50% by weight based on the total weight of the pharmaceutical composition.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, which comprises microcrystalline cellulose as a pharmaceutically acceptable additive.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, which comprises a superdisintegrant as a pharmaceutically acceptable additive.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the composition is prepared by wet granulation.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the composition is prepared by dry granulation.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the composition is prepared by direct compression.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the composition optionally comprises one or more anti-HIV drugs.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate.

Detailed Description:

This invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate and the method of preparing the same. The composition of the invention can be administered to the patients who are in need of the drug for the treatment of HIV or AIDS.

The term "tenofovir disoproxil oxalate" includes various forms of tenofovir disoproxil oxalate such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art. Tenofovir disoproxil oxalate can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "tenofovir disoproxil oxalate" as used in the present invention.

The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The active ingredient, active agent and drug herein can be interchangeably used. As used herein,"%" refers to the weight percent of a substance as it relates to the overall composition unless otherwise indicated.

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

In one embodiment, a pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil oxalate. The composition may further comprise other additives for the preparation of the composition.

In another embodiment, a pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the active agent is present in an amount of more than 35% by weight based on the total weight of the pharmaceutical composition. The active agent may be present preferably more than 40%, more preferably more than 45% by weight based on the total weight of the pharmaceutical composition.

In another embodiment, a pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the active agent is present in an amount of more than 50% by weight based on the total weight of the pharmaceutical composition.

In another embodiment, a pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil oxalate, which comprises microcrystalline cellulose as a pharmaceutically acceptable additive. Microcrystalline cellulose may perform one or more functions.

In another embodiment, a pharmaceutical composition comprises tenofovir disoproxil oxalate and a superdisintegrant. The composition may further comprise a binder and a diluent. A disintegrating agent is a substance, or mixture of substances added to the mixture of ingredients which are used to prepare pharmaceutical composition, to facilitate the composition to breakup or disintegration after administration, or disintegration into the primary particles, when placed in water to form a solution which can be drank by the patient. The pharmaceutically active ingredient must be released from the composition matrix as efficiently as possible to allow for its dissolution. There are some disintegrating agents which provide for a more rapid disintegration than others disintegrating agents called superdisintegrants. "Superdisintegrants" are defined to be those disintegrants which can be used in small amount as compared to normal disintegrants, such as corn starch, to obtain the same effect. The non limiting examples of superdisintegrants are crospovidone, modified starches especially sodium starch glycolate and carmellose especially croscarmellose sodium, carboxymethylcellulose calcium. The superdisintegrant can be used in both the wet and dry stages of the granulation process (intra- and extra granularly) as well as in direct compression, so that the wicking and swelling ability of the disintegrant is best utilized. Croscarmellose sodium is the preferred superdisintegrant.

The superdisintegrant is present in the composition in an amount of from about 1% to about 20 %, preferably from about 1% to about 15%, more preferably from about 1% to about 10%. It is advantageous to use the superdisintegrant in an amount where the weight ratio between tenofovir disoproxil oxalate and superdisintegrant is from 50: 1 to 0.5: 1, preferably around 20: 1 to 0.5: 1. In another embodiment it is from 20: 1 to 0.5: 1, preferably around 10: 1 to 0.5:1.

The suitable superdisintegrants for compositions of this invention are carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), croscarmellose sodium available as e.g. Ac-Di-Sol®, Primellose®, Pharmacelt XL, Explocel®, and Nymcel® ZSX, having a molecular weight of 90 000-700 000; crosslinked polyvinylpyrrolidones (PVP), e. g. crospovidones, e. g. Polyplasdone® XL and Kollidon CL, in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns; modified starches especially sodium starch glycolate e.g. Explosol®, Explotab , Glycolys®, Primojel®, Tablo®, Vivastar® P, in particular having molecular weight is 500000-11000000. The most preferred disintegrant is Croscarmellose sodium.

In another embodiment, a pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil oxalate, which comprises croscarmellose sodium as a pharmaceutically acceptable additive.

Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), micro fine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, methacrylates (e g Eudragit®}, potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc

In another embodiment, a pharmaceutical composition comprises tenofovir disoproxil oxalate and a binder. The composition may further comprise a superdisintegrant and a diluent. The composition according to the invention can comprise binders, such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolyzed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. It is preferable to use a binder with good water solubility. In a preferred embodiment of the invention the excipients include at least one binder selected from hydroxypropyl cellulose and povidone.

