Pharmaceutical Composition of Tenofovir Disoproxil

Field of the Invention:

The present invention relates to a pharmaceutical composition comprises an active agent containing effective amount of hot-melt extruded (HME) tenofovir disoproxil or a pharmaceutically acceptable salt thereof and a process for preparing the pharmaceutical 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]propyl]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.

WO 2006135932 discloses that initial efforts to simply combine the three drugs (active pharmaceutical intermediates, or APIs) into a unitary, essentially homogeneous composition manufactured by wet granulation failed to produce a chemically stable tablet as tenofovir disoproxil or a pharmaceutically acceptable salt thereof. Tenofovir disoproxil or a pharmaceutically acceptable salt thereof is highly unstable and rapidly degraded in contact with water or aqueous solutions. So preparation of composition comprising Tenofovir disoproxil or a pharmaceutically acceptable salt thereof and it combination with other active ingredients by wet granulation is not at all suitable.

During formulation development of tenofovir disoproxil or a pharmaceutically acceptable salt thereof, direct compression is not possible due to very poor flow properties of the active ingredient. The dry granulation of tenofovir disoproxil or a pharmaceutically acceptable salt thereof involves several steps of compaction and a large number of studies need to be performed to optimize the process. So there is a need to develop a suitable method to prepare a pharmaceutical composition of tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

The present invention relates to a pharmaceutical composition comprises an active agent containing effective amount of hot-melt extruded (HME) tenofovir disoproxil or a pharmaceutically acceptable salt thereof. 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 hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded 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.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, wherein the active agent is present in an amount of more than 50% by weight.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, which comprises a hot-melt extrudable binder as a pharmaceutically acceptable additive.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, which comprises a hot-melt extrudable binder as a pharmaceutically acceptable additive and optionally a plasticizer.

Another embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, 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 hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, polyethylene glycol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

Another embodiment of the invention relates to a process for preparing a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof. Another embodiment of the invention relates to a process for preparing a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, wherein the process comprises the steps of:

a) mixing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof with a hot-melt extrudable binder and optionally one or more pharmaceutically acceptable excipients,

b) hot-melt extruding said mixture to hot-melt extruded composition,

c) optionally mixing with one or more pharmaceutically acceptable excipients to prepare the composition.

Another embodiment of the invention relates to a process for preparing a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, wherein the mixture comprising effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof with a hot-melt extrudable binder and optionally one or more pharmaceutically acceptable excipients are extruded at a temperature below the melting point of tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

Detailed Description:

This invention relates to a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded 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 pharmaceutical^ 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, propionic, succinic, saccharic, glycolic, stearic, lactic, malic, fumaric, saccharic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, flunaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

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 aspect of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof. The composition may further comprise other additives for the preparation of the composition.

The term hot-melt extrusion or hot-melt extruded is used herein to describe a process whereby a composition is heated and/or compressed to a molten (or softened) state and subsequently forced through an orifice in a die where the extruded product is formed into its final shape in which it solidifies upon cooling. The hot-melt granulations by other methods are also equivalent to hot-melt extrusion and are also covered under the definition of as hot-melt extrusion. The other method of hot-melt granulation includes but not limited to melt agglomeration, spray congealing melt granulation, tumbling melt granulation etc.

The hot-melt extrusion process preferably employed is conducted at an elevated temperature, i.e. the heating zone(s) of the extruder is above room temperature. It is important to select an operating temperature range that will minimize the degradation or decomposition of the effervescent composition during processing. The operating temperature range is generally in the range of from about 15°C to about 100°C as determined by the setting for the extruder heating zone(s). The temperature of the mixture being hot-melt extruded will not exceed 110°C and preferably will not exceed 100°C.

The hot-melt extrusion is conducted employing a dry granular or powdered feed.

Although the process referred to above has been called a hot-melt extrusion, other equivalents processes such as injection molding, hot dipping, melt casting and compression molding may be used. By using any of these methods, the formulation may be shaped as needed according to the desired mode of administration, e.g. tablets, pills, lozenges, suppositories and the like.

Hot-melt granulation is another preferred method of preparation of the invention. The formulation can be prepared by mixing drug with other excipients like binder component
and subjecting the binder component to only softening, without complete fusion, followed by cooling and sizing. The other method of preparation is to suspend or dissolve drug at elevated temperature in a fused carrier material, the "melt vehicle", and the melt is granulated during or after solidification.

