DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“PHARMACEUTICAL COMPOSITION”

2. APPLICANT:

(a) NAME: CIPLA LIMITED

(b)NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: Cipla House, Peninsula Business Park, Ganpatrao Kadam
Marg, Lower Parel, Mumbai – 400013, Maharashtra. India.

3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION:

The present invention relates to a pharmaceutical composition comprising an integrase inhibitor, and more particularly, relates to a pharmaceutical composition comprising dolutegravir, a process for preparing such pharmaceutical composition, and its use in the treatment of HIV infections.

BACKGROUND AND PRIOR ART:

One of the major obstacles to the development of highly potent pharmaceutical formulations is the poor water solubility of many drugs. Approximately 40% of potential drugs identified by pharmaceutical companies are poorly soluble in water, which greatly hinders their clinical use. Low water solubility limits the bioavailability and absorption of these agents.

Dolutegravir has the chemical name (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3] oxazine-9-carboxamide, and is reported to have the following chemical structure.

Dolutegravir is an orally active integrase inhibitor, and has been approved for the treatment of HIV infections.

The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS"), a disease characterized by the destruction of the immune system, particularly of CD4 T-cells with susceptibility to opportunistic infections. In nearly all cases where individuals receive no treatment for HIV infection, the proliferation of the virus gives rise to AIDS. As of early 1999, an estimated 33.4 million people are infected with HIV worldwide. Furthermore, in 2009 approximately 50,000 people were newly infected with HIV in the United States [Prejean J, Song R, Hernandez A, et al. Estimated HIV incidence in the United States, 2006–2009. PLoS ONE 2011; 6(8):e17502]. It has also been observed that the annual rate of new infection with HIV in the entire human population has not declined. Despite this fact, the rate of death due to AIDS has begun to drop in some nations primarily through the recent use of combination drug therapies against HIV infection.

The means by which such therapies counter HIV infection is best understood with reference to the biological mechanisms of the HIV life cycle. HIV is a member of a class of infectious agents known as retroviruses. The infectious form of HIV, a virion, is a particle that consists of a viral genome composed of RNA that is surrounded by proteins encoded by the genome. Infection occurs when an HIV virion enters a susceptible host cell, such as a T lymphocyte within the bloodstream. At this point, one of the viral proteins that comprise the virion, reverse transcriptase, synthesizes a double-stranded DNA copy of the HIV RNA genome. The resulting HIV DNA enters the cell nucleus as part of a stable complex with other virion proteins. This complex contains all the necessary molecular apparatus for integration wherein the HIV DNA is covalently inserted into the host cell's genomic DNA which is absolutely required for prolific HIV infection. It is only after integration that the HIV DNA can serve as the template for the production of HIV proteins and RNA that will comprise progeny virions. Among these viral proteins is the HIV protease, the activity of which is necessary for proper formation of new virions. This process, from viral entry to new virion production, is termed viral replication. Upon release from an infected host cell, the newly produced virions are capable of further infecting uninfected host cells. It is through successive rounds of HIV replication and productive host cell infection that HIV disease spreads throughout numerous host cells and ultimately progresses to AIDS.

Dolutegravir is a HIV-1 integrase strand transfer inhibitor which inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid integration which is essential for the HIV replication cycle.

Dolutegravir is commercially available as conventional tablet (TIVICAY®) for oral administration. TIVICAY® is available as a tablet containing 50 mg of dolutegravir per tablet.

Dolutegravir exhibits very slight water solubility. According to the Bio-pharmaceutics Classification System (BCS), it has been classified as a Class II drug, implying that it is a poorly soluble, and a highly permeable drug. The oral bioavailability of this class of drugs is generally limited during the dissolution phenomenon when administered in the final dosage form.

Further, the bioavailability of dolutegravir depends upon the meal content. It has been observed that administration of low, moderate, and high fat meals exhibit increased AUC(0-8) by 33%, 41%, and 66% respectively, increased Cmax by 46%, 52%, and 67% respectively and prolonged Tmax to 3, 4, and 5 hours respectively from 2 hours under fasted conditions.

Dolutegravir has been first disclosed specifically in EP1874117 and its use in the treatment of HIV infections has also been disclosed.

WO2011094150 discloses a combination of dolutegravir with other therapeutic agents such as abacavir, efavirenz, and lopinavir.

The prior art discloses the use of dolutegravir for the treatment of HIV as well as is combinations with few antiretroviral agents. However, problems that are associated with the solubility and bioavailability of dolutegravir are yet to be addressed to yield the best bioavailability and a better ADME profile.

Generally, several strategies and formulations are known and have been employed to overcome these limitations of solubility and bioavailability of drugs that are associated with food. Food effect exhibited by the drug is also a limiting factor which has to be addressed to some extent.

Although strategies such as complexing drugs with cyclodextrins, conjugation to dendrimers, salt formation of ionizable drugs and the use of co-solvents have been shown to improve drug solubility, solubilization methods that can improve the absorption of the drug are still highly desirable.

Hence, there is a need for a dosage form which would exhibit acceptable dissolution and absorption which leads to better bioavailability.

OBJECT OF THE INVENTION:

The object of the present invention is to provide a pharmaceutical composition comprising dolutegravir and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a pharmaceutical composition comprising nanosized dolutegravir.

Another object of the present invention is to provide a pharmaceutical composition comprising nanosized dolutegravir along with pharmaceutically acceptable excipients.

Another object of the present invention is to provide a pharmaceutical composition comprising dolutegravir exhibiting improved surface area and solubility.

Another object of the present invention is to provide a pharmaceutical composition comprising nanosized dolutegravir exhibiting improved surface area and solubility.

Yet another object of the present invention is to provide a pharmaceutical composition comprising dolutegravir exhibiting increased bioavailability.

Yet another object of the present invention is to provide a pharmaceutical composition comprising nanosized dolutegravir exhibiting increased bioavailability.

Another object of the present invention is to provide a pharmaceutical composition comprising dolutegravir exhibiting minimal food effect.
Another object of the present invention is to provide a pharmaceutical composition comprising nanosized dolutegravir exhibiting minimal food effect.

Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of dolutegravir.

Yet another object of the present invention is to provide a pharmaceutical composition comprising a reduced dose of nanosized dolutegravir.

Another object of the present invention is to provide a pharmaceutical composition comprising dolutegravir for once or twice a day administration.

Another object of the present invention is to provide a pharmaceutical composition comprising nanosized dolutegravir for once or twice a day administration.

Another object of the present invention is to provide a low dose pharmaceutical composition comprising dolutegravir.

Another object of the present invention is to provide a low dose pharmaceutical composition comprising nanosized dolutegravir.

Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising dolutegravir.

Another object of the present invention is to provide a process for preparing the pharmaceutical composition comprising nanosized dolutegravir.

Yet another object of the present invention is to provide a method of treatment caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection which method comprises administering a pharmaceutical composition comprising dolutegravir.

Yet another object of the present invention is to provide a method of treatment caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection which method comprises administering a pharmaceutical composition comprising nanosized dolutegravir.

Another object of the present invention is to provide the use of a pharmaceutical composition comprising dolutegravir, in the manufacture of a medicament for the treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.

Another object of the present invention is to provide the use of a pharmaceutical composition comprising nanosized dolutegravir, in the manufacture of a medicament for the treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.

Another object of the present invention is to provide a pharmaceutical composition comprising dolutegravir for the use in treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.

Another object of the present invention is to provide a pharmaceutical composition comprising nanosized dolutegravir for the use in treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection

SUMMARY OF THE INVENTION:

According to an aspect of the present invention, there is provided a pharmaceutical composition comprising dolutegravir and one or more pharmaceutically acceptable excipients.

According to one aspect of the present invention there is provided a pharmaceutical composition comprising nanosized dolutegravir, wherein the particles have an average particle size of less than or equal to about 2000 nm.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising nanosized dolutegravir along with at least one pharmaceutically acceptable excipient.

According to another aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising dolutegravir with at least one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention there is provided a process for preparing a pharmaceutical composition comprising nanosized dolutegravir with at least one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention there is provided a method of treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, such method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising dolutegravir according to the present invention to a patient in need thereof.

According to another aspect of the present invention there is provided a method of treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, such method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising nanosized dolutegravir according to the present invention to a patient in need thereof.

According to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising dolutegravir according to the present invention in the manufacture of a medicament for the treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.

According to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising nanosized dolutegravir according to present invention in the manufacture of a medicament for the treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
According to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising dolutegravir according to the present invention for use in treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.

According to another aspect of the present invention there is provided the use of a pharmaceutical composition comprising nanosized dolutegravir according to the present invention in ttreating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.

DETAILED DESCRIPTION OF THE INVENTION:

For the treatment of diseases caused by retroviruses, especially Acquired Immune Deficiency Syndrome (AIDS) or an HIV infection, it is essential that maximum amount of drug reaches the site of action. Most antiretroviral drugs either have poor solubility or poor permeability which deteriorates the bioavailability of the drug to a major extent.

Dolutegravir is a highly potent integrase inhibitor which is widely used in the treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection. However, dolutegravir being a BCS class II drug exhibits very slight water solubility, which, in turn, causes it to demonstrate low bioavailability.

Thus there is a dire need to develop suitable pharmaceutical compositions which address the bioavailability issues of dolutegravir.

The recommended dosage of dolutegravir is about 50 mg once daily, and this dose may be adjusted up to a maximum of 50 mg twice daily in certain cases.

The inventors of the present invention have found ways to address the solubility problems of dolutegravir. In particular, the inventors have found that, the solubility properties of dolutegravir are improved by using nanosized dolutegravir thus leading to better bioavailability of the drug.

The term “Dolutegravir” is used in broad sense to include not only “Dolutegravir” per se but also its pharmaceutically acceptable derivatives thereof. Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.

Preferably, the pharmaceutical composition of the present invention comprises dolutegravir in the form of dolutegravir sodium or dolutegravir potassium.

The term “low dose” as used herein refers to a therapeutically effective dose of dolutegravir, which dose is less than the usual or the conventional dose required to produce equal or higher therapeutic effect.

Accordingly, the pharmaceutical composition, according to the present invention may be administered once or twice a day. Preferably the pharmaceutical composition is administered once a day in a low dose wherein a “low dose” is less than the conventionally administered dose. Such low dose may be from about 5 mg to about 75 mg, preferably from about 10 mg to about 50 mg, most preferably from about 15 mg to about 40 mg. The conventional dose of TIVICAY®, the current trade name for dolutegravir, is 50 mg.

Further, the pharmaceutical composition according to the present invention may be administered as a pediatric formulation wherein the dose of such formulation may be from about 5 mg to about 20 mg, preferably less than about 15 mg.

Nanonization of hydrophobic or poorly water-soluble drugs generally involves the production of drug nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle size of the hydrophobic or poorly water soluble drugs. [Huabing Chen et al., discusses the various methods to develop nanoformulations in “Nanonization strategies for poorly water-soluble drugs,” Drug Discovery Today, Volume 00, Number 00, March 2010].

The present invention thus provides a pharmaceutical composition comprising dolutegravir in the form of nanoparticles.

The term “nanosize” as used herein refers to dolutegravir particles having an average particle size of less than or equal to about 2000 nm, preferably less than or equal to about 1000 nm.

The particles may have an average particle size of not less than or equal to 700 nm, optionally less than or equal to 500 nm, optionally less than or equal to about 250 nm, optionally less than or equal to about 150 nm.

The dolutegravir particles may have a particle size distribution with a D90 not less than or equal to 700 nm, preferably less than or equal to 300 nm, optionally less than or equal to 100 nm.

The present invention thus provides a pharmaceutical composition comprising dolutegravir wherein dolutegravir is in the nanosize range.

The term “particle” as used herein refers to an individual particle of dolutegravir, or particles of dolutegravir, or dolutegravir granules and/or mixtures thereof. In addition, the particles of the present invention may comprise dolutegravir and the one or more pharmaceutically acceptable excipients.

The nanosize particles of the present invention can be obtained by any process such as but not limited to milling, precipitation, homogenization, high pressure homogenization, spray-freeze drying, supercritical fluid technology, double emulsion/solvent evaporation, Particle replication in non-wetting templates (PRINT), thermal condensation, ultrasonication, spray drying or the like. Such nanoparticles obtained by any of these processes may further be formulated into desired dosage forms.

The pharmaceutical composition comprising dolutegravir according to the present invention may be administered orally through unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like; liquid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, spot-on), injection preparations etc. may also be envisaged under the ambit of the invention. Preferably, the unit dosage forms comprise nanosized dolutegravir.

Preferably, the pharmaceutical composition comprising dolutegravir according to the present invention may be administered in a solid oral dosage form such as tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates) and sprinkles. Preferably, the solid oral dosage forms comprise nanosized dolutegravir.

Suitable excipients may be used for formulating the solid oral dosage form according to the present invention such as, but not limited to, surface stabilizers, viscosity modifying agents, polymers, disintegrants, diluents, plasticizers, binders, glidants, lubricants, anti-adherents, channeling agents, carriers, fillers, sweeteners, flavoring agents, anti-caking agents, anti-microbial agents, antifoaming agents, emulsifiers, surfactants, buffering agents and coloring agents.

Suitable surface stabilizers, according to the present invention mean surfactants that are capable of stabilizing the increased surface charge of the nanosized drug. Suitable amphoteric, non-ionic, cationic or anionic surfactants may be included as surface stabilizers in the pharmaceutical composition of the present invention.

According to the present invention, surfactants may comprise of one or more, but not limited to, Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB)
Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, N–dimethyldodecylamine–N–oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate Cyclodextrins, Lecithin, Methylbenzethonium chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide linkages, Polyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2- alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic acid/ sodium salt, N-tallow 3 -iminodipropionate disodium salt, N-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine sodium salt, Phosal 53 MCT, Polyoxyethylene (20) sorbitan trioleate (Tween 85), Oleoyl macrogolglycerides (Labrafil M1944CS), Linoleoyl macrogolglycerides (Labrafil M2125CS), PG monolaurate (Lauroglycol 90), D-alpha-tocopheryl PEG 1000 succinate (Vitamin E TPGS), Polyoxyl 35 castor oil (Cremophor EL, Cremophor ELP), Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40, Cremophor RH 60), Lauroyl macrogolglycerides (Gelucire 44/14, Gelucire 50/13), Lauroyl macrogol-32 glycerides, Lauroyl polyoxyl-32 glycerides, Lauroyl polyoxylglycerides, Caprylocaproyl macrogol glycerides (Labrasol), Polyoxyethylene (20) sorbitan monooleate, (Polysorbate 80/ Tween 80), Polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/ Tween 20), polyglycerol (polyglyceryl oleate: Plural™ Oleique CC497) propylene glycol (propylene glycol monocaprylate: Capryol™ 90, propylene glycol monolaurate: Lauroglycol 90), polyoxyethylene glycols (PEG-8 stearate: Mirj 45, PEG- 40 stearate: Mirj® 52, PEG-15 hydroxystearate: Solutol® HS15), sorbitan or monoanhydrosorbitol (sorbitan monooleate: Span® 80, sucrose (sucrose monopalmitate: Surfhope® D-1616), Lutrol E 300, Transcutol HP, Transcutol P, Soyabean oil, Labrafac PG, Milyol 840, Pluronic L44, Pluronic L64, Polaxamer 188, and the like or mixtures thereof.

The amount of surface stabilizers in the pharmaceutical composition comprising dolutegravir range from about 2 % to about 10 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

Suitable viscosity modifying agents are excipients that are capable of stabilizing the nanoparticles by increasing the viscosity of the composition and thus preventing physical interaction of nanoparticles under the operating conditions employed.

According to the present invention, viscosity modifying agents, may comprise one or more, but not limited to derivatives of sugars, such as lactose, lactose monohydrate, saccharose, hydrolyzed starch (maltodextrin) or mixtures thereof.