The binding agent is present in the composition in an amount of from about 1% to about 25%, preferably from about 1%, to about 15%, more preferably from about 1% to about 10%. The weight ratio of tenofovir disoproxil oxalate to binder is from 60: 1 to 1: 1 (preferably 40: 1 to 1: 1), the weight ratio of superdisintegrant to binder is from 30: 1 to 0.1: 1 (preferably 5:1 to 0.5: 1).

In one embodiment, a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the active agent is present in an amount of more than 35% by weight, the binder in an amount from about 1% to about 25% and the superdisintegrant in an amount from about 0.01% to about 20% all percentages being based on the total weight of the composition.

In another embodiment, a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, wherein the active agent is present in an amount of more than 40% by weight, 0.5-20% of a superdisintegrant, 1-20% of a , preferably more 40% of tenofovir disoproxil oxalate, 1-15% of a superdisintegrant and 1-15% of a binder and most preferably more than 50% of tenofovir disoproxil oxalate, 1-10% of a superdisintegrant and 1-10% of a binder. The composition further may comprise 10-65% of a diluent, 0-10% of a lubricant and additives other than the ones mentioned above.

In another embodiment, a pharmaceutical composition comprising the above- indicated components wherein the weight ratio of tenofovir disoproxil oxalate to superdisintegrant is from 50: 1 to 0.5: 1 (preferably 20: 1 to 0.5: 1), the weight ratio of tenofovir disoproxil oxalate to binder is from 60: 1 to 1: 1 (preferably 40: 1 to 1: 1), the weight ratio of superdisintegrant to binder is from 30: 1 to 0.1: 1 (preferably 5: 1 to 0.5: 1).

In another embodiment, a pharmaceutical composition, e. g. in form of a tablet, of tenofovir disoproxil oxalate and a superdisintegrant in a weight ratio of e. g. between 50: 1 to 0.5: 1, e. g. 50: 1 to 0.5:1, 40: 1 to 0.5:1, 30: 1 to 0.5:1, 20: 1 to 0.5:1, 15: 1 to 0.5:1, 10: 1 to 0.5:1, 8:1 to 0.5: 1, 7.5:1 to 0.5: 1, 5:1 to 0.5: 1, 3: 1 to 0.5:1, 2.5:1 to 0.5:1, 2:1 to 0.5:1, 1.5:1 to 0.5:1.

In another embodiment, a pharmaceutical composition comprising tenofovir disoproxil oxalate as the active agent and diluent wherein the weight ratio of tenofovir disoproxil oxalate to diluent is from 5: 1 to 0.1: 1, e. g., 3:1 to 0.1:1, 2: 1 to 0.1: 1, 1:1 to 0.2:1.

A typical composition may comprise: more than 35% of tenofovir disoproxil oxalate, 1 to 20% of pregelatinized starch, 1 to 20% of lactose, 1 to 20% croscarmellose sodium, 0 to 10 % of magnesium stearate and 0 to 5 % of colloidal anhydrous silica.

In another embodiment, a pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil oxalate optionally contains other excipients.

Other excipients such as diluents, lubricants and glidants commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe, Paul J Sheskey & Sian C Owen (2006)] the content of which is incorporated herein by reference.

Other excipients are also used in the preparation of the pharmaceutical composition like diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof. A preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica. Preferably, the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.
The composition according to the invention can also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof. It is preferred that the excipients include at least one lubricant, selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate. The composition can also comprises glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

One or more of these additives may be selected and used by the skilled artisan having regard to the particular desired properties of the pharmaceutical composition by routine experimentation and without any undue burden. The absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the pharmaceutical composition and may also be chosen by the skilled artisan by routine experimentation without undue burden.

Optionally, cores/tablets can be coated with conventional materials used for film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995, edited by Graham Cole. Film coating formulations usually contain the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s). In film coating suspension the minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials. Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, ydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/dissolution of the film.

The commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol and macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, and triacetin), and oils/glycerides (castor oil, acetylated monoglycerides, and fractionated coconut oil).

Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials form each group can be combined in defined ratios. Film coating suspensions can be used as ready-to-make preparations which are available on the market.
Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.

