Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

• 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 FflV infections.
• 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[r,2':4,5]pyrazino[2,l -b][l,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 FflV 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.
• HIV human immunodeficiency virus
• AIDS acquired immunodeficiency syndrome
• 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 FHV disease spreads throughout numerous host cells and ultimately progresses to AIDS.
• Dolutegravir is a FflV-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.
• BCS Bio-pharmaceutics Classification System
• 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(o-oo) by 33%, 41%, and 66% respectively, increased C max by 46%, 52%, and 67% respectively and prolonged T max 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 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.
• 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 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.
• a pharmaceutical composition comprising dolutegravir and one or more pharmaceutically acceptable excipients.
• a pharmaceutical composition comprising nanosized dolutegravir, wherein the particles have an average particle size of less than or equal to about 2000 nm.
• composition comprising nanosized dolutegravir along with at least one pharmaceutically acceptable excipient.
• a process for preparing a pharmaceutical composition comprising dolutegravir with at least one or more pharmaceutically acceptable excipients.
• a process for preparing a pharmaceutical composition comprising nanosized dolutegravir with at least one or more pharmaceutically acceptable excipients.
• a method of treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection comprising administering a therapeutically effective amount of a pharmaceutical composition comprising dolutegravir according to the present invention to a patient in need thereof.
• a method of treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection comprising administering a therapeutically effective amount of a pharmaceutical composition comprising nanosized dolutegravir according to the present invention to a patient in need thereof.
• 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.
• 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.
• 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.
• 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.
• 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.
• dolutegravir being a BCS class II drug exhibits very slight water solubility, which, in turn, causes it to demonstrate low bioavailability.
• 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.
• the inventors have found that, the solubility properties of dolutegravir are improved by using nanosized dolutegravir thus leading to better bioavailability of the drug.
• 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.
• the pharmaceutical composition of the present invention comprises dolutegravir in the form of dolutegravir sodium or dolutegravir potassium.
• low dose 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.
• the pharmaceutical composition may be administered once or twice a day.
• the pharmaceutical composition is administered once a day in a low dose wherein a "low dose" is less than the conventionally administered dose.
• a 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 TrVICAY ® is 50 mg.
• 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 ah, 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.
• nanosize 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.
• particles refers to an individual particle of dolutegravir, or particles of dolutegravir, or dolutegravir granules and/or mixtures thereof.
• 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),
• 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, micropellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates) and sprinkles.
• 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.
• surface stabilizers 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
• Suitable surface stabilizers 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.
• 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.
• CTAB Cetyl trimethyl ammonium bromide
• 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, ⁇ , ⁇ , ⁇ , ⁇ tetrakis substituted ethylenediamines 2- al
• 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.
• 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 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 s
• 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, tragaeanth, sodium alginate, or mixtures thereof or any other suitable binder.
• polyvinyl pyrrolidone also known as povidone
• polyethylene glycol(s) polyethylene glycol(s)
• acacia alginic acid
• agar calcium carragenan
• cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium
• 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, ⁇ -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),
• 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.
• 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.
• 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.
• 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.
• 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 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.
• colour mix systems such as Opadrycolour mix systems
• Aqueous Acrylic Enteric System such as Acryl-EZE ®
• Kollicoat ® Protect Kollicoat ® Protect.
• the pharmaceutical composition 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.
• 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.
• 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.
• NRTIs nucleoside reverse transcription inhibitors
• NtRTIs nucleotide reverse transcription inhibitors
• NRTIs non-nucleoside reverse transcriptase inhibitors
• Pro protease inhibitors
• Mis maturation inhibitors
• Suitable NRTIs 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, P-L-FD4 (also called P-L-D4C and named P-L-2',3'-dicleoxy-5- fluoro-cytidene); DAPD, the purine nucleoside, (-)-P-D-2,6-diamino-purine dioxolane; and lodenosine (FddA), 9-(2,3-dideoxy), 9-(2,3-dideoxy
• 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-l -(4-pyridyl)methyl-lH-imidazol- 2- -ylmethyl carbonate); emivirine [MKC-442; (l -(ethoxy-methyl)-5-(l-methylethyl)-6- (phenylmethyl)-(2,4(lH,3H)-pyrimid- inedione)]; (+)-calanolide A (NSC-67545 1) and B, coumarin derivatives; DAPY (TMC120; 4- ⁇ 4-[4-((
• Suitable Pis 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-y-[[(carbocyclic- or heterocyclic-substituted) amino) carbonyl]alkanamide derivatives; y-hydroxy-2- (fluoroalkylaminocarbonyl)-l-piperazinepentanamides; dihydropyrone derivatives and a- and ⁇ -amino acid hydroxy ethylaminosulfonamides; and N-aminoacid substituted L-lysine derivatives.
• 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, pam
• 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.
• 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 ste
• the present invention further provides a method of treating diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HTV 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.
• step (2) The dispersion obtained in step (2) was homogenized and then nanomilled.
• step (3) The nanomilled slurry obtained in step (3) was adsorbed by spraying on lactose and crospovidone to produce the granules.
• step (4) The dried granules obtained in step (4) were blended with sodium chloride, silicified microcrystalline cellulose and crospovidone.
• step (5) The blend obtained in step (5) was lubricated by magnesium stearate.
• step (6) The lubricated granules obtained in step (6) were finally compressed into tablets.
• step (7) The tablets obtained in step (7) were then film coated.
• step (2) The dispersion obtained in step (2) was homogenized and then nanomilled.
• step (3) The nanomilled slurry obtained in step (3) was adsorbed by spraying on lactose and crospovidone to produce the granules.
• step (4) The dried granules obtained in step (4) were blended with sodium chloride, silicified microcrystalline cellulose and crospovidone.
• step (5) The blend obtained in step (5) was lubricated by magnesium stearate.
• step (6) The lubricated granules obtained in step (6) were finally compressed into tablets.
• step (7) The tablets obtained in step (7) were then film coated.

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• 2015
  • 2015-03-20 IN IN916MU2014 patent/IN2014MU00916A/en unknown
  • 2015-03-20 WO PCT/GB2015/050826 patent/WO2015140569A1/en not_active Ceased

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