The amount of viscosity modifying agents in the pharmaceutical composition comprising dolutegravir range from about 4 % to about 20 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

Suitable polymers according to the present invention, may comprise one or more hydrophilic polymers, but not limited to cellulose derivates like hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid, acrylamide, and maleic anhydride polymers, acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, agar, pectin, carrageenan, gelatin, casein, zein and alginates, carboxypolymethylene, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives and copolymers.

The amount of polymers in the pharmaceutical composition comprising dolutegravir range from about 2 % to about 15 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

Suitable disintegrants or super disintegrants according to the present invention include, but are not limited to, agar-agar, calcium carbonate, microcrystalline cellulose, crospovidone, povidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, alginic acid, alginates such as sodium alginate other algins, other celluloses, gums, ion-exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxymethyl cellulose, croscarmellose sodium, polyvinylpyrollidone, cross-linked PVP, carboxymethyl cellulose calcium, crosslinked sodium carboxymethyl cellulose, docusate sodium, guar gum, low-substituted HPC, polacrilin potassium, poloxamer, povidone, sodium glycine carbonate and sodium lauryl sulfate or mixtures thereof.

The amount of disintegrants in the pharmaceutical composition comprising dolutegravir range from about 5 % to about 30 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

Suitable glidants, anti-adherents and lubricants according to the present invention include, but are not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, mineral oil, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), glycerin, sorbitol, mannitol, other glycols, sodium lauryl sulfate, talc, long chain fatty acids and their salts, ethyl oleate, ethyl laurate, agar, syloid silica gel (a coagulated aerosol of synthetic silica (Evonik Degussa Co., Plano, Tex. USA), a pyrogenic silicon dioxide (CAB-O-SIL, Cabot Co., Boston, Mass. USA), or mixtures thereof.
The amount of glidants, anti-adherants and lubricants in the pharmaceutical composition comprising dolutegravir range from about 0.25 % to about 5 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

Suitable channeling agents according to the present invention, include, but are not limited to sodium chloride, sugars, polyols and the like or mixtures thereof.

The amount of channeling agents in the pharmaceutical composition comprising dolutegravir range from about 2 % to about 10% of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

Suitable binders may also be present in the in the pharmaceutical compositions of the present invention, which may include, but are not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or mixtures thereof or any other suitable binder.

The amount of binder in the pharmaceutical composition comprising dolutegravir range from about 5 % to about 20 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

Suitable carriers, diluents and fillers for use, in the pharmaceutical composition of the present invention may include, but are not limited to lactose (for example, spray-dried lactose, a-lactose, ß-lactose) lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) or mixtures thereof.

The amount of carriers, diluents and fillers in the pharmaceutical composition comprising dolutegravir range from about 15 % to about 60 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

There is also provided a process for preparing a pharmaceutical composition as described herein which process comprises admixing one or more pharmaceutically acceptable excipients with dolutegravir, wherein the dolutegravir is preferably in a nanosized form.

The process may comprise homogenizing dolutegravir and at least one excipient to produce a homogenized dispersion of the dolutegravir in the excipient. Optionally, the process further comprises processing said homogenized dispersion to produce dolutegravir particles. The processing may comprise milling said homogenized dispersion to produce a slurry of dolutegravir particles. The dolutegravir particles may be dried and blended.

Optionally, the dispersion comprises dolutegravir, at least one surfactant, at least one polymer and at least one carrier, diluent or filler and purified water.

The dolutegravir particles may be adsorbed by spraying the slurry onto a combination of at least one channeling agent, at least one anti-adherent and at least one disintegrant or super-disintegrant in a fluidized bed granulator.

The dolutegravir particles may be compressed into unit dosage forms. Optionally, the dolutegravir particles are lubricated before being compressed into unit dosage forms. The unit dosage forms may be coated.

The dolutegravir particles may have an average particle size of less than or equal to about 2000 nm.

The pharmaceutical composition of the present invention, may be prepared by a process which comprises (a) preparing a dispersion of dolutegravir with docusate sodium, hydroxyl propyl methylcellulose, sodium lauryl sulphate and lactose in purified water; (b) homogenizing the dispersion of step (a) and then nanomilling the homogenized dispersion; (c) adsorbing the nanomilled drug by spraying the nanomilled slurry on sodium chloride, magnesium stearate, silicified microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator; (d) drying and blending the granules obtained in step (c). The granules may be lubricated and finally compressed into tablets.

The pharmaceutical composition, according to the present invention, may also optionally be coated including, but not limited to seal coating, enteric coating, film coating and combinations thereof.

The pharmaceutical composition may be film coated, seal coated or enteric coated with, but not limited to, colour mix systems (such as Opadrycolour mix systems), Aqueous Acrylic Enteric System (such as Acryl-EZE®) and Kollicoat® Protect.

Preferably, the pharmaceutical composition, according to the present invention, is film coated.

The amount of film coat in the pharmaceutical compositions comprising dolutegravir range from about 2 % to about 15 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

According to the present invention, the seal coat comprises film forming polymeric materials, such as but not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hypromellose, acacia, gelatin to increase adherence and coherence of the seal coat.

The amount of seal coating system in the pharmaceutical composition comprising dolutegravir range from about 1 % to about 4 % of the total weight of the composition wherein the dolutegravir is preferably in a nanosized form.

According to the present invention, pharmaceutically acceptable opacifiers for use in the pharmaceutical composition of the present invention may comprise but are not limited to titanium dioxide.

The amount of opacificer in the pharmaceutical composition comprising dolutegravir range from about 1 % to about 4 % of the total weight of the composition, wherein the dolutegravir is preferably in a nanosized form.

The pharmaceutical composition comprising dolutegravir may further comprise at least one additional active ingredient selected from nucleoside reverse transcription inhibitors (NRTIs), and nucleotide reverse transcription inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and maturation inhibitors (MIs) and any combination thereof wherein the dolutegravir is preferably in a nanosized form.

Suitable NRTIs that may be employed in the pharmaceutical composition of the present invention may comprise zidovudine; didanosine; stavudine; lamivudine; abacavir; adefovir; lobucavir; entecavir; apricitabine; emtricitabine; zalcitabine; dexelvucitabine; alovudine; amdoxovir; elvucitabine; AVX754; BCH-189; phosphazid; racivir; SP1093V; stampidine; BCH-10652, ß-L-FD4 (also called ß-L-D4C and named ß-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, the purine nucleoside, (-)-ß-D-2,6-diamino-purine dioxolane; and lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-ß-D-threo-pentofuranosyl)adenine and any combination thereof.

Suitable NtRTIs that may be employed in the pharmaceutical composition of the present invention may comprise tenofovir and adefovir.

Suitable NNRTI’s that may be employed in the pharmaceutical composition of the present invention may comprise nevirapine, rilpivirine, delaviridine, efavirenz, etravirine. Other NNRTIs include PNU-142721, a furopyridine-thiopyrimide; capravirine (S-1153 or AG-1 549; 5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2- -ylmethyl carbonate); emivirine [MKC-442; (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimid- inedione)]; (+)-calanolide A (NSC-67545 1) and B, coumarin derivatives; DAPY (TMC120; 4-{4-[4-((E)-2-cyano-vinyl)-2,6-dimethyl-phenylamino]-pyrimidin-2-ylamino- }-benzonitrile); BILR-355 BS (12-ethyl-8-[2-(1-hydroxy-quinolin-4-yloxy)-ethyl]-5-methyl-11,12-dihydro--5H-1,5,10,12-tetraaza-dibenzo[a,e]cycloocten-6-one; PHI-236 (7-bromo-3-[2-(2,5-dimethoxy-phenyl)-ethyl]-3,4-dihydro-1H-pyrido[1,2-a][- 1,3,5]triazine-2-thione) and PHI-443 (TMC-278, 1-(5-bromo-pyridin-2-yl)-3-(2-thiophen-2-yl-ethyl)-thiourea).

Suitable PIs that may be employed in the pharmaceutical composition of the present invention may comprise saquinavir; ritonavir; nelfinavir; amprenavir; lopinavir, indinavir; nelfinavir; atazanavir; lasinavir; palinavir; tipranavir; fosamprenavir; darunavir; TMC114; DMP450, a cyclic urea; BMS-2322623, BMS-232623; GS3333; KNI-413; KNI-272; LG-71350; CGP-61755; PD 173606; PD 177298; PD 178390; PD 178392; U-140690; ABT-378; and AG-1549 an imidazole carbamate. Additional PIs include N-cycloalkylglycines, a-hydroxyarylbutanamides; a-hydroxy-?-[[(carbocyclic- or heterocyclic-substituted) amino) carbonyl]alkanamide derivatives; ?-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides; dihydropyrone derivatives and a- and ß-amino acid hydroxyethylaminosulfonamides; and N-aminoacid substituted L-lysine derivatives.

Preferably, the pharmaceutical composition comprising dolutegravir may further comprise abacavir and lamivudine, optionally wherein the abacavir is in the form of abacavir sulfate, wherein at least the dolutegravir is preferably in a nanosized form.

The antiretroviral agents according to the present invention may be used in the form of salts or esters derived from inorganic or organic acids. These salts include but are not limited to sodium, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamylsulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and the like.

The present invention further provides a method of treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection, such method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising dolutegravir to a patient in need thereof wherein the dolutegravir is preferably in a nanosized form.

The present invention also provides the use of a pharmaceutical composition comprising dolutegravir according to the present invention in the manufacture of a medicament for the treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection wherein the dolutegravir is preferably in a nanosized form.

The present invention also provides a pharmaceutical composition comprising dolutegravir according to the present invention for use in the treatment of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection wherein the dolutegravir is preferably in a nanosized form.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1

Sr. No. Ingredients Quantity (mg/tab)
Binder Slurry
1. Dolutegravir sodium 26.3
2. Sodium Lauryl Sulphate 1.725
3. Hydroxy propyl methyl cellulose 6.25
4. Docusate Sodium 0.625
5. Lactose Monohydrate 6.25
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 15.63
8. Crospovidone 6.25
Blending & Lubrication
9. Sodium Chloride 3.75
10. Crospovidone 2.5
11. Silicified Microcrystalline Cellulose 9.98
12. Magnesium Stearate 0.75
Total weight of core tablet 80.0
Coating
13. Opadry Yellow 1.6
14. Purified Water q.s.
Total weight of coated tablet 81.6

Process:
1. Docusate sodium, hydroxy propyl methyl cellulose, sodium lauryl sulphate and lactose were solubilized in water.
2. Dolutegravir was dispersed in the solution obtained in step (1).
3. The dispersion obtained in step (2) was homogenized and then nanomilled.
4. The nanomilled slurry obtained in step (3) was adsorbed by spraying on lactose and crospovidone to produce the granules.
5. The dried granules obtained in step (4) were blended with sodium chloride, silicified microcrystalline cellulose and crospovidone.
6. The blend obtained in step (5) was lubricated by magnesium stearate.
7. The lubricated granules obtained in step (6) were finally compressed into tablets.
8. The tablets obtained in step (7) were then film coated.

Example 2

Sr. No. Ingredients Quantity (mg/tab)
Binder Slurry
1. Dolutegravir sodium 26.3-105.2
2. Sodium Lauryl Sulphate 1.725-6.9
3. Hydroxy propyl methyl cellulose 6.25-25.0
4. Docusate Sodium 0.625-2.5
5. Lactose Monohydrate 6.25-25.0
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate 15.625-62.5
8. Crospovidone 6.25-25.0
Blending & Lubrication
9. Sodium Chloride 3.75-15.0
10. Crospovidone 2.5-10.0
11. Silicified Microcrystalline Cellulose 9.98-39.9
12. Magnesium Stearate 0.75-3.0
Total weight of core tablet 80.0-320.0
Coating
13. Opadry Yellow 1.6-6.4
14. Purified Water q.s.
Total weight of coated tablet 81.6-326.4

Process:
1. Docusate sodium, hydroxy propyl methyl cellulose, sodium lauryl sulphate and lactose were solubilized in water.
2. Dolutegravir was dispersed in the solution obtained in step (1).
3. The dispersion obtained in step (2) was homogenized and then nanomilled.
4. The nanomilled slurry obtained in step (3) was adsorbed by spraying on lactose and crospovidone to produce the granules.
5. The dried granules obtained in step (4) were blended with sodium chloride, silicified microcrystalline cellulose and crospovidone.
6. The blend obtained in step (5) was lubricated by magnesium stearate.
7. The lubricated granules obtained in step (6) were finally compressed into tablets.
8. The tablets obtained in step (7) were then 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 "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like. ,CLAIMS:WE CLAIM:

1. A pharmaceutical composition comprising dolutegravir and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1 comprising dolutegravir in the form of nanoparticles.

3. The pharmaceutical composition according to claim 2, wherein the nanoparticles have an average particle size of less than about 2000 nanometers.

4. The pharmaceutical composition according to claim 3, wherein the nanoparticles have an average particle size of less than about 1000 nanometers.

5. The pharmaceutical composition according to any preceding claim comprising dolutegravir in the form of a pharmaceutically acceptable derivative thereof.

6. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable derivative is selected from the list consisting of a salt, a solvate, a hydrate, an anhydrate, an enantiomer, an ester, an isomer, a tautomer, a complex, a polymorph, a prodrug, or a combination thereof.

7. The pharmaceutical composition according to any preceding claim, wherein the one or more pharmaceutically acceptable excipients comprise disintegrants or super disintegrants; carriers, diluents; fillers, plasticizers; binders; glidants; anti-adherents; lubricants; solvents, sweetening agents; taste-masking agents; flavoring agents; anti-caking agents; anti-microbial agents; preservatives; antifoaming agents; emulsifiers; surfactants; antioxidants; viscosity modifying agents; texture enhancers; surface stabilizers; buffering agents; coloring agents; channeling agents; or any combination thereof.

8. The pharmaceutical composition according to claim 7, wherein the composition comprises one or more surfactants optionally in an amount of from about 2% to about 10% of the total weight of the composition.

9. The pharmaceutical composition according to claim 7 or 8, wherein the composition comprises one or more viscosity modifying agents, optionally in an amount of from about 4% to about 20% of the total weight of the composition.

10. The pharmaceutical composition according to claim 7, 8 or 9, wherein the composition comprises at least one polymer, optionally in an amount of from about 2% to about 15% of the total weight of the composition.

11. The pharmaceutical composition according to any preceding claim, wherein the composition is in an oral dosage form.

12. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition is for once or twice a day administration.

13. The pharmaceutical composition claim 11 or 12, wherein the oral dosage form is in the form of a tablet, a coated tablet, powder, powder for reconstitution, pellets, beads, a mini-tablet, a multilayer tablet, a bilayered tablet, a tablet-in-tablet, a pill, a micro-pellet, a small tablet unit, capsules, MUPS (multiple unit pellet system), a disintegrating tablet, a dispersible tablet, granules, microspheres, multiparticulates, a capsule (optionally filled with powder, powder for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, sprinkles, microspheres and multiparticulates), a sachet (optionally filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, sprinkles microspheres and multiparticulates) or sprinkles.

14. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition comprises less than 50 mg of dolutegravir.

15. The pharmaceutical composition according to any preceding claim, further comprising at least one additional active ingredient selected from nucleoside reverse transcription inhibitors (NRTIs), nucleotide reverse transcription inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and maturation inhibitors (MIs).

16. A process for preparing a pharmaceutical composition according to any preceding claim which process comprises admixing one or more pharmaceutically acceptable excipients with dolutegravir.

17. The pharmaceutical composition according to any one of claims 1 to 15, for use in treating acquired immune deficiency syndrome or human immunodeficiency virus.

18. A method of treating acquired immune deficiency syndrome or human immunodeficiency virus, the method comprising administering an therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 15 to a subject in need thereof.

19. Use of a pharmaceutical composition according to any one of claims 1 to 15, in the manufacture of a medicament for the treatment of acquired immune deficiency syndrome or human immunodeficiency virus.

20. A pharmaceutical composition substantially as described herein with reference to the examples.

21. A process for the preparation of a pharmaceutical composition as substantially described herein with reference to the examples.

Dated this 20th day of March, 2015

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates