Field of the invention

The present invention relates to solid oral dosage forms of HIV protease inhibitors. More particularly, the present invention relates to solid oral dosage forms comprising ritonavir. The present invention further relates to a process for the preparation of solid oral dosage form comprising ritonavir.

Background of the invention

Acquired Immunodeficiency Syndrome (AIDS) and related diseases caused by human immunodeficiency virus (HIV) is a major health problem worldwide. It is the condition in human in which the immune system begins to fail, leading to life-threatening opportunistic infections. To overcome this deadly disease many antiretroviral drugs are developed which include HIV protease inhibitors (Pi's), nucleoside/nucleotide reverse transcriptase inhibitors (NRTI's) and non-nucleoside reverse transcriptase inhibitors (NNRTI's).

For the treatment of HIV, most of the available dosage regimens require combination of these drugs.

Ritonavir is chemically known as 10-hydroxy-2-methyl-5-(l-methylethyl)-l-[2-(l-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11 -bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester,[5S-(5R*,8R*,10R*,HR*)] and is disclosed in US 5,541,206 and US 5,648,497. Ritonavir is currently marketed in the form of tablets, capsules and oral solution with the trade name Norvir® in United States.
Most of the protease inhibitors such as lopinavir, ritonavir, nelfinavir and indinavir are less bioavailable due to poor water solubility and hence difficult to formulate. Dosage forms for these products are prepared by dissolving the drug in a solvent and further processed into liquid formulation or liquid filled soft gelatin capsule in which the drug is properly dissolved. To overcome the disadvantages associated with soft gelatin capsule such as drug loading capacity, variability of drug and need for refrigeration, hard gelatin capsule and tablet formulations have been developed. The currently available tablet dosage form is formulated using hot melt extrusion (Meltrex®) technology, which helps in increasing the bioavailability by dispersing the active ingredient in molecular level. Moreover, this technology is advantageous over conventional technologies by suspending the drug particles to deaggregate in the polymer melt due to intense mixing and agitation and also by allowing high drug loading. This technology is disclosed in US 2005/0143404, US 2005/0084529, US 2005/0048112 and US 2007/024964.

US 5,559,158 discloses a solid composition comprising adsorbent or a mixture of adsorbents to which is adsorbed a mixture of organic solvent or a mixture of organic solvents, ritonavir and acid or a combination of acids.

US 7,148,359 disclose compositions comprising crystalline Form II and amorphous ritonavir. This patent discloses that substantially pure amorphous ritonavir is prepared from the Form I crystalline polymorph of ritonavir by melting Form I ritonavir and rapidly cooling the melt and isolation of the resulting solid provides amorphous ritonavir.

US 7,364,752 discloses a pharmaceutical composition comprising ritonavir, wherein ritonavir in said composition is formulated as a solid dispersion of amorphous ritonavir in a matrix including a water soluble polymer. This patent further discloses that the composition may be prepared by dissolving or dispersing the HIV protease inhibiting compound in a sufficient amount of an organic solvent followed by dispersion into a suitable water soluble carrier. The solvent is then evaporated followed by cooling, leaving the drug dispersed or dissolved in the molten matrix.

US 8,268,349 discloses a solid pharmaceutical dosage form comprising a solid dispersion, wherein said solid dispersion comprises (1) sorbitan monolaurate, (2) at least one pharmaceutically acceptable water-soluble polymer having a Tg of at least 50°C, (3) colloidal silica (4) at least one HIV protease inhibitor, and wherein said at least one HIV protease inhibitor comprises ritonavir, and said dosage form comprises from 50 to 85% by weight of the total dosage form of said at least one pharmaceutically acceptable water-soluble polymer.

US 8,367,080 discloses a process of preparing a pharmaceutical formulation comprising essentially of: a) dissolving or suspending at least one anfi-retro viral drug and optionally at least one additive, in an organic solvent to obtain a solution or dispersion; b) drying said solution or dispersion to obtain granules; c) optionally lubricating said granules; d) compressing said granules into tablets or filling it into capsules.

US 8,399,015 discloses a solid pharmaceutical dosage form comprising a solid dispersion which includes (i) ritonavir, (ii) a pharmaceutically acceptable water-soluble polymer having a Tg of at least 50°C, and (iii) a pharmaceutically acceptable surfactant having an HLB value of from 4 to 10.

US 2005/0048112 discloses a solid dosage form, which comprises a solid dispersion of at least one HIV protease inhibitor and at least one water-soluble polymer and at least one surfactant.

US 2007/0249643 discloses a solid dosage form which comprises a solid dispersion of at least one HIV protease inhibitor in at least one water-soluble polymer and at least one surfactant, wherein said HIV protease inhibitor is selected from the group consisting of ritonavir and lopinavir and said water-soluble polymer has a Tg of at least about 50° C and is present in an amount of from about 50 to about 85% by weight of the dosage form.

US 2007/0249692 discloses a solid composition comprising a molecular dispersion of ritonavir and a hydrophilic, amorphous polymer in a matrix comprising a water soluble polymer.

US 2008/0181948 discloses a dosage form comprising a solid dispersion or solid solution of ritonavir in a matrix, wherein said matrix comprises at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, wherein said ritonavir is present in an amount of at least 10 wt%, based on the weight of said solid dispersion or solid solution, wherein each of said at least one pharmaceutically acceptable surfactant has an HLB value of from 12 to 18, and at least 50 percent by weight of all surfactant(s) in said solid dispersion or solid solution have an HLB value of from 12 to 18, wherein each of said at least one pharmaceutically acceptable water-soluble polymer has a Tg of at least 50°C, and wherein said solid dispersion or solid solution does not comprise, or comprises only an insignificant amount of PEG.

US 2008/0312300 discloses a composition comprising a therapeutically effective amount of a storage stable Form I of ritonavir having no detectable quantity of Form II of ritonavir, and one or more pharmaceutically acceptable carriers, excipients or diluents.

US 2010/0021540 discloses a process of making tablets, comprising: compressing a pre-tabletting material in a die to form a tablet, wherein an internal surface of the die is lubricated with at least one lubricant, and said pre-tabletting material comprises at least one therapeutic agent and at least one pharmaceutically acceptable polymer; and ejecting said tablet from said die, wherein said pre-tabletting material does not include (1) any therapeutic agent that is denaturalized or inactivated when compressed at a pressure of greater than or equal to 1 ton/cm2, (2) any low molecule active ingredient the elution of which is delayed when compressed at a pressure of greater than or equal to 1 ton/cm2, or (3) any therapeutic agent that is affected by said at least one lubricant.

WO 2006/037827 discloses a composition comprising ritonavir and a compound enabling gastrointestinal fluid to penetrate that composition which is selected from the group comprising silicates and silica oxide and further discloses a process, which comprises a kneading step in which the speed and the time of addition of the solvent is thoroughly controlled.

WO 2008/009689 discloses a composition comprising active ingredients including lopinavir and ritonavir along with at least one pharmaceutically acceptable polymer and a solubilizing composition comprising at least one tocopheryl compound having a polyalkylene glycol and at least one alkylene glycol fatty acid monoester, wherein the composition is prepared by homogeneous melting of active ingredients, polymers and solubilizing composition and allowing the melt to solidify to obtain a solid dispersion.

WO 2008/017867 discloses a composition comprising one or more antiretroviral drugs including lopinavir and ritonavir or their pharmaceutically acceptable salts, solvates or hydrates and at least one water insoluble polymer prepared by various methods such as melt granulation, melt extrusion, spray drying and solution evaporation, wherein the melt extrusion process comprises the steps of a) preparing a homogeneous melt of each drug; water insoluble polymer and excipients; (b) cooling the melt obtained in step (a); (c) allowing the cooled melt to solidify to obtain extrudates; and (d) processing the extrudates into a desired shape. The melting temperature is ranging from about 70°C to about 200° C.

WO 2012/164575 A2 discloses a pharmaceutical composition comprising amorphous form of ritonavir co-precipitated on copovidone and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients.

IN 1605/CHE/2007 discloses a solid dosage form comprising a solid dispersion of at least one anti retroviral drug, at least one water soluble non-polymeric excipient, at least one surface active agent and pharmaceutically acceptable excipients and further discloses a process for preparing solid dosage form comprises: (i) preparing a homogenous melt of atleast one anti retroviral drug, water soluble non-polymeric excipient(s) and surface active agent(s), and (ii) allowing said melt to solidify to obtain a solid dispersion product, and (iii) additionally adding additives to said solid dispersion product and compressing solid dispersion into a tablet.

IN 1730/CHE/2007 discloses a process of preparing a solid pharmaceutical composition for oral administration of HIV protease inhibitor(s) which comprises (i) preparing a solution or dispersion comprising said HIV protease inhibitor(s) and a water soluble carrier and a surfactant(s) in pharmaceutically acceptable solvent(s); (ii) evaporating said solution or dispersion to obtain solid dispersion product; (iii) milling/grinding said solid dispersion product to produce granules/particles; (iv) optionally adding other pharmaceutically acceptable excipients; (v) compacting said granules/particles to tablets and (vi) optionally coating said tablet.

The prior art references discloses the various ways of improving the solubility of ritonavir by converting crystalline ritonavir in the composition to amorphous form using various techniques such as solid dispersion. However, still there is a need to develop an improved solid oral dosage form comprising ritonavir that is bioequivalent w.r.t commercialized ritonavir dosage form.

Objective of the invention

The main objective of the present invention is to provide a solid oral dosage form comprising ritonavir and one or more pharmaceutically acceptable excipients having improved/ comparable bioavailability with respect to the commercialized dosage form

Summary of the invention

The present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1 and the dosage form comprises at least 10% of crystalline ritonavir.

Detailed description of the invention

In an embodiment, the present invention relates to a solid oral dosage form comprising ritonavir and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

wherein the dosage form comprises at least 10% of crystalline ritonavir.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1 and the dosage form comprises at least 10% of crystalline ritonavir.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir, a polymer, surfactant and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir, a polymer, surfactant and one or more
pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically
acceptable excipients,

wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir, a polymer, surfactant and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1 and the dosage form comprises at least 10% of crystalline ritonavir.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir, a water soluble non-polymeric excipient,
surfactant and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically
acceptable excipients,

wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1 and the dosage form comprises at least 10% of crystalline ritonavir.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir, lopinavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to a solid oral dosage form comprising:

(a) intragranular component comprising ritonavir, lopinavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1.

"Ritonavir" according to the present invention includes, but not limited to, ritonavir free base, its pharmaceutical acceptable salts, esters, ethers, solvates, hydrates, polymorphs and the like.

"Intragranular component" according to the present invention includes a composition which is prepared by melt extrusion, melt granulation and/or solid dispersion techniques.

"Extragranular component" according to the present invention includes a composition which is prepared by methods other than melt extrusion, melt granulation and/or solid dispersion techniques, including, but not limited to, blending, wet granulation, dry granulation, compaction and the like. Extragranular component can be in the form of powder, granules, pellets, beads etc.

In another embodiment of the present invention, the solid oral dosage form comprising ritonavir may be in the form of tablet, capsule, powder and granules.

In another embodiment of the present invention, the solid oral dosage form comprising ritonavir may be prepared by any method known in the art such as melt extrusion, melt granulation, solid dispersion, complexation, solvent evaporation, spray drying, common solvent method, melt solvent method, kneading, wet granulation, dry granulation and direct compression.

In another embodiment of the present invention, the solid dosage form comprises crystalline ritonavir in both intragranular and extragranular components.

In another embodiment of the present invention, the crystalline ritonavir present in the intragranular component of the dosage form is converted into amorphous form insitu.

In another embodiment, the solid oral dosage form of the present invention further comprises one or more antiretroviral agents including but not limited to protease inhibitors such as lopinavir, nelfinavir, atazanavir, darunavir, tipranavir, indinavir and saquinavir; integrase inhibitors such as raltegravir, elvitegravir; nucleoside reverse transcriptase inhibitors such as abacavir, emtricitabine, lamivudine, zidovudine, didanosine; nucleotide reverse transcriptase inhibitors such as tenofovir; Non- nucleoside reverse transcriptase inhibitors such as efavirenz, nevirapine, etravirine, rilpivirine, lersivirine or combinations thereof.

"Pharmaceutically acceptable excipient/s" are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipients includes, but not limited to, diluents/fillers, binders, disintegrants, water soluble polymers, water insoluble polymers, non-polymeric excipients, sugars, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, etc.

Binders hold the ingredients in the composition together. Exemplary binders include, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives; hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combinations comprising one or more of the foregoing binders. The binder may be used in the range of 1-40% by weight of the dosage form.

Diluents increase the bulk of the composition. Diluents according to the present invention include, but not limited to, sugars such as lactose, sucrose, dextrose; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol; Starlac® (co-processed mixture of Starch and lactose), Microcelac® (co-processed mixture of microcrystalline cellulose and lactose), starch, corn starch, modified starches, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combinations thereof. The diluent may be used in the range of 5-95% by weight of the dosage form.

Disintegrants according to the present invention include, but not limited to, water swellable substances, for example, cellulose and its derivatives including low-substituted hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums, and combinations comprising one or more of the foregoing water swellable substances. The disintegrant may be used in the range of 1-30% by weight of the dosage form.

The water soluble polymers according to the present invention include, but not limited to, homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinylpyrrolidone, copolymers of N-vinyl pyrrolidone and vinyl acetate e.g. copovidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose phthalates or succinates, cellulose acetate phthalate hydroxypropyl methylcellulose phthalate, polyethylene oxide, polyacrylates, methyl methacrylate, butyl methacrylate, polysaccharides such as alginate, xanthan gum and the like, acrylic acid copolymers such as carbomer; maleic anhydride/methyl vinyl ether copolymers and derivatives and the like or combinations thereof. The water soluble polymer may be used in the range of about 10 to 90% by weight of the composition.

The water insoluble polymers according to the present invention include, but not limited to, wax materials such as hydrogenated vegetable oil, hydrogenated castor oil, carnauba wax, candellia wax, beeswax, paraffin wax, stearic acid, glyceryl behenate, cetyl alcohol, cetostearyl alcohol, lanolin alcohol and mixtures thereof; cellulose derivatives such as ethyl cellulose or cellulose acetate; copolymers of polyvinyl alcohol, high molecular weight polyvinyl alcohols and the like or combinations thereof. The amount of water insoluble polymer used may be in the range of about 10 to 90% by weight of the composition.

The non-polymeric excipients according to the present invention include, but not limited to, lactose, maltose, dextrose, sucrose, fructose, non-polymeric carbohydrate, alpha-hydroxy acid, mannitol, sorbitol, xylitol, dicalcium phosphate, calcium sulfate, lactitol, glucose, maltitol, citric acid, succinic acid, tartaric acid and derivatives of the foregoing, or combinations thereof.

Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants.

Surfactants according to the present invention include, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as PEG monolaurate, PEG dilaurate, Polyethylene glycol 660 12- hydroxyl Stearate Ph. Eur. or Polyoxyl 15 hydroxystearate NF (Solutol HS 15), PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate, monooleate, monolaurate, monopalmitate, monostearate, sodium dioctyl sulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, Cremophore RH 40, and the like or combinations thereof. The surfactant may be used in the range of 0.001-5% by weight of the dosage form.

Lubricants and glidants aids in the processing of powder materials. Exemplary lubricants include, but not limited to, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, fumaric acid, talc, vegetable oil, zinc stearate, and combinations comprising one or more of the foregoing lubricants. The lubricant may be used in the range of 0.01-5% by weight of the dosage form. Exemplary glidants include, but not limited to, talc, silicon dioxide, silicic acid, cornstarch and the like. The glidant may be used in the range of 0.01-5% by weight of the dosage form.
The proper distribution of excipients in the formulation is the most important factor as it ultimately affects the bioavailability. As most of the surfactants have low pourability due to viscous nature, it is difficult to properly mix with other excipients and the drug. Moreover, they may form small lumps due to uneven distribution. However, their pourability increases when melted, which can be easily sprayed, to form homogeneous blend. This process also helps in maintaining less temperature in the extruder, which ultimately helps in reduction of hard lumps and also prevents the drug from decomposition.

In another embodiment, the present invention relates to a process for preparing a solid oral dosage form comprising ritonavir, which comprises the steps of:

(a) blending ritonavir with one or more pharmaceutically acceptable excipients,

(b) loading the blend of step (a) to hot melt extruder to get extrudates and milling the extrudates,

(c) blending the extrudates of step (b) with extragranular ritonavir and one or more pharmaceutically acceptable excipients, and

(d) compressing the blend of step (c) into tablets or filled into capsules.

In another embodiment, the present invention relates to a process for preparing a solid oral dosage form comprising ritonavir, which comprises the steps of:

(a) blending ritonavir with one or more pharmaceutically acceptable excipients,
(b) heating a surfactant to about 50-80°C to form a clear transparent solution,
(c) spraying the surfactant solution of step (b) on the blend of step (a),
(d) loading the blend of step (c) to hot melt extruder to get extrudates and milling the extrudates,
(e) blending the extrudates of step (d) with extragranular ritonavir and one or more pharmaceutically acceptable excipients, and

(f) compressing the blend of step (e) into tablets or filled into capsules.

In another embodiment, the present invention relates to a process for preparing a solid oral dosage form comprising ritonavir, which comprises the steps of:

(a) blending ritonavir with one or more pharmaceutically acceptable excipients,
(b) loading the blend of step (a) to hot melt extruder to get extrudates and milling the extrudates,
(c) blending extragranular ritonavir with one or more pharmaceutically acceptable excipients,
(d) spraying a surfactant solution on the blend of step (c),
(e) blending the extrudates of step (b) with the granules of step (d),
(f) compressing the blend of step (e) into tablets or filled into capsules.

In another embodiment, the present invention relates to a process for preparing a solid oral dosage form comprising ritonavir, which comprises the steps of:

(a) blending ritonavir with one or more pharmaceutically acceptable excipients,
(b) loading the blend of step (a) to hot melt extruder to get extrudates,
(c) blending extragranular ritonavir with one or more pharmaceutically acceptable excipients,
(d) spraying a solution comprising surfactant and one or more pharmaceutically acceptable excipients on the blend of step (c),
(e) blending the extrudates of step (b) with the granules of step (d) and one or more pharmaceutically acceptable excipients,
(f) compressing the blend of step (e) into tablets.

The dosage form according to the present invention may be uncoated or optionally coated with film coating composition. If desired, the film coat may be an aqueous moisture barrier. The coating composition mainly comprises of film forming polymers and one or more of plasticizers, opacifier, surfactant, anti tacking agents, coloring agent and the like. The coating according to the present invention is applied by solubilising or suspending the excipients in solvents such as isopropyl alcohol, water, acetone, ethanol, methylene chloride and the like or mixtures thereof.

In another embodiment, the dosage form according to the present invention comprises ritonavir in the range of 10 to 500 mg.

In another embodiment, the dosage form comprising ritonavir according to the present invention can be used for the treatment of HIV-infection in combination with other antiretroviral agents.

In another embodiment, the composition comprising ritonavir can be packed in any suitable packaging material known in the art such as, but not limited to, HDPE bottles and Clear PVC/PVDC Plain Aluminium Foil Blister.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1
The processing steps involved in manufacturing solid dosage form comprising ritonavir are given below:

i) ritonavir, copovidone and colloidal silicon dioxide were sifted and blended using rapid mixer granulator,

ii) sorbitan monolaurate was heated to about 60-70°C to form a clear transparen solution,

iii) the solution of step (ii) was sprayed on to the blend of step (i),

iv) the material obtained in step (iii) was loaded to a hot melt extruder to get extrudates,

v) the extrudates of step (iv) were milled and blended with the extragranular ritonavir dibasic calcium phosphate anhydrous and colloidal silicon dioxide,

vi) the blend of step (v) was lubricated with sodium stearyl fumarate and compressed t( form tablet,

viii) the prepared tablets of step (vi) were coated with the film coating solution to obtair
film-coated tablets.

Example 2
Example 3

The compositions given in examples 2-3 were prepared using similar procedure described in Example 1.

Example 4

The processing steps involved in manufacturing solid dosage form comprising ritonavir are
given below:

i) ritonavir, lanolin alcohol, lactose monohydrate and colloidal silicon dioxide were sifted and blended using rapid mixer granulator,

ii) the material obtained in step (i) was loaded to a hot melt extruder to get extrudates,

iii) extragranular ritonavir and dibasic calcium phosphate anhydrous were sifted separately and blended,

iv) sorbitan monolaurate was dissolved in isopropyl alcohol,

v) the solution of step (iv) was sprayed on to the blend of step (iii) to obtain granules,

vi) the extrudates of step (ii) were blended with the granules of step (v),

vii) the blend of step (vi) was blended with colloidal silicon dioxide and lubricated with sodium stearyl fumiarate and compressed to form tablet,

viii) the prepared tablets of step (vii) were coated with the film coating solution to obtain film-coated tablets.