Melt agglomeration is a process by which the solid fine particles are bound together into agglomerates, by agitation, kneading, and layering, in the presence of a molten binding liquid. Dry agglomerates are obtained as the molten binding liquid solidifies by cooling.

During a melt agglomeration process, the meltable binder may be added as molten liquid, or as dry powder or flakes. In the latter, the binder may be heated by hot air or by a heating jacket to above the melting point of the binder. Alternatively, the melt agglomeration process exploits an extremely high shear input, of a high-shear mixer, where the heat of friction alone raises the temperature of the binder and effects melting.

Typically, the melting points of meltable binders range from 50 to 100°C. A lower-melting-point binder risks situations where melting or softening of the binder occurs during handling and storage of the agglomerates.

Spray congealing is a melt technique of high versatility. Processing of meltable materials by spray congealing involves spraying a hot melt mixture of drug and melt vehicle into an air chamber below the melting point of the meltable materials or at cryogenic temperature. Spray-congealed particles (10-3000 ^m in diameter) are obtained upon cooling.

Tumbling Melt Granulation is process in which a powdered mixture of meltable and non-meltable materials is fed onto the seeds in a fluid-bed granulator. The mixture adheres onto the seeds with the binding forces of a melting solid to form the spherical beads.

A pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, which comprises a hot-melt extrudable binder as a pharmaceutically acceptable additive.

The term "hot-melt extrudable" is taken to mean that a material or composition can be hot-melt-extruded with no significant thermal degradation, e.g. less than 5% wt. or less than 10% wt. degradation. Examples of hot-melt extrudable binders which can be used in the composition include but not limited to polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, polypropylene oxide, polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinylacetate, acrylate and methacrylate copolymers, acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, pectins, poloxamers (PLURONIC F68, PLURONIC F127), collagen, albumin, gelatin, cellulosics in non-aqueous solvents, wax such as carnauba wax, beeswax and combinations of the above and the like.

Hot-melt extrudable binders may be used in an amount of up to about 60 weight percent and preferably about 3 to about 30 weight percent of the total composition. All binders used in this invention are hot-melt extrudable. While the melting and/or softening point temperatures of these binders usually rise with increase of their molecular weights, preferable ones are those with a melting or softening point temperature less than about 100°C. However, binders having melting or softening points greater than about 100°C can be used. Hot-melt extrudable binders having a melting or softening point temperature greater than about 100°C will require use of a plasticizer during hot-melt extrusion such that the binder melting or softening point temperature will be lowered below 100°C.

Among the above-mentioned binders, polyethylene glycol is preferable.

The pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded 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.

The pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof optionally contains a plasticizer. Non limiting examples of plasticizers including citrate esters, polyethylene glycols, PG, triacetin, diethylphthalate, castor oil, and others known to those or ordinary skill in the art.

The pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded 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.

A specific embodiment of the invention relates to a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, polyethylene glycol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. A typical composition may comprise: more than 35% of tenofovir disoproxil or a pharmaceutically acceptable salt thereof, 3 to 30% of polyethylene glycol, 1 to 20% of microcrystalline cellulose, 1 to 20% croscarmellose sodium, 0 to 10 % of magnesium stearate and 0 to 5 % of colloidal anhydrous silica.

Another aspect of the invention is to a process for preparing a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded 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 a hot-melt extrudable binder and optionally one or more pharmaceutically acceptable excipients,

b) hot-melt extruding said mixture to hot-melt extruded composition,

c) optionally mixing with one or more pharmaceutically acceptable excipients to prepare the composition.

The hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof is prepared by hot-melt extruding effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof, a hot-melt extrudable binder and optionally one or more pharmaceutically acceptable excipients at a temperature below the melting point of tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

The pharmaceutical formulation of the present invention may be provided in a variety of ways. Additional components that would not significantly prohibit the hot-melt extrusion process may be added to the formulation prior to hot-melt extrusion. The pharmaceutical formulation of the present invention 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. Such methods of administration and others contemplated within the scope of the present invention are known to the skilled artisan.

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. Such additives include, but are not limited to, 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 (eg Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, glidants, buffers, coatings, and coloring agents can also be incorporated. Suitable binders can include 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 and the like, preferable to use a binder with good water solubility. Disintegrating agents include microcrystalline cellulose, starch, crospovidone, modified starches especially sodium starch glycolate and carmellose especially croscarmellose sodium, carboxymethylcellulose calcium and the likes. Glidants include colloidal silicon dioxide, talc, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearyl fumarate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated. 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). The dosage forms can be prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients.

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.

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.

For rectal administration, the pharmaceutical formulation may be in the form of a suppository, ointment, enema, tablet or cream for release of compound into the intestines, sigmoid flexure and/or rectum.

The pharmaceutical formulations may also be administered as liquid suspensions comprising hot-melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, with or without the addition of pharmaceutically suitable surfactants, suspending agent, or emulsifying agent for oral or parenteral administration.

For suspension preparations, the pharmaceutical formulation may include oils, for example, fixed oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; fatty acids, such as oleic acid, stearic acid and isotearic acid; and fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. They may also be mixed with alcohols, such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; with glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol; with ethers, such as poly(ethylene glycol) 450, with petroleum hydrocarbons, such as mineral oil and petrolatum; with water, or with mixtures thereof; with or without the addition of a pharmaceutically suitable surfactant, suspending agent or emulsifying agent.

It is contemplated that either one or a combination of long-acting, sustained release, controlled release or slow release dosage forms may be prepared in the present invention.

The course and duration of administration of and the dosage requirements for the formulation of the present invention will vary according to the subject being treated, the compound being administered, the formulation used, the method of administration used, the severity and type of indication being treated, the coadministration of other drugs and other factors.

For nasal administration, the pharmaceutical formulation may be a paste, cream or ointment containing the appropriate solvents (such as water, aqueous, nonaqueous, polar, nonpolar, hydropic, hydrophilic and/or combinations thereof) and optionally other compounds (stabilizers, perfumes, antimicrobial agents, antioxidants, pH modifiers, surfactants and/or bioavailability modifiers). It is contemplated that bioavailability enhancers such as alcohols or other compounds that enhance the penetration of the therapeutic compound from the pharmaceutical formulation into the nasal mucosa may be needed to prepare suitable formulations for nasal administration.

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 pharmaceutically 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 D5o of said tenofovir disoproxil or a pharmaceutically acceptable salt thereof particles is less than 1000 mm, preferably less than 200 |xm and more preferably 175 mm.

The composition of the invention containing hot-melt extruded 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 hot melt extruded 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.

Example 1-3:

Manufacturing Procedure:

All the intragranular components were sifted through # ASTM 40, blended together and extruded at 120-130 RPM with an extrusion temperature from about 30-65°C. Then extrudate were dried, sized and mixed with other excipients and compressed into tablet.

Example 4-6:

Manufacturing Procedure:

All the intragranular components were sifted through # ASTM 40, blended together and extruded at 130-150 RPM with an extrusion temperature from about 16-105°C. Then extrudate were dried, sized and mixed with other excipients and compressed into tablet.

Example 7-9

Manufacturing Procedure:
All the intragranular components were sifted through # ASTM 40, blended together and extruded at 130-150 RPM with an extrusion temperature from about 17-65°C. Then extrudate were dried, sized and mixed with other excipients and compressed into tablet.

Example 10:

Manufacturing Procedure:
Tenofovir disoproxil, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium were sifted through # ASTM 40 and mixed with for 10 minutes at 100 RPM. PEG 4000 was melted at 60°C and drug mixture blend was granulated with the melted PEG 4000. The granules were dried, sized and mixed with extragranular excipients, followed compressing into tablet.

We claim:

1. A pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

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 2 wherein the active agent is present in an amount of more than 50% by weight.

4. The pharmaceutical composition according to claim 1 wherein the composition comprises a hot-melt extrudable binder as a pharmaceutically acceptable additive.

5. The pharmaceutical composition according to claim 4 wherein the composition comprises optionally a plasticizer.

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

7. A pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof, polyethylene glycol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

8. A process for preparing a pharmaceutical composition comprising an active agent containing effective amount of hot melt extruded tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

9. The process for preparing a pharmaceutical composition according to claim 8 wherein the process comprises the steps of:

d) mixing effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof with a hot-melt extrudable binder and optionally one or more pharmaceutically acceptable excipients,

e) hot-melt extruding said mixture to hot-melt extruded composition,

f) optionally mixing with one or more pharmaceutically acceptable excipients to prepare the composition.

10. The process for preparing a pharmaceutical composition according to claim 9, wherein the mixture comprising effective amount of tenofovir disoproxil or a pharmaceutically acceptable salt thereof with a hot-melt extrudable binder and optionally one or more pharmaceutically acceptable excipients are extruded at a temperature below the melting point of tenofovir disoproxil or a pharmaceutically acceptable salt thereof.