A composition of coating suspension (calculated on dry material) is particularly preferred which comprises: 1-99% by weight of polymer, preferably 1- 95% of polymer; 1-50% by weight of plasticizer, preferably 1-40% of plasticizer; 0.1-20% of colourant/opacifier, preferably 0.1- 10% of colourant/opacifier, all the percentage are based on the total weight of coating material.

As tenofovir disoproxil oxalate is water soluble, particle size of API does not have any impact on the dissolution and bioavailability of the composition of the invention. Hence, there are no particular restrictions to the average particle size of the drug substance contained in the pharmaceutical composition of the invention. But use of drug particles having uniform diameter is advantageous for handling and preparing the composition. In another embodiment, the present invention relates to a pharmaceutical composition containing tenofovir disoproxil oxalate particles characterized in that the D50 of said tenofovir disoproxil oxalate particles is less than 1000 urn, preferably less than 200 urn and more preferably 175 \im.

In one embodiment, the compositions can be in the form of tablets, pills, powders, granulates lozenges, troches, sachets, soft and hard gelatine capsules, suppositories as well as liquid syrups, suspensions and elixirs etc. The dosage form is preferably suitable for oral application. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of tenofovir disoproxil oxalate calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The pharmaceutical composition of the present invention is preferably a tablet which may or may not be coated. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

A pharmaceutical composition according to the present invention may be in the form of dragees in which case the composition is provided with a coating typically a sugar, shellac or other film coating entirely conventional in the art. Attention is drawn to the numerous known methods of coating employed in the art, e. g. spray coating in a fluidized bed, e. g. by the known methods using apparatus available from Aeromatic, Glatt, Wurster or Huttlin, in a perforated pan by the Accela Cota method, or to the submerged sword coating method. The additives commonly used in confectioning are employed in such methods are well known in the art.

The present pharmaceutical compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of tenofovir disoproxil oxalate, the active ingredient will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the tenofovir disoproxil oxalate.

The composition preparations of the invention can be produced by compressing a mixture of the drug substance of the invention with excipients. For example, one method for the production includes mixing the tenofovir disoproxil oxalate with the materials for the preparation by a suitable mixer, and directly compressing the mixture to tablets. Other methods include a dry granulating step to produce granules for tablets using dry granulating machines or roller compacters, and a wet granulating step to produce granules for tablets using water, ethanol and solutions containing binders.

One of the preferred methods of preparation is wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a binding solvents or solutions to clump the powders into granules. The granulate is sized suitably either through screening or milling or both, dried and then screened and/or milled to the desired particle size. The granulate may then be tabletted/compressed, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.

Likewise the composition of the invention can also be prepared by dry granulation. The drugs and excipients are blended, compacted into a slug or a sheet and then comminuted into compacted granules of suitable size. The compacted granules may subsequently be compressed into a tablet. The composition can also be prepared by direct compression by compressed directly into a compacted dosage form.

A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting; however, they are not subjected to a final tableting step.

In another embodiment, at least 75 % of drug are dissolved from the pharmaceutical composition in a phosphate buffer of pH=6.2 in 30 minutes, when dissolution is performed using a paddle apparatus according to Ph. Eur. or an apparatus 2 according to USP, at a temperature of the dissolution medium of 37±0.5°C, speed of rotation of the paddle 75 rpm and volume of the dissolution medium 900 ml. Preferably the drug release rate of the composition of the invention is more than 70% in 15 minutes, above 80%, e. g. 90%, over 30 minutes, and above 95% over 45 minutes.

The composition of the invention containing tenofovir disoproxil oxalate is preferably administered once daily in an amount of 10 to 300 mg/day. The exact dose of active agent and the particular formulation to be administered depend on a number of factors, e. g. the condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.

In one embodiment, the pharmaceutical composition comprises from about 10 to about 300 mg of tenofovir disoproxil oxalate. In one preferred embodiment, the pharmaceutical composition comprises 40, 80, 120mg, 15mg, 200mg, 250mg or 300mg of tenofovir disoproxil oxalate.

The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein including treatment of HIV, hepatitis or both. In one embodiment, a method for treating the HIV or hepatitis by administering to patient in need thereof, the pharmaceutical composition of the invention containing tenofovir disoproxil oxalate, and a method for producing the therapeutic agent for treating the HIV and hepatitis.