Example 5

The composition given in example 5 was prepared using similar procedure described in Example 4.
Example 6

The processing steps involved in manufacturing solid dosage form comprising ritonavir are given below:

i) ritonavir, copovidone and colloidal silicon dioxide were sifted and blended using rapid mixer granulator,

ii) Sorbitan monolaurate was heated to 60-70°C or till it forms a clear transparent solution and was sprayed onto the material of step (i),

iii) the material obtained in step (ii) was loaded to a hot melt extruder to get extrudates and the extrudates were milled,

iv) ritonavir and colloidal silicon dioxide were sifted and loaded into fluid bed equipment,

v) polysorbate 80, sorbitan monolaurate and copovidone were dispersed in purified water,

vi) the solution of step (v) was sprayed on to the blend of step (iv) to obtain granules,

vii) extragranular microcrystalline cellulose, dicalcium hydrogen phosphate dihydrate, corn starch, starch 1500, mannitol SD 200, dibasic calcium phosphate anhydrous and colloidal silicone dioxide were sifted and blended with materials of step (iii) and step (vi), viii) the blend of step (vii) was lubricated with sodium stearyl fumarate and compressed into tablets, ix) the prepared tablets of step (viii) were coated with Aquarius Prime coating solution to obtain film-coated tablets.

Examples 7-10

Examples 11-14
The compositions given in examples 7-14 were prepared using similar procedure described in Example 6.
Table 1 given below shows the comparative dissolution profile of ritonavir formulations according to the present invention (Examples 6-14) and Norvir® tablets carried out in 900ml of 60 mM polyoxyethylene 10 lauryl ether in water using USP Apparatus II (Paddle) at 75 rpm speed.

Table 1

We claim:
1. A solid oral dosage form comprising:

(a) intragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients.

2. The solid oral dosage form according to claim 1, wherein the dosage form further comprises one or more antiretroviral agents.

3. The solid oral dosage form according to claim 2, wherein one or more antiretroviral agent is selected from the group consisting of lopinavir, nelfinavir, atazanavir, darunavir, tipranavir, indinavir and saquinavir.

3. The solid oral dosage form according to claim 1, wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1 and the dosage form comprises at least 10% of crystalline ritonavir.

4. The solid oral dosage form according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising diluents/fillers, binders, disintegrants, water soluble polymers, water insoluble polymers, lubricants, glidants and surfactants.

5. The solid oral dosage form according to claim 4, wherein the water soluble polymer is selected from the group consisting of polyvinyl pyrrolidone, copovidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide and combination thereof.

6. The solid oral dosage form according to claim 4, wherein the surfactant is selected from the group consisting of polysorbate, sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sodium lauryl sulphate, sodium dioctyl sulfosuccinate, lecithin, poloxamer, polyoxyl castor oil and combination thereof.

7. The solid oral dosage form according to claim 4, wherein the diluent is selected from the group consisting of lactose, sucrose, dextrose, mannitol, sorbitol, xylitol, lactitol, starch, corn starch, modified starches, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose and combination thereof.

8. The solid oral dosage form according to claim 4, wherein the disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium starch glycolate, ion-exchange resins, starch, pregelatinized starch, formalin-casein, alginates, gums and combination thereof.

9. A solid oral dosage form comprising:

(a) intragranular component comprising ritonavir, lopinavir and one or more pharmaceutically acceptable excipients,

(b) extragranular component comprising ritonavir and one or more pharmaceutically acceptable excipients,

wherein the ratio of intragranular ritonavir to extragranular ritonavir is the range of 1:1 to 10:1.

10. A process for preparing a solid oral dosage form comprising ritonavir, which comprises the steps of:

(a) blending ritonavir with one or more pharmaceutically acceptable excipients,
(b) loading the blend of step (a) to hot melt extruder to get extrudates,
(c) blending extragranular ritonavir with one or more pharmaceutically acceptable excipients,
(d) spraying a solution comprising surfactant and one or more pharmaceutically acceptable excipients on the blend of step (c),
(e) blending the extrudates of step (b) with the granules of step (d) and one or more pharmaceutically acceptable excipients,
(f) compressing the blend of step (e) into tablets.