Technical Field of the Invention
The present invention relates to a unit dosage form comprising a binary solid dispersion composition of at least one HIV protease inhibitor, and a process of preparation thereof, wherein the said solid dispersion is substantially free of surfactant.
Background of the Invention
Human immuno-deficiency virus (HIV), the causative agent for AIDS, belongs to a class of viruses known as retroviruses, which carry genetic information in the form of RNA. As the virus enters the host cell its RNA is reverse-transcribed to DNA by a virally encoded enzyme, reverse transcriptase. The viral DNA enters the host cell nucleus, where it is integrated into the genetic material of the cell by a second virally encoded enzyme called integrase. Activation of the host cell results in the transcription of the viral DNA to messenger RNA, which is then translated onto viral proteins. HIV protease, a 99-amino acid homodimer, is the enzyme which mediates this step of viral maturation by cleaving the viral gag-pol polyprotein precursor into essential functional proteins. In an event, when these polyproteins are not cleaved the virus fails to mature and is incapable of infecting a new cell.
The HIV protease inhibitors are a class of antiretroviral agents that competitively compete for this HIV proteinase or protease enzyme. These are peptide like molecules that mimic the gag-pol protein, binding onto HIV proteases to prevent the accumulation of structural proteins required for new virion formation. The HIV protease inhibitors have contributed greatly to the reductions in HIV-associated morbidity and mortality over the last decade and remain a cornerstone of highly-active antiretroviral therapy (HAART).
Ritonavir is one of the prominent members of this class of compounds, which is commercialized as NORVIR® oral solution and soft gelatin capsules by Abbott Laboratories, USA. The US Patent Nos. 5,542,206 and 5,648,497 disclose ritonavir and describes its use as an inhibitor of the HIV protease enzyme. Additionally, ritonavir is used extensively as a pharmacokinetic enhancer when co-administered

with other protease inhibitors. The US Patent Nos. 6,037,157 and 6,703,403 disclose the use of ritonavir in combination with an HIV protease inhibitor which is metabolized by cytochrome P450 monooxygenase, such that the amount of ritonavir is sufficient to improve the pharmacokinetics of the HIV protease inhibitor in a patient, relative to the pharmacokinetics of the HIV protease inhibitor when administered alone. Ritonavir is dosed as a pharmacokinetic enhancer with amprenavir, atazanavir, fosamprenavir, lopinavir, saquinavir, tipranavir, darunavir and the like.
Ritonavir is also available as a co-formulated composition with lopinavir, another potent HIV protease inhibitor, under the proprietary names KALETRA®/ALUVIA® as soft gel capsules and tablets from Abbott Laboratories, USA. Lopinavir is described specifically in US Patent No. 5,914,332.
Despite their tremendous success worldwide, the main drawback which remains associated with HIV protease inhibitors is that they exhibit low oral bioavailability. A majority of such HIV protease inhibitors and ritonavir specifically poses great difficulty with regards to formulating into appropriate, patient-complaint dosage forms, owing to the fact that these are BCS class II and IV active ingredients. Formulating the protease inhibitors in liquid dosage forms is not always a preferable solution to improve upon the problem of bioavailability, for various reasons, namely, unpleasant taste, stability problems, handling and storage hazards, patient incompliance, etc.
One solution to provide a solid unit dosage composition of such drugs is to formulate a solid dispersion composition. A "solid dispersion" of a poorly soluble active ingredient, can be defined as an even dispersion of the active ingredient in an inert carrier in solid state. The active ingredient is dispersed in the carrier by coprecipitation from a suitable solution containing both the active ingredient and carrier, by melting both components together or by some other process involving a phase change. The use of surfactant in such solid dispersion compositions to form a ternary system is also well documented. Such systems have higher dissolution rates than binary dispersion systems (systems with two components), Pharmaceutical solid dispersion technology By Muhammad J. Habib, CRC Press. Alternately, certain

surfactants, for e.g., poloxamer, polyoxyethylene stearate, Renex 650, have also been used extensively as the carrier material to achieve enhanced dissolution in a binary solid dispersion system. Therefore, it is quite evident from the art that presence of a surfactant in an intimate admixture with the drug is one of the critical parameters to formulate a stable solid dispersion composition with improved bioavailability.
The PCT application WO/2005/039551 teaches ternary solid dispersion composition comprising at least one HIV protease inhibitor and at least one pharmaceutically acceptable water-soluble polymer having a Tg of at least about 50°C and at least one pharmaceutically acceptable surfactant. Another PCT application WO/2006/095129 discloses similar formulations which do not exhibit any food effects.
However, unlike the teachings of the prior art, in the present case a stable bioavailable unit dosage form comprising a binary solid dispersion of at least one HIV protease inhibitor is provided, wherein the said solid dispersion is substantially free of surfactant.
Summary of the Invention
In one general aspect, it relates to a unit dosage form comprising
(a) a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and a pharmaceutically acceptable carrier, and
(b) a pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients.
In another general aspect, it relates to a unit dosage form comprising
(a) a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and a pharmaceutically acceptable carrier, and
(b) a pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients,
wherein the said solid dispersion is substantially free of surfactant.

In another general aspect, it relates to a unit dosage form comprising
(a) a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and pharmaceutically acceptable carrier, and
(b) a pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients,
wherein the said pharmaceutically acceptable carrier is a hydrophilic polymer.
In another general aspect, it relates to a unit dosage form comprising
(a) a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and a pharmaceutically acceptable carrier, and
(b) a pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients,
wherein the said unit dosage form comprises two HIV protease inhibitors in a ratio of about 1:15 to about 15:1 by weight.
In another general aspect, it relates to process of preparation of a unit dosage form comprising
(a) a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and a pharmaceutically acceptable carrier, and
(b) a pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients,
wherein the process comprises of the following steps:
1. at least one HIV protease inhibitor is blended with a pharmaceutically acceptable carrier and optionally, other pharmaceutically acceptable excipients in a suitable mixer;
2. the blend of step (1) is transferred in a suitable melt-extruder and molten at appropriate temperature to form a molten extrudate mass;
3. the molten extrudate mass of step (2) is cooled, and sized to obtain a solid dispersion;
4. pharmaceutically acceptable surfactant is blended with other pharmaceutically acceptable excipient(s) in a suitable blender;
5. the blend of step (4) is further blended with the solid dispersion of step (3) to obtain the final blend; and
6. the final blend of step (5) is processed into unit dosage form using appropriace tooling.
In another general aspect, it relates to process of preparation of a unit dosage form comprising
(a) a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and a pharmaceutical^ acceptable carrier, and
(b) a pharmaceutically acceptable surfactant and other pharmaceutical^ acceptable excipients,
wherein the process comprises of the following steps:
1. at least one HIV protease inhibitor is blended with a pharmaceutically acceptable carrier and optionally, other pharmaceutically acceptable excipients in a suitable mixer;
2. the blend of step (1) is transferred in a suitable melt-extruder and molten at appropriate temperature to form a molten extrudate mass;
3. the molten extrudate mass of step (2) is cooled, and sized to obtain a solid dispersion;
4. the dispersion of step (3) is blended with other pharmaceutically acceptable excipient(s) to obtain a homogeneous blend;
5. the blend of step (4) is granulated using a solution/dispersion of pharmaceutically acceptable surfactant in a granulating solvent to obtain granules;
6. the granules of step (5) are dried, sized and blended with other pharmaceutically acceptable excipient(s) to obtain the final blend; and
7. the final blend of step (6) is processed into unit dosage form using appropriate tooling.
Detailed Description of the Invention
The term "unit dosage form" as used herein encompasses all standard pharmaceutical unit dosage forms and may be in the form of coated or uncoated tablets, multilayer tablets, hard gelatin capsules, soft gelatin capsules, pills, and the like.
The unit dosage form as described herein comprises of a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and a pharmaceutically acceptable carrier. The term solid dispersion refers to a group of solid products consisting generally a pharmaceutically acceptable carrier matrix and at least one HIV protease inhibitor drug homogeneously dispersed therein. The matrix may be either crystalline or amorphous. The drug may be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles.
The recital of the term "consists essentially of renders that the said solid dispersion provides only for the inclusion of ingredients which would not materially affect the basic and novel characteristics of the product defined in the present case. For example, the solid dispersion composition is "substantially free of surfactant". The term "substantially free of surfactant" defines that no surfactant is present in the herein described solid dispersion, or if any present, it is not in an amount so as to provide an impact on the basic properties of the said dispersion. It also refers that if any surfactant is present it is in a non-intimate admixture with the HIV protease inhibitor drug(s).
The "HIV protease inhibitor" as described herein includes an effective amount of the compound, pharmaceutically acceptable salts, solvates, enantiomers, diastereomers or polymorphs thereof. The suitable "HIV protease inhibitor" for use herein, includes without limitation, ritonavir; lopinavir; indinavir; saquinavir; amprenavir; fosamprenavir; mozenavir; nelfinavir; atazanavir ; tipranavir; palinavir; darunavir; Ro033-4649; DMP-323; 5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenyl methyl hexanoyl-(L)-V-al-(L)-Phe-morpholin-4-ylamide; [1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)3-amino-2-hydroxy-4-butanoyl- 1,3-thiazolidine-4t-butylamide; 5 -isoquinolinoxyacetyl-beta-methylthio - Ala - (2S,3S)-3amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-tbutylamide;[1S-[1R-(R-),2S*])-N'[3-[[[(1,1-dimethyl ethyl) amino ] carbonyl ](- 2- methyl propyl)amino]-2hydroxy-1-(phenyl methyl) propyl] -2 -[(2-quinolinyl carbonyl) amino] -butanediamide; P-1946; BMS 186,318; SC-55389a; BILA 1096 BS; U-140690, or combinations thereof.
The term "effective amount" in the present invention refers to the HIV protease inhibitor in amounts suitable to elicit a particular biological or medicinal or clinical
response being sought by the person skilled in the art. The effective amount further refers to a "therapeutically effective amount" which results in the alleviation of the symptoms of the disease or condition being treated by the drug. The effective amount also refers to a "prophylactically effective amount" which results in prophylaxis of the symptoms of the disease or condition being prevented by the drug. The effective amount also refers to an amount that would provide enhanced therapeutic activity of another drug that is co-administered with it, in a way that if the later drug was administered alone, would not have achieved the desired response (e.g., unsatisfactory pharmacokinetic values for the drug and/or an unsatisfactory drug circulation level resulting in little or no efficacy).
In one embodiment, the "HIV protease inhibitor" is ritonavir.
The solid dispersion may comprise of more than one HIV protease inhibitor.
In one embodiment, a combination of lopinavir and ritonavir is used.
In one embodiment, a combination of atazanavir and ritonavir is used.
In one embodiment, a combination of amprenavir and ritonavir is used.
In one embodiment, a combination of fosamprenavir and ritonavir is used.
In one embodiment, a combination of saquinavir and ritonavir is used.
In one embodiment, a combination of tipranavir and ritonavir is used.
In one embodiment, a combination of darunavir and ritonavir is used.
In one embodiment, a combination of lopinavir, ritonavir and atazanavir is used.
The amount of HIV protease inhibitor may be in an amount ranging from 1mg to 1500mg. When two HIV protease inhibitors are present, it may be present in a ratio
of about 1:15 to about 15:1 by weight, particularly in a ratio of about 1:10 to about 10:1 by weight, more particularly in a ratio of about 1:4 to about 4:1 by weight.
The "pharmaceutically acceptable carrier" as described herein refers to both polymeric and non-polymeric carriers; hydrophilic and hydrophobic carriers; that are capable of dissolving and/or dispersing one or more of the HIV-protease inhibitor(s) and includes without limitation, homopolymers and copolymers of N-vinyl lactams, e.g. N-vinyl-2-pyrrolidone, crosslinked N-vinyl-2-pyrrolidone, copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (copovidone); cellulose esters and cellulose ethers, e.g. hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; cellulose phthalates or succinates; polyacrylates and polymethacrylates; polyacrylamides; vinyl acetate polymers; high molecular weight polyalkylene oxides such as polyethylene oxide; polyethylene glycols, cyclodextrin, oligo- and polysaccharides like xanthan gum; and the combinations thereof. In one embodiment, copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (copovidone) such as those which are available as PLASDONE® or KOLLIDON® from ISP and BASF respectively may be used as the pharmaceutically acceptable carrier. The amount of pharmaceutically acceptable carrier may vary from about 1% to about 99% by weight of the unit dosage form, more particularly from about 50% to about 85% by weight of the unit dosage form.
The solid dispersion composition may comprise of one or more of pharmaceutically acceptable excipients, for example, lubricants and/or glidants which includes without limitation, colloidal silica, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oils, wax and the combinations thereof.
The unit dosage form as described herein further comprise of pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients. The term "pharmaceutically acceptable surfactant" as described herein includes without limitation polyoxyethylene alkyl ethers, e.g. polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ethers; polyoxyethylene alkylaryl ethers, e.g. polyoxyethylene nonylphenyl ethers, polyoxyethylene octylphenyl ethers; polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate,
PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate ; sucrose fatty acid esters, e. g. sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate; or sorbitan fatty acid mono esters such as sorbitan monolaurate (Span 20), sorbitan monooleate, sorbitan monopalmitate (Span 40), or sorbitan stearate, polyoxyethylene castor oil derivates, e. g. polyoxyethyleneglycerol triricinoleate or (Cremophor® EL; BASF Corp.) or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor® RH 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60); or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, Poloxamer® 407 (BASF Wyandotte Corp.); Polyglycolized glycerides for example lauroyl macrogolglycerides (Gelucire® 44/14), stearoyl macrogolglycerides (Gelucire® 50/13); Labrasol®, Transcutol® (Gattefosse Canada Inc.); Vitamin E/TPGS: Tocopheryl propylene glycol 1000 succinate, sold by Eastman; Polyethylene glycol 15 hydroxystearate (Solutol® HS15 sold by BASF); or a mono fatty acid ester of polyoxyethylene (20) sorbitan, e. g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween®), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20) or mixtures of one or more thereof. In one embodiment, the pharmaceutically acceptable surfactant is sorbitan monolaurate. The amount of pharmaceutically acceptable surfactant may vary from about 1% to about 10% by weight of the unit dosage form.
One or more of other pharmaceutically acceptable excipients which includes the likes of fillers, disintegrants, glidants, lubricants and combinations thereof may be used in the unit dosage form as described herein.
Fillers may be selected from saccharides like lactose, dextrose, sucrose, fructose, maltose; sugars like mannitol, erythritol, sorbitol, xylitol and lactitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, kaolin, starch and starch derivatives like pregelatinized starch, partially pregelatinized starch; cellulose
ethers such as carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; carboxy vinyl polymers like carbomers; acrylates such as Eudragits; polyvinylpyrrolidone; xanthan gum, guar gum and other such materials routinely used in the art of solid dosage form manufacturing.
Disintegrants may be selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone, corn starch, potato starch, pregelatinized starch, low-substituted hydroxypropylcellulose, alginates, carboxymethyl starches, methacrylic acid divinylbenzene copolymer salts and microcrystalline cellulose.
Lubricants and/or glidants that may be used include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate, sodium suberate, vegetable oil, mineral oil, talc, colloidal silicon dioxide, corn starch and the like.
One or more of the solvent may be used to dissolve and/or disperse the pharmaceutically acceptable carrier; one or more of the HIV protease inhibitor(s), and/or the pharmaceutically acceptable solvent in a way that it does not create any stability issues and/or environmental hazards. Such solvents or the solutions/dispersions formed may further be used as granulating solvents. Such solvents include one or more of alcohols, e.g. isopropyl alcohol; aliphatic hydrocarbons, e.g. acetone and esters.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, lopinavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, lopinavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant;
wherein the said ritonavir and lopinavir is present in a ratio of 1:4 by weight.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, atazanavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, atazanavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant;
wherein the said ritonavir and atazanavir is present in a ratio of 1:3 by weight.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, amprenavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler(s), disintegrant(s), glidant(s) and lubricant(s).
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, amprenavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant; wherein the said ritonavir and amprenavir is present in a ratio of 1:6 by weight.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, fosamprenavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, fosamprenavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant;
wherein the said ritonavir and fosamprenavir is present in a ratio of 1:7 by weight.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, saquinavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, saquinavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant;
wherein the said ritonavir and saquinavir is present in a ratio of 1:10 by weight.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, tipranavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, tipranavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant;
wherein the said ritonavir and tipranavir is present in a ratio of 2:5 by weight.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, darunavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant filler, disintegrant, glidant and lubricant.
In one embodiment, a unit dosage form comprises of
(a) a solid dispersion composition which consists essentially of ritonavir, darunavir, pharmaceutically acceptable carrier, glidant and lubricant; and
(b) a pharmaceutically acceptable surfactant, filler, disintegrant, glidant and lubricant;
wherein the said ritonavir and darunavir is present in a ratio of 1:6 by weight.
In one aspect of the above embodiments, the said solid dispersion is substantially free of surfactant.
In one aspect of the above embodiments, the pharmaceutically acceptable carrier is a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate (Copovidone).
The unit dosage form may be prepared by employing conventional techniques known in the art, comprising of dry granulation, aqueous and non-aqueous granulation, fluidized bed granulation, direct compression and roller compactation,
melt granulation, melt extrusion, pelletization, solvent evaporation and the combinations thereof.
In one embodiment the unit dosage form is prepared by the following steps:
a) an effective amount of HIV protease inhibitor is blended with a pharmaceutically acceptable carrier and glidant(s) and lubricant(s) in a suitable mixer;
b) the blend of step (1) is transferred in a suitable melt-extruder and molten at appropriate temperature to obtain a molten extrudate mass;
c) the molten extrudate mass of step (2) is cooled and sized to obtain a solid dispersion;
d) the pharmaceutically acceptable surfactant, is blended with filler, disintegrant, glidant and lubricant in a suitable blender;
e) the blend of step (4) is further blended with the solid dispersion of step (3) to obtain the final blend; and
f) the final blend of step (5) is processed into unit dosage form using appropriate tooling.
In one embodiment the unit dosage form is prepared by the following steps:
1. effective amounts of ritonavir and another HIV protease inhibitor is blended with a pharmaceutically acceptable carrier, glidant(s) and lubricant(s) in a suitable mixer;
2. the blend of step (1) is transferred in a suitable melt-extruder and molten at appropriate temperature to obtain a molten extrudate mass;
3. the molten extrudate mass of step (2) is cooled and sized to obtain a solid dispersion;
4. the pharmaceutically acceptable surfactant, is blended with filler, disintegrant, glidant and lubricant in a suitable blender;
5. the blend of step (4) is further blended with the solid dispersion of step (3) to obtain the final blend; and
6. the final blend of step (5) is processed into unit dosage form using appropriate tooling.
In one embodiment the unit dosage form is prepared by the following steps:
1. an effective amount of HIV protease inhibitor is blended with a pharmaceutically acceptable carrier and glidant(s) and lubricant(s) in a suitable mixer;
2. the blend of step (1) is transferred in a suitable melt-extruder and molten at appropriate temperature to obtain a molten extrudate mass;
3. the molten extrudate mass of step (2) is cooled and sized to obtain a solid dispersion;
4. the dispersion of step (3) is blended with filler(s) to obtain a homogeneous blend;
5. the blend of step (4) is granulated using a solution of the pharmaceutically acceptable surfactant(s) in a granulating solvent, to obtain granules;
6. the granules of step (5) are dried, sized and blended disintegrant(s), filler(s), glidant(s) and lubricant(s) to obtain the final blend; and
7. the final blend of step (6) is processed into unit dosage form using appropriate tooling.
In one embodiment the unit dosage form is prepared by the following steps:
1. effective amounts of ritonavir and another HIV protease inhibitor is blended with a pharmaceutically acceptable carrier, glidant(s) and lubricant(s) in a suitable mixer;
2. the blend of step (1) is transferred in a suitable melt-extruder and molten at appropriate temperature to obtain a molten extrudate mass;
3. the molten extrudate mass of step (2) is cooled and sized to obtain a solid dispersion;
4. the dispersion of step (3) is blended with filler(s) to obtain a homogeneous blend;
5. the blend of step (4) is granulated using a solution of the pharmaceutically acceptable surfactant(s) in a granulating solvent, to obtain granules;
6. the granules of step (5) are dried, sized and blended disintegrant(s), filler(s), glidant(s) and lubricant(s) to obtain the final blend; and
7. the final blend of step (6) is processed into unit dosage form using appropriate tooling.
The unit dosage form may further comprise of a non-functional coating. Proprietary non-functional coating materials, such as Opaspray and Opadry, obtainable from Colorcon Ltd., UK, may be used.
From the above it is apparent that various modifications and combinations of the formulations detailed in the text may be made without departing from the spirit and scope of the invention. The invention as described herein may be illustrated by the following examples but is not to be construed to be limiting by them. Examples 1-4:

(Table Removed)
Procedure for preparation of Examples 1. 2 and 4:
Part (a):
The effective amounts of ritonavir and lopinavir was blended with copovidone and
colloidal silicon dioxide in a suitable mixer. The blend so obtained was melted and
The unit dosage form may further comprise of a non-functional coating. Proprietary non-functional coating materials, such as Opaspray and Opadry, obtainable from Colorcon Ltd., UK, may be used.
From the above it is apparent that various modifications and combinations of the formulations detailed in the text may be made without departing from the spirit and scope of the invention. The invention as described herein may be illustrated by the following examples but is not to be construed to be limiting by them. Examples 1-4:

(Table Removed)
Procedure for preparation of Examples 1. 2 and 4:
Part (a):
The effective amounts of ritonavir and lopinavir was blended with copovidone and
colloidal silicon dioxide in a suitable mixer. The blend so obtained was melted and
the molten mass was subjected to extrusion under a temperature up to about 130°C in a suitable Melt Extruder. The molten extrudate mass was cooled and suitably sized.
Part (b):
Part (a) was blended with lactose and the resulting blend was granulated using a solution of the pharmaceutically acceptable surfactant (sorbitan monolaurate in Example 1, Cremophor® RH 40 in Example 2, and a combination of Cremophor® RH 40 and Gelucire® 50/13 in Example 4) in isopropyl alcohol. The granules so obtained were dried and sized.
Part (c):
The excipients of part (c) were blended to form a homogeneous blend with Part (b) and compressed using appropriate tooling. The tablets so formed were finally coated using an aqueous dispersion of opadry.
Procedure for preparation of Example 3:
Part (a):
The effective amounts of ritonavir and lopinavir was blended with copovidone and
colloidal silicon dioxide in a suitable mixer. The blend so obtained was melted and
the molten mass was subjected to extrusion under a temperature up to about 130°C
in a suitable Melt Extruder. The molten extrudate mass was cooled and suitably
sized.
Part (bV.
The excipients of part (b) were blended to form a homogeneous blend.
Part (c):
The excipients of part (c) were blended to form a homogeneous blend.
Parts (a), (b) and (c) were admixed and compressed using appropriate tooling. The tablets so formed were finally coated using an aqueous dispersion of opadry.

WE CLAIM:
1. A unit dosage form comprising (a) a solid dispersion composition which consists essentially of at least one HIV protease inhibitor, and pharmaceutically acceptable carrier, and (b) a pharmaceutically acceptable surfactant and other pharmaceutically acceptable excipients.
2. The unit dosage form, according to claim 1, wherein the solid dispersion is substantially free of surfactant.
3. The unit dosage form, according to claim 1, wherein the pharmaceutically acceptable carrier is a hydrophilic polymer.
4. The unit dosage form, according to claims 1 and 3, wherein the pharmaceutically acceptable carrier is copovidone.
5. The unit dosage form, according to claim 1, wherein the solid dispersion comprises of two HIV protease inhibitors.
6. The unit dosage form, according to claim 5, wherein the two HIV protease inhibitors are present in a ratio of about 1:15 to about 15:1 by weight.
7. The unit dosage form, according to claim 1, wherein the HIV protease inhibitor is selected from ritonavir alone or in combination with one of the other HIV protease inhibitors selected from lopinavir, atazanavir, amprenavir, fosamprenavir, saquinavir, tipranavir and darunavir.
8. A process of preparation of the unit dosage form according to claim 1, wherein the process comprises of comprises of the following steps:
a) at least one HIV protease inhibitor is blended with a pharmaceutically acceptable carrier and other pharmaceutically acceptable excipients in a suitable mixer;
b) the blend of step (a) is transferred in a suitable melt-extruder and molten at appropriate temperature to form a molten extrudate mass;
c) the molten extrudate mass of step (b) is cooled and sized to obtain a solid dispersion;
d) pharmaceutically acceptable surfactant is blended with other pharmaceutically acceptable excipient(s) in a suitable blender;
e) the blend of step (d) is further blended with the solid dispersion of step (c) to obtain the final blend; and
f) the final blend of step (e) is processed into unit dosage form using appropriate tooling.
9. The process of preparation of the unit dosage form, according to claim 1,
wherein the process comprises of the following steps:
a) at least one HIV protease inhibitor is blended with a pharmaceutically acceptable carrier and optionally, other pharmaceutically acceptable excipients in a suitable mixer;
b) the blend of step (a) is transferred in a suitable melt-extruder and molten at appropriate temperature to form a molten extrudate mass;
c) the molten extrudate mass of step (b) is cooled, and sized to obtain a solid dispersion;
d) the dispersion of step (c) is blended with other pharmaceutically acceptable excipient(s) to obtain a homogeneous blend;
e) the blend of step (d) is granulated using a solution/dispersion of pharmaceutically acceptable surfactant in a granulating solvent to obtain granules;
f) the granules of step (e) are dried and blended with other pharmaceutically acceptable excipient(s) to obtain the final blend; and
g) the final blend of step (6) is processed into unit dosage form using appropriate tooling.
10. A unit dosage form comprising (a) a solid dispersion composition which consists
essentially of at least one HIV protease inhibitor, and pharmaceutically
acceptable carrier, and (b) a pharmaceutically acceptable surfactant and other
pharmaceutically acceptable excipients and process of preparation thereof, substantially as described and illustrated by examples herein.