In yet another embodiment, the pharmaceutical composition comprises, besides tenofovir disoproxil oxalate, a further one or more active ingredient. Preferably, the further active ingredient is another anti-HIV agent like abacavir, zidovudine, lamivudine, efavirenz, emitrictabine, rilpivirine, cobicistat, elvitegravir and/or gemcitabine.

In one embodiment, a pharmaceutical composition comprising tenofovir disoproxil oxalate or a pharmaceutically acceptable salt thereof of the invention has a comparable bioavailability to the commercial form of tenofovir disoproxil oxalate. In one preferred embodiment, a pharmaceutical composition comprising tenofovir disoproxil oxalate is bioequivalent to commercial form of tenofovir disoproxil oxalate.

The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.

Example 1:

Preparation:

1. Weighed required quantity of API, lactose monohydrate, microcrystalline Cellulose pHlOl, croscarmellose sodium and Pregelatinized starch were passed through sieve # 40 ASTM.

2. Load ingredients of step 1 into Rapid Mixer Granulator (RMG) and mix for 10 minutes with impeller 150 rpm and chopper off.

3. Granulate step 2 materials in Rapid Mixer Granulator (RMG) using water as granulating fluid.

4. Dry the wet mass of step 4 in Rapid drier at 55°C ± 5°C to achieve desired LOD.

5. Passed dried granules through sieve # 20 ASTM.

6. Weighed the Extragranular material such as Croscarmellose sodium, rnicrocrystalline cellulose pH 101 were passed through # 40 mesh and magnesium stearate was passed through # 60 mesh.

7. Add step 5 materials to the step 6 material and blend for 5 minutes

8. Step 7 material was compressed by almond shaped punches.

9. Preparation of coating solution: 15 gm of Opadry blue was added to 85 gm of purified water under continuous stirring for 45 minutes.

10. Coating the step-8 material with step-9 material upto 2.5 % weight buildup.

Examples 2-4:

Preparation:

1. Sift API, rnicrocrystalline cellulose, lactose monohydrate fast flow, crospovidone xllO, HPC and Aerosil 200 through sieve # ASTM 40.

2. Load Ingredients of step 1 into blender and mixed for 10 min

3. Sift Magnesium Stearate through sieve # ASTM 60.

4. Add step 3 to the Step 2 and blend in blender for 5 min.

5. Compress the lubricated blend of step 4 using almond shaped punches. Example 5-10:

Preparation:

1. Weighed required quantity of APIS, lactose monohydrate, macrocrystalline Cellulose pHlOl, croscarmellose sodium and Pregelatinized starch were passed through sieve # 40 ASTM.

2. Load ingredients of step 1 into Rapid Mixer Granulator (RMG) and mix for 10 minutes with impeller 150 rpm and chopper off.

3. Granulate step 2 materials in Rapid Mixer Granulator (RMG) using water as granulating fluid.

4. Dry the wet mass of step 4 in Rapid drier at 55°C ± 5°C to achieve desired LOD.

5. Passed dried granules through sieve # 20 ASTM.

6. Weighed the Extragranular material such as Croscarmellose sodium, microcrystalline cellulose pH 101 were passed through # 40 mesh and magnesium stearate was passed through # 60 mesh.

7. Add step 5 materials to the step 6 material and blend for 5 minutes

8. Step 7 material was compressed by almond shaped punches.

9. Preparation of coating solution: 15 gm of Opadry blue was added to 85 gm of purified water under continuous stirring for 45 minutes.

10. Coating the step-8 material with step-9 material upto 2.5 % weight buildup.

Claims:

1. A pharmaceutical composition comprising an active agent containing effective - amount of tenofovir disoproxil oxalate.

2. The pharmaceutical composition according to claim 1 wherein the active agent is present in an amount of more than 35% by weight based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1 wherein the active agent is present in an amount of more than 50% by weight based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 1 which comprises microcrystalline cellulose as a pharmaceutically acceptable additive.

5. The pharmaceutical composition according to claim 1 which comprises a superdisintegrant as a pharmaceutically acceptable additive.

6. The pharmaceutical composition according to claim 1 wherein the composition is prepared by wet granulation.

7. The pharmaceutical composition according to claim 1 wherein the composition is prepared by dry granulation.

8. The pharmaceutical composition according to claim 1 wherein the composition is prepared by direct compression.

9. The pharmaceutical composition according to claim 1 wherein the composition optionally comprises one or more anti-HIV drugs.

10. A pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate.