WO2015136294A1

WO2015136294A1 - Pharmaceutical composittion comprising rilpivirine

Info

Publication number: WO2015136294A1
Application number: PCT/GB2015/050726
Authority: WO
Inventors: Preeti Raut; Geena Malhotra
Original assignee: Cipla Limited; Turner, Craig
Priority date: 2014-03-13
Filing date: 2015-03-12
Publication date: 2015-09-17

Abstract

This invention provides a pharmaceutical composition comprising rilpivirine and one or more pharmaceutically acceptable excipients. Preferably, the rilpivirine is in the form of nanoparticles. The nanoparticles may have an average particle size of less than about 2000nanometers. Preferably the pharmaceutical composition is administered once a day in a low dose, wherein a "low dose" is less than the conventionally administered dose. The pharmaceutical composition may comprise less than 25mg of rilpivirine. The pharmaceutical composition of the present invention may be used to treat acquired immune deficiency syndrome or human immunodeficiency virus.

Description

PHARMACEUTICAL COMPOSITION COMPRISING RILPIVIRINE

FIELD OF INVENTION:

The present invention relates to a pharmaceutical composition comprising a non- nucleoside reverse transcriptase inhibitor (NNRTI), and more particularly, relates to a pharmaceutical composition comprising rilpivirine, 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.

Rilpivirine (TMC278) has the chemical name 4-{[4-({4-[(E)-2-cyanovinyl]-2, 6- dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile, and is reported to have the following chemical structure.

Rilpivirine is an orally active NNRTI, 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):el7502 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.

Rilpivirine is a diary Ipyrimi dine NNRTI of HIV- 1. