Stable Pharmaceutical Compositions of Tenofovir disoproxil

Field of the Invention:

The present invention relates to a stable pharmaceutical composition comprises tenofovir disoproxil or a pharmaceutically acceptable salt thereof and an acidic compound; and a process for preparing the stable pharmaceutical composition.

Background of the Invention:

Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors, acts by blocking reverse transcriptase enzyme. 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. 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] mefhoxy]propyl ] adenine fumarate (1 :1). It is also marketed in combination with other antiretroviral agents. US 5935946, US 5922695, US 5977089, US 6043230, US 6069249 disclose tenofovir, tenofovir disoproxil and tenofovir disoproxil fumarate. Further, US 8049009 discloses Tenofovir disoproxil hemifumarate and it method of preparation. US 20110009368 discloses various salt form of tenofovir disoproxil like succinate, tartrate, saccharate, citrate, salicylate.

WO 2010142761 discloses tenofovir disoproxil succinate and various dosage forms containing tenofovir disoproxil succinate. EP 2389929 Al discloses a pharmaceutical composition of tenofovir or pharmaceutically acceptable salts thereof prepared by direct compression which includes starch or mixtures of starches in the range of 5%-l 5% by total weight. WO 2006135932 discloses that tenofovir disoproxil or a pharmaceutically acceptable salt thereof is highly unstable and rapidly degraded. Simply combining two more drugs with tenofovir or pharmaceutically acceptable salt thereof to prepare a unitary, essentially homogeneous composition manufactured by wet granulation is failed to produce a chemically stable tablet as tenofovir is degraded rapidly. So there is a need to develop a stable pharmaceutical composition of tenofovir disoproxil or a pharmaceutically acceptable salt thereof. The invention relates to a stable pharmaceutical composition comprises an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof and an acidic compound. The composition may further comprise other additives for the preparation of the composition. The invention also relates to a process of preparation of a stable pharmaceutical composition of tenofovir or a pharmaceutically acceptable salt thereof using an acidic compound as a stabilizer.

Summary of the Invention:

One aspect of the invention relates to a stable pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof and an acidic compound. Another aspect of the invention relates to a process for preparing a stable pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof and an acidic compound.

Detailed Description:

This invention relates to stable pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof 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 or a pharmaceutically acceptable salt thereof includes various forms of tenofovir disoproxil or a pharmaceutically acceptable salt thereof, 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 or a pharmaceutically acceptable salt thereof 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 or a pharmaceutically acceptable salt thereof 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 therapeutic compounds contained within the formulation may be formulated as their pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent therapeutic compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as amino acids, acetic acid, alginic acid, adipic acid, propionic acid, butyric acid, ascorbic acid, benzoic acid, oleic acid, succinic acid, saccharic acid, glycolic acid, stearic acid, tartaric acid, sorbic acid, fumaric acid, glutaric acid, valeric acid, caproic acid, benzoic acid, lactic acid, malic acid, maleic acid, hydroxymaleic acid, malonic acid, citric acid, pamoic acid, maleic anhydride, phthalic anhydride, phenylacetic acid, glutamic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, oleic acid, formic acid, trifluoroacetic phthalic, methanesulfonic acid, p-toluenesulfonic acid and the like. The preferable salts of tenofovir disoproxil are hydrochlorate, nitrate, phosphate, sulphate, fumarate, succinate, oxalate, tartrate, ascorbate, benzoate, lacatate, malate, maleate, citrate, adiapate, stearate.

In one embodiment, the pH of the aqueous solution of the compound used to prepare the salt of tenofovir disoproxil i.e. inorganic or organic acids or a mixture thereof, is less than 7, preferably pH<5.5, more preferably pH<5, or pH<4.
The pharmaceutically acceptable salts of the present invention can be synthesized from a parent therapeutic compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a predetermined amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. 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. One embodiment of the invention relates to a stable pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof, an acidic compound and a pharmaceutically acceptable excipient. The pH of an acidic compound is measured under the following conditions. To be specific, the pH of an aqueous solution or dispersion obtained by dissolving or dispersing the acidic compound in water at 1% w/v is measured at 25°C with a commercially available pH meter. In one of embodiments of the present invention, the pH of the aqueous solution of the acidic compound is less than 7, preferably pH<5.5, more preferably pH<5, or pH<4. As the "acidic compound" to be used in the present invention, an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or an organic acid particularly preferable examples thereof include edible organic acids such as amino acids, acetic acid, alginic acid, adipic acid, propionic acid, butyric acid, ascorbic acid, benzoic acid, oleic acid, succinic acid, saccharic acid, glycolic acid, stearic acid, tartaric acid, sorbic acid, fumaric acid, glutaric acid, valeric acid, caproic acid, benzoic acid, lactic acid, malic acid, maleic acid, hydroxymaleic acid, malonic acid, citric acid, pamoic acid, maleic anhydride, phthalic anhydride, phenylacetic acid, glutamic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, flunaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, oleic acid, formic acid, trifluoroacetic phthalic, methanesulfonic acid, p-toluenesulfonic acid and the like. The organic acid may be a salt.

Examples of the salt with an organic acid include sodium ascorbate, sodium fumarate, and the salt with an organic acid similar to the above mentioned respective organic acids are preferable. These organic acids and salts thereof may be used alone or two or more kinds thereof may be used simultaneously. The acidic compound to be used in the formulation as a stabilizer, may be the same or different from the compound used for pharmaceutical acceptable salts of tenofovir disoproxil. The pharmaceutically acceptable organic acid preferably has a pKa of at least about 2, preferably wherein the pharmaceutically acceptable organic acid has a pKa of about 5.4 or less. The pharmaceutically acceptable organic acid preferably has a pKa of at least about 2.5. Particularly, the pharmaceutically acceptable organic acid has a pKa of about 2.5 to about 5.4. In one of the embodiment, the acidic compound to be used in the formulation as a stabilizer is same as that of the compound used for pharmaceutical acceptable salts of tenofovir disoproxil. Examples like oxalic acid is used as a stabilizer for stabilizing the formulation containing tenofovir disoproxil oxalate, fumaric acid is used as a stabilizer for stabilizing the formulation containing tenofovir disoproxil fumarate, succinic acid is used as a stabilizer for stabilizing the formulation containing tenofovir disoproxil succinate. Other acidic compounds can also be used in combination.

The content (%) of the acidic compound in the whole pharmaceutical composition of the present invention is preferably 0.1-70% (more preferably 0.5-50%), further preferably 1-40%, particularly preferably 1-30%. In another embodiment, it is 0.01-40%, preferably 0.05-19%, more preferably 0.1-10%. In the pharmaceutical composition of the present invention, the mixing ratio of tenofovir disoproxil or a pharmaceutically acceptable salt thereof to the "acidic compound" to the tenofovir disoproxil or a pharmaceutically acceptable salt thereof is preferably pharmaceutically active ingredient: acidic compound is 1:0.001-1:200, further preferably 1:0.015-1:200, particularly preferably 1:0.04-1:100. In one embodiment of the invention relates to a stable pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof, an acidic compound having total impurities not more than 4.0% by weight of the total active ingredient. The Third Supplement to the Fourth Edition of "The International Pharmacopoeia" discloses different impurities of tenofovir disoproxil that has to be monitored during shelf life of any composition containing tenofovir disoproxil.

The impurities are (1-methylethyl) (8R)-9-(6-amino-9H-purin-9-yl)-5-hydroxy-8-methyl-5-oxo-2,4,7-trioxa-5-A,5-phosphanonanoate (tenofovir monosoproxil); (1 -methylethyl) (5RS,8R)-9-(6-amino-9H-purin-9-yl)-5-mefhoxy-8-methyl-5-oxo-2,4,7-trioxa-5-X5-phosphanonanoate; methyl (1-methylethyl) (5RS)-5-{[(1 R)-2-(6-amino-9H-purin-9-yl)-1 -methylethoxyjmethyl} -5-oxo-2,4,6,8-tetraoxa-5-A,5-phosphanonanedioate; (1-methylethyl) (5RS,8R)-9-(6-amino-9H-purin-9-yl)-8-methyl-5-(l-methylethoxy)-5-oxo-2,4,7-trioxa-5-A,5-phosphanonanoate; (1-methylethyl) (8R)-5-hydroxy-8-methyl-9-(6-{[(l-methylethoxy)carbonyl]amino}-9H-purin-9-yl)-5-oxo-2,4,7-trioxa-5-X,5-phosphanonanoate; bis(l -methylethyl) 9,9'-[methylenebis(imino-9H-purine-6,9-diyl)]bis[(8R)-5-hydroxy-8-methyl-5-oxo-2,4,7-trioxa-5-X5-phosphanonanoate] (tenofovir monosoproxil dimer); bis( 1-methylethyl) 5-{[(lS)-2-(6-amino-9H-purin-9-yl)-l-methylethoxy]methyl}-5-oxo-2,4,6,8-tetraoxa-5-X,5-phosphanonanedioate (tenofovir disoproxil (S)-enantiomer); 1-methylethyl propyl (5RS)-5-{[(lR)-2-(6-amino-9H-purin-9-yl)-1 -methylethoxyjmethyl} -5-oxo-2,4,6,8-tetraoxa-5-A,5-phosphanonanedioate; bis(l-methylethyl) 5- {[(1 R)-2-(6- {[({9-[(2R)-5-hydroxy-2,11 -dimethyl-5,9-dioxo-3,6,8,10-tetraoxa-5-A,5-phosphadodecyl]-9H-purin-6-yl}amino) methyljamino}-9H-purin-9-yl)-1 -methylethoxy]methyl}-5-oxo-2,4,6,8-tetraoxa-5-X,5-phosphanonanedioate (tenofovir di-and monosoproxil heterodimer); tetrakis( 1-methylethyl) 5,5'-(methylenebis{imino-9H-purine-6,9-diyl[(2R)-propane-l,2-diyl]oxy methylene})bis[5-oxo-2,4,6,8-tetraoxa-5-^5-phosphanonanedioate] (tenofovir disoproxil dimer); 9-(prop-l-enyi)-9H-purin-6-amine; (1-methylethyl) (5RS)-5-{[(lR)-2-(6-amino-9H-purin-9-yl)-l-methylethoxy]methyl}-10-methyl-5,9-dioxo-2,4,6,8-tetraoxa-10-aza-5-X.5-phosphaundecanoate; ethyl 1-methylethyl (5RS)-5- {[(1 R)-2-(6-amino-9H-purin-9-yl)-1 -methylethoxyjmethyl} -5 -oxo-2,4,6,8-tetraoxa-5-A,5-phosphanonanedioate.

The total impurities are not more than 6.0%, more preferably not more than 4.0% by weight of the total active ingredient. Another embodiment of the invention relates to a stable pharmaceutical composition of tenofovir disoproxil fumarate, fumaric acid and one or more pharmaceutically acceptable excipient.
Another embodiment of the invention relates to a stable pharmaceutical composition of tenofovir disoproxil oxalate, oxalic acid and one or more pharmaceutically acceptable excipient. Another embodiment of the invention relates to a stable pharmaceutical composition of tenofovir disoproxil succinate, succinic acid and one or more pharmaceutically acceptable excipient. Another embodiment of the invention relates to a stable pharmaceutical composition of tenofovir disoproxil tartrate, tartaric acid and one or more pharmaceutically acceptable excipient. When producing the pharmaceutical composition of the present invention, the "acidic compound" may be added as a powder in a granulation step or a mixing step. In addition, an acidic compound can be sprayed by dissolving or dispersing in a binder solution in the granulation step or in a film coating solution in a film coating step.

The pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof, wherein the active agent is present in an amount of more than 35% by weight based on the total weight of the pharmaceutical composition, preferably in an amount of more than 50% by weight. According to the invention, the composition 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.
According to the invention, the composition can also comprise a disintegrant. The non limiting examples of disintegrants are crospovidone, modified starches especially sodium starch glycolate, carmellose especially croscarmellose sodium, carboxymethylcellulose calcium and the mixture thereof. The disintegrant 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%.

According to the invention, the composition can also comprise a surfactant. Surface-active agents include but are not limited to surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination thereof. Non-limiting examples of surfactants include non-ionic, anionic, cationic, amphoteric or zwitterionic or any combination thereof. Non-ionic surfactant is preferable.
According to the invention, the composition can also comprise a binder. 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 hydrolysed 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%.

According to the invention, 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 can also comprises glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate. Other excipients 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.

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, powder; 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, hydroxypropylmethylcellulose 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 from 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.

The pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof may optionally contain one or more anti-HIV drugs. Preferably, the further active ingredient is another anti-HIV agent like abacavir, zidovudine, lamivudine, efavirenz, emitrictabine, rilpivirine, cobicistat, elvitegravir and/or gemcitabine. One embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate, oxalic acid, lactose, microcrystalline cellulose, pregelatinized starch, povidone and talc. One embodiment of the invention is a process for preparing a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof. The process comprises the steps of:

a) mixing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

b) granulating the said mixture either by wet granulation or dry granulation,

c) sieving the granules for size reduction,

d) mixing with the granules with acidic compound and other excipient,

e) compressing the mixture of step d into tablet or filling the mixture into capsule.

The pharmaceutical formulation may be provided in a variety of ways. The pharmaceutical formulation may be administered by a variety of methods. Such methods include, by way of example and without limitation: oral, nasal, buccal, rectal, ophthalmic, otic, urethral, vaginal, or sublingual dosage administration.
The pharmaceutical formulations described herein can be formulated into solid pharmaceutical dosage forms that can be administered orally, buccal, and sublingually. Oral pharmaceutical dosage forms can be in the form of individualized or multi-unit doses, such as tablets including suspension tablets, chewable tablets, rapid melt tablets, effervescent tablets; caplets; powders including effervescent powders; capsules including single or double shell gelatin capsule, tablet-filled capsules; pellets or granules. While the embodiments described herein contemplate any solid dosage form suitable for oral administration, tablets, capsules, tablet-filled capsules and caplets are especially preferred. When the pharmaceutical compositions of the present invention are formed into tablets or caplets, it is to be understood that the tablets or caplets may be scored, and that they may be of any suitable shape and size, such as round, square, rectangular, oval, diamond, pentagon, hexagon or triangular, so long as the objectives of the present invention are not defeated. It is to be further understood that when tablet-filled capsules are selected, the tablets utilized therewith may be formed into shapes that either (a) correspond to the capsules to permit over-coating or encapsulation via the capsules or (b) readily fit inside the capsules.

When the pharmaceutical formulations described herein are formed into solid, oral pharmaceutical dosage forms, such formulations may also include pharmaceutically acceptable additives. 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 or a pharmaceutically acceptable salt thereof 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.
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. '. As tenofovir disoproxil or a pharmaceutical^ acceptable salt thereof 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 hot-melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof particles characterized in that the D50 of said tenofovir disoproxil or a pharmaceutically acceptable salt thereof particles is less than 1000 um, preferably less than 200 urn and more preferably 175 um. The composition of the invention containing tenofovir disoproxil or a pharmaceutically acceptable salt thereof 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.

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 or a pharmaceutically acceptable salt thereof, and a method for producing the therapeutic agent for treating the HIV and hepatitis. The pharmaceutical composition comprising containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof of the invention has a comparable bioavailability to the commercial form of tenofovir disoproxil or a pharmaceutically acceptable salt thereof. In one preferred embodiment, a pharmaceutical composition comprising tenofovir disoproxil or a pharmaceutically acceptable salt thereof is bioequivalent to commercial form of tenofovir disoproxil or a pharmaceutically acceptable salt thereof.
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.

Examples: Manufacturing Procedure: All intragranular materials through sieved, mixed and then granulated with water. The granules are dried and mixed with the sieved mixture of extragranular materials. The granules are compressed into tablet. An accelerated stability test of the resulting tablets was performed over two months at 40°C and 75% RH (relative humidity) using bottle-sealing conditions. The impurities were detected and quantified by HPLC method.
The impurity profile of the different formulations when stored at 40°C/75% RH condition. Impurities are presented as concentration by weight (w/w) to the total weight of actives.

We claim:

1. A stable pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof and an acidic compound.

2. The pharmaceutical composition according to claim 1, wherein the active agent contains effective amount of a pharmaceutical acceptable salt of tenofovir disoproxil.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical acceptable salt of tenofovir disoproxil is derived from pharmaceutically acceptable inorganic or organic acids with pKa less than about 5.5

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable inorganic or organic acids for preparing pharmaceutical acceptable salt of tenofovir disoproxil and an acidic compound are same.

5. The pharmaceutical composition according to claim 1, wherein the acid compound is selected from the group consisting of inorganic acid, organic acid, organic acid salt or a mixture thereof.

6. The pharmaceutical composition according to claim 5, wherein the acid compound is an organic acid.

7. The pharmaceutical composition according to claim 6, wherein the organic acid is selected from the group consisting of amino acids, acetic acid, alginic acid, adipic acid, propionic acid, butyric acid, ascorbic acid, benzoic acid, oleic acid, succinic acid, saccharic acid, glycolic acid, stearic acid, tartaric acid, sorbic acid, fumaric acid, glutaric acid, valeric acid, caproic acid, benzoic acid, lactic acid, malic acid, maleic acid, hydroxymaleic acid, malonic acid, citric acid, pamoic acid, maleic anhydride, phthalic anhydride, phenylacetic acid, glutamic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, flunaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, oleic acid, formic acid, trifluoroacetic phthalic, methanesulfonic acid, p-toluenesulfonic acid or a mixture thereof.

8. The pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil oxalate and oxalic acid as acidcompound.

9. The pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil fumarate and fumaric acid as acid compound.

10. The pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil succinate and succinic acid as acid compound.

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

12. A process for preparing a pharmaceutical composition comprising an active agent containing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof and an acidic compound.