FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Anti - Retroviral Combination"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

Field of Invention:
The present invention relates to a novel antiretroviral combination in particular, to a pharmaceutically stable composition and a process for manufacturing the same thereof.
Background and Prior Art:
The human immunodeficiency virus (HIV) is a pathogenic retrovirus and the causative agent of acquired immune deficiency syndrome (AIDS) and related disorders (Barre-Sinossi, F. et al; 1983, Science 220:868-870; Gallo, R. et al., 1984, Science 224:500-503). There are at least two distinct types of HIV-1 (Barre-Sinossi, F. et al; 1983, Science 220:868-870; Gallo, R. et al., 1984, Science 224:500-503) and HIV-2 (Clavel. F. et al., 1986, Science 223:343-346; Guyader, M. et al., 1987, Nature 326:662-669). Further, a large amount of genetic heterogeneity exists within populations of each of these types. Infection of human CD-4+ T-lymphocytes with an HIV virus leads to depletion of the cell type and eventually to opportunistic infections, neurological dysfunctions, neoplastic growth, and untimely death.
HIV is a member of the lentivirus family of retroviruses (Teich, N. et al., 1984; RNA Tumor Viruses, Weiss, R. et al., eds., CSH-press, pp. 949-956). Retroviruses are small enveloped viruses that contain a diploid, single-stranded RNA genome, and replicate via a DNA intermediate produced by a virally-encoded reverse transcriptase, an RNA-dependent DNA polymerase (Varmus, H., 1988, Science 240:1427-1439). Other retroviruses include, for example, oncogenic viruses such as human T-cell leukemia viruses (HTLV-1,-II,-III), and feline leukemiavirus. The HIV viral particle consists of a viral core, made up of proteins designated p24 and pi 8. The viral core contains the viral RNA genome and those enzymes required for replicative events. Myristylated gag protein forms an outer viral shell around the viral core, which is, in turn, surrounded by a lipid membrane envelope derived from the infected cell membrane.


The HIV envelope surface glycoproteins are synthesized as a single 160 kD precursor protein which is cleaved by a cellular protease during viral budding into two glycoproteins, gp41 and gpl20. gp41 is a transmembrane protein and gpl20 is an extracellular protein which remains noncovalently associated with gp41, possibly in a trimeric or multimeric form (Hammerwskjold, M. and Rekosh, D., 1989, Biochem. Biophys. Acta 989:269-280).
Attention is also being given to the development of vaccines for the treatment of HIV infection. The HIV-1 envelope proteins (gpl60, gpl20, gp41) have been shown to be the major antigens for anti-HIV antibodies present in AIDS patients (Barin et al., 1985, Science 228:1094-1096). Thus far, these proteins seem to be the most promising candidates to act as antigens for anti-HIV development. To this end, several groups have begun to use various portions of gpl60, gpl20, and/or gp41 as immunogenic targets for the host immune systems. See for example, Ivanoff, L. et al., U.S. Pat. No. 5,141,867; Saith, G. et al., WO 92/22, 654; Schafferman, A., WO 91/09,872; Formoso, C. et al., WO 90/07,119. Clinical results concerning these candidate vaccines, however, still remain far in the future.
U. S. Pat. No. 5,541,206 and EP 0674513 Bl discloses the synthesis of Ritonavir.
U. S. Patent No. 5,541,206 discloses the use of ritonavir to inhibit an HIV infection.
U. S. Patent No. 5,674,882 discloses the use of ritonavir in combination with one or more HIV protease inhibitors to inhibit an HIV infection.
U. S. Patent 6,037, 157 and WO 97/01349 discloses the use of ritonavir to enhance the pharmacokinetics of compounds metabolized by cytpchrome P450 monooxygenase.
U. S. Patent No. 5,484,801 discloses a liquid dosage form of ritonavir for oral administration.
W095/07696 discloses an encapsulated solid or semi-solid dosage form for ritonavir.


WO 9967254 discloses the synthesis of darunavir and the manner in which it may be used to treat HIV infection.
WO 9967254 discloses the dosage forms suitable for the oral administration of darunavir.
US 20070208009 discloses a combination comprising tenofovir, ritonavir and darunavir for treatment or prevention of HIV infections.
None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Some drugs and, in particular, some HIV protease inhibitors are metabolized by cytochrome P450 monooxygenase, leading to unfavorable pharmacokinetics and hence require more frequent and higher doses, although administration of such drugs with an agent that inhibits metabolism by cytochrome P450 monooxygenase will improve the pharmacokinetics (i.e., increase half-life, increase the time to peak plasma concentration, increase blood levels) of the drug.
Moreover, combination therapy is potentially problematic given the high toxicity of most anti-HIV therapeutics and their low level of effectiveness. Thus, there is a need of a combination therapy which is effective yet non-toxic for treatment-naive and treatment experienced patients.
Surprisingly, the present inventors have found that a selective combination of darunavir and ritonavir with pharmaceutically acceptable excipients and using simpler manufacturing processes achieves the desired formulation.
Further, the present inventors have also found that with selective combination of darunavir and ritonavir with pharmaceutically acceptable excipients potentially


increases the treatment potency particularly against drug-resistant HIV-1 strains, without significantly raising the risk for toxicity in treatment-naive and treatment-experienced patients.
Object of the invention:
The object of the present invention is to provide an oral composition comprising a novel antiretroviral combination which may be administered simultaneously; separately, or sequentially.
Another object of the present invention is to provide an oral composition comprising a novel antiretroviral combination with superior efficacy across the range of treatment-experienced and naive patients.
Another object of the present invention is to provide an oral composition comprising a novel antiretroviral combination which is highly potent against wild-type and multidrug-resistant HIV strains.
Still another object of the present invention is to provide an oral antiretroviral composition with ease of manufacture.
Summary of the invention:
According to one aspect of the present invention there is provided a pharmaceutical combination comprising one or more protease inhibiting drug/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more cytochrome P450 inhibitor/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs.


According to another aspect of the present invention there is provided an oral antiretroviral composition comprising one or more protease inhibiting drug/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more cytochrome P450 inhibitor/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more pharmaceutically acceptable excipients in a single dose regimen.
According to another aspect of the present invention there is provided a process of manufacturing the oral antiretroviral composition comprising one or more protease inhibiting drug/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more cytochrome P450 inhibitor/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more pharmaceutically acceptable excipients.
According to yet another aspect of the present invention there is provided an pharmaceutical combination comprising one or more protease inhibiting drug/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more cytochrome P450 inhibitor/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more pharmaceutically acceptable excipients for use in treatment against HIV/ AIDS.


According to still another aspect of the present invention there is provided an pharmaceutical combination comprising one or more protease inhibiting drug/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and one or more cytochrome P450 inhibitor/s or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof and one or more pharmaceutically acceptable excipients for use in the manufacture of a medicament used in the treatment against HIV/ AIDS.
Detailed description of the invention;
As discussed above and hereinafter, the inventors have surprisingly found that coadminstration of low dose of cytochrome P450 inhibitor (e.g. ritonavir) with protease inhibitor e.g. darunavir, increased the systemic exposure by increase in plasma concentration of the protease inhibitor thus avoiding the incompliant practice of higher dosing to the patient and increasing the treatment potency.
It was observed that co-administration of combination achieved reduction of the total fasting triglyceride and cholesterol levels, and the therapy doesn't require any additional lipid lowering agents as required in case of known combination for treatment against HIV/ AIDS.
In a preferred embodiment of the present invention, there is provided a composition comprising said combination for inhibition, treatment or prophylaxis of an HIV infection or AIDS (acquired immune deficiency syndrome) in humans by co administering the ritonavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs with darunavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers,


pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs.
It will be well appreciated that the combination of protease inhibitor (E.g. Darunavir) and cytochrome P450 inhibitor (E.g. ritonavir, ketoconazole, cimetidine, bergamottin) or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs may further comprise one or more pharmaceutically acceptable excipients yielding the desired Anti HIV/AIDS oral composition.
Suitably, the formulation according to the invention are presented in solid dosage form, conveniently in unit dosage form, and include dosage form suitable for oral and buccal administration.
Solid dosage forms according to the present invention are preferably in the form of tablets but other conventional dosages such as powders, pellets, capsules and sachets may fall within the scope of the invention.
A preferred formulation according to the invention is in tablet dosage form wherein the drug combination viz. darunavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and ritonavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and further one or more pharmaceutically acceptable excipients.
It is further well known in the art that a tablet formulation is the preferred solid dosage form due to its greater stability, less risk of chemical interaction between different medicaments, smaller bulk, accurate dosage, and ease of production.


According to the preferred embodiment, the formulation may be administered simultaneously, separately or sequentially in a single unit dosage form wherein both the drugs and excipients are present in a single layer entity (such as tablet).
According to the preferred embodiment, the combination may be administered by oral, rectal, intravenous, subcutaneous or intramuscular routes. For first line therapy of HIV infection, simultaneous administration employing a unitary pharmaceutical formulation is preferred.
For these purposes, the compositions comprising a combination of the present invention, whether co-formulated in a single formulation or formulated for simultaneous, separate or sequential use, may be administered orally (including suspensions, capsules, tablets, sachets, solutions, suspensions, emulsions, parenterally (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray (including nasal sprays), or rectally (including suppositories) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
According to the preferred embodiment, the present invention also relates to a pharmaceutical composition in a form adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and as active ingredients an effective amount of a combination according to the present invention. As appropriate special adapted compositions there may be cited all compositions usually employed for being applied to the vagina, rectum, mouth and skin such as for example gels, jellies, creams, ointments, films, sponges, foams, intravaginal rings, cervical caps, suppositories for rectal or vaginal application, vaginal or rectal or buccal tablets, mouthwashes. To prepare such pharmaceutical compositions, an effective amount of each of the particular compounds of the combination as the active ingredients is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of administration. In order to increase the residence time of such pharmaceutical composition at the site of


administration, it may be advantageous to include in the composition a bioadhesive, in particular a bioadhesive polymer. A bioadhesive may be defined as a material that adheres to a live biological surface such as for example a mucus membrane or skin tissue. Preferably, the site of application is the vagina, rectum, mouth or skin, most preferred is the vagina.
According to the preferred embodiment, the formulation may be administered as a bilayer tablet wherein each layer separately contains a drug and pharmaceutically acceptable excipients which are then compressed to give a bilayer tablet.
According to yet another embodiment, the formulation may be seal coated. According to yet another embodiment, the formulation may be seal coated and further film coated.
It will be understood, however, that specific dose level and frequency of dosage of the combination according to the invention for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
According to the preferred embodiment, the combination, according to the invention, will be administered in the following daily dosages; darunavir about 300 to 800 mg, preferably 300 to 600mg or 400 to 800mg and ritonavir ranging about 50 to l00mg.
The present invention may be manufactured through various techniques or processes known in the art which includes, but not limited to direct compression, melt granulation, melt extrusion, spray drying and solution evaporation.
According to a preferred embodiment, the invention may be processed through hot melt extrusion technique which involves hot melt extrusion of one or more drug(s) with one or more polymer(s), wherein the polymer comprise of one or more water


insoluble polymer(s) and/or a combination of one or more water soluble polymer(s) and one or more water insoluble polymer(s) wherein the drug : polymer ratio ranges from 1:1 to 1:6.
In general terms, the process of hot melt extrusion is carried out in the conventional extruders as known to a person skilled in the art.
The melt-extrusion process comprises the steps of preparing a homogeneous melt of one or more drugs, the polymer and the excipients, and cooling the melt until it solidifies. "Melting" means a transition into a liquid or rubbery state in which it is possible for one component to get embedded homogeneously in the other.
Typically, one component will melt and the other components will dissolve in the melt thus forming a solution. Melting usually involves heating above the softening point of the polymer. The preparation of the melt can take place in a variety of ways. The mixing of the components can take place before, during or after the formation of the melt. For example, the components can be mixed first and then melt extruded or be simultaneously mixed and melt extruded. Usually, the melt is homogenized in order to disperse the active ingredients efficiently. Also, it may be convenient first to melt the polymer and then to mix in and homogenize the active ingredients.
Usually, the melt temperature is in the range of about 70°C to about 200 ° C, preferably from about 80°C to about 180°C, most preferred from about 90° C to about 150° C.
Suitable extruders include single screw extruders, intermeshing screw extruders or else multiscrew extruders, preferably twin screw extruders, which can be co - rotating or counter - rotating and, optionally, be equipped with kneading disks. It will be appreciated that the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used. The extrudates can be in the form of beads, granulates, tube, strand or cylinder and this can be further processed into any desired shape.


The term 'extrudates' as used herein refers to solid product solutions, solid dispersions and glass solutions of one or more drugs with one or more polymers and optionally pharmaceutically acceptable excipients.
According to a preferred embodiment, a powder blend of the one or more active drug(s) and polymers and optionally pharmaceutical excipients are transferred by a rotating screw of a single screw extruder through the heated barrel of an extruder whereby the powder blend melts and molten solution product is collected on a conveyor where it is allowed to cool to form an extrudate. Shaping of the extrudate can be conveniently be carried out by a calender with two counter - rotating rollers with mutually matching depressions on their surface.
A broad range of tablet forms can be attained by using rollers with different forms of depressions. Alternatively, the extrudate is cut into pieces after solidification and can be further processed into suitable dosage forms. More preferably the extrudates thus finally obtained from the above process are then milled and ground to granules by the means known to a person skilled in the art.
Further, hot melt extrusion is a fast, continuous, single pot manufacturing process without requirement of further drying or discontinuous process steps; it provides short thermal exposure of active allows processing of heat sensitive actives; process temperatures can be reduced by addition of plasticizers; comparatively lower investment for equipment as against other processes. The entire process is anhydrous and the intense mixing and agitation of the powder blend that occur during processing contribute to a very homogenous extrudate(s).
In one aspect, the preferred embodiment in accordance with the present invention may comprise one or more protease inhibiting drug(s), one or more cytochrome P450 inhibitor/s and one or more water insoluble polymers which are melt extruded by the process as described herein, where a powder blend of protease inhibiting drug most preferably darunavir or its pharmaceutically acceptable salts, pharmaceutical ly acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically


acceptable prodrugs & cytochrome P450 inhibitor, more preferably ritonavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and polymer or a combination thereof and other excipients which may comprise suitable bulking agents and flavourants. These are so processed to form a powder blend which is transferred through the heated barrel of the extruder, whereby the powder blend melts and molten solution product is collected on a conveyor whereby it is allowed to cool and form an extrudate.
Alternatively, the extrudate is cut into pieces after solidification and can be further processed into suitable dosage forms. More preferably the extrudates thus finally obtained from the above process are then milled and ground to granules by the means known to a person skilled in the art.
In another aspect, the preferred embodiment in accordance with the present invention may comprise one or more protease inhibiting drug/s, one or more cytochrome P450 inhibitor/s and a combination of one or more water insoluble polymer and one or more water soluble polymer which are melt extruded by the process as described herein, where a powder blend of protease inhibitor drugs most preferably darunavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs & cytochrome P450 inhibitor, more preferably ritonavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and a combination of water soluble polymer(s) & water insoluble polymer(s) and other excipients which may comprise suitable bulking agents, plasticizer and flavourants.
These are so processed to form a powder blend which is transferred through the heated barrel of the extruder, whereby the powder blend melts and molten solution


product is collected on a conveyor whereby it is allowed to cool and form an extrudate.
Alternatively, the extrudate is cut into pieces after solidification and can be further processed into suitable dosage forms. More preferably the extrudates thus finally obtained from the above process are then milled and ground to granules by the means known to a person skilled in the art.
The water soluble polymers that can be used, according to the present invention, comprises of homopolymers and co-polymers of N-vinyl lactams, especially homopolymers and co-polymers of N-vinyl pyrrolidone e.g. polyvinylpyrrolidone (PVP), co-polymers of PVP and vinyl acetate, co-polymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, cellulose esters and cellulose ethers, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide and propylene oxide. It is present in the range wherein the ratio of drug to polymer is 1:1 to 1:6.
The water insoluble polymer that can be used, according to the present invention, comprises of acrylic copolymers e.g. Eudragit El 00 or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze (Colorcon Co.); polyvinylacetate, for example, Kollicoat SR 30D (BASF Co.); cellulose derivatives such as ethylcellulose, cellulose acetate e.g. Surelease (Colorcon Co.), Aquacoat ECD and Aquacoat CPD (FMC Co.). Most preferable being Eudragit El 00 and is present in the range wherein the ratio of drug to polymer is 1:1 to 1:6.
Plasticizers can be incorporated depending on the polymer and the process requirement.These, advantageously, when used in the hot melt extrusion process decrease the glass transition temperature of the polymer. Plasticizers also help in reducing the viscosity of the polymer melt and thereby allow for lower processing temperature and extruder torque during hot melt extrusion. Examples of plasticizers which can be used in the present invention, include, but are not limited to, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; citrate ester type plasticizers like


triethyl citrate, citrate phthalate; propylene glycol; glycerin; low molecular weight polyethylene glycol; triacetin; dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate. It is present in an amount ranging from 0% to 10% to the weight of polymer.
According to a preferred embodiment, the present invention may comprise suitable disintegrating agents which includes, but not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, maize starch and modified starches, calcium silicates, low substituted hydroxy- propylcellulose.
According to a preferred embodiment, the present invention may further comprise suitable bulking agents which includes, but are not limited to, saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol lactitol, and other bulking agents such as powdered cellulose, microcrystalline cellulose, purified sugar and derivatives thereof. The formulation may incorporate one or more of the above bulking agents, preferably, lactose & microcrystalline cellulose forms the bulking agent.
Accordingly, the present invention may further incorporate suitable lubricants and glidants which may include, but are not limited to, stearic acid and its derivatives or esters like sodium stearate, magnesium stearate and calcium stearate and the corresponding esters such as sodium stearyl fumarate; talc and colloidal silicon dioxide respectively.
According to another embodiment, the present invention may further involve one or more manufacturing process to obtain a single unitary dosage form i.e. wherein the or each drug is processed by the techniques as discussed above and finally compacted to yield a single dosage form. Preferably, darunavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs in combination with one or more excipients & ritonavir or its pharmaceutically acceptable salts, pharmaceutically acceptable


solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs in combination with one or more excipients may be processed with the techniques as discussed above separately and may be combined to form single unitary dosage form. Preferably, the darunavir blend is mixed with ritonavir blend and may be compressed into a single - layered tablet. Alternatively, the darunavir blend may be compacted and compressed into a tablet and ritonavir blend may be compacted and compressed into tablet and finally each individual layer may be compressed into a bilayer tablet. More preferably, the tablet may be seal coated. Most preferably, the tablet may be seal coated and finally film coated. The formulation can be coated with Ready colour mix systems (such as Opadry colour mix systems).
According to yet another embodiment, the present invention may be formulated wherein the or each drug, preferably, darunavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more excipients may be processed through wet granulation, direct compression and the like as mentioned above and ritonavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs and one or more excipients may be processed through melt granulation, melt extrusion and the like as mentioned above.
Preferably, darunavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs are mixed with intragranular excipients which includes, but not limited to, diluents, disintegrants and granulated with water, sieved, sifted and lubricated and dried. Alternatively, the dried granules may be compressed into tablets. Preferably, ritonavir or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically


acceptable prodrugs and one or more excipients which includes, but are not limited to, polymers (i.e. either water soluble or water insoluble or mixture thereof), one or more plasticizer, one or more disintegrants, one or more lubricants and glidants are extruded through hot melt extrusion technique wherein extrudates are obtained which can be molded into desired shapes that can be filled in sachets or can be granulated. Alternatively, the granules may be compressed into tablets.
According to a preferred embodiment, the granules (comprising the individual actives) as obtained above may be further mixed, sieved, sifted and compressed into a single tablet or may be filled into capsules or sachets or the granules may be administered directly. Alternatively, the tablet may be seal coated and finally film coated.
According to yet another embodiment, the or each granules (comprising the individual actives) as obtained above may be individually compressed into two tablets and finally compacted and compressed into a bilayer tablet. Alternatively, the tablet may be seal coated and finally film coated.
The formulation can be coated with Ready colour mix systems (such as Opadry colour mix systems).
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the present invention.


Formula:

Sr. No. Ingredients Qty/Tab (mg)
Drug Premix
1 Ritonavir 100.00
2 Colloidal silicon dioxide 5.00
Polymer Premix
3 Kollidon VA64 400.00
4 Span 20 40.00
Blending
5 Crosspovidone NF 50.00
6 Colloidal silicon dioxide 5.00
7 Microcrystalline cellulose 50.00
Lubrication 5.00
8 Sodium stearyl fumarate 10.00
Total 650.00
Darunavir Layer
10 Darunavir 300.00
11 Crosspovidone 10.00
Binder
12 PVP K 30 15.00
13 Purified water q.s.
Blending and Lubrication
14 Crosspovidone 10.00
15 Yellow Iron oxide 0.50
16 Microcrystalline cellulose 254.00
17 Colloidal silicon dioxide 4.00
18 Magnesium stearate 6.00
Total 600.00
Seal coating


19 Opadry AMB OY-B-29000 translucent 5.00
20 Purified water q.s.
Film coating
21 Opadry 04F 52201 Yellow 15.00
22 Purified water q.s.
Total 1270 mg
Process:
(1) Darunavir was mixed with pre-sieved and pre-sifted amounts of crospovidone,
yellow iron oxide, polyvinyl pyrrolidone K30, microcrystalline cellulose, colloidal
silicon dioxide, magnesium stearate and granulated with purified water.
(2) Ritonavir with small amount of colloidal silicon dioxide was sifted & mixed together with Kollidon VA 64 and Span 20 in a mixer.
(3) The contents obtained in (2) were mixed and finally subjected to hot melt extrusion (HME) wherein the melting temperature for the extrusion process ranges from 70 to 200° C, with the molten mass thus obtained was collected on a conveyor where it was cooled to form extrudates and these extrudates on further milling were converted into granules which was followed by addition of crosspovidone, colloidal silicon dioxide and microcrystalline cellulose and further lubricated with sodium stearyl monostearate.
(4) The granules obtained in (1) and (3) were compressed together to form a bilayer
tablet which was then seal coated and finally film coated.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.


It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a polymer" includes a single polymer as well as two or more different polymers; reference to a "plasticizer" refers to a single plasticizer or to combinations of two or more plasticizer, and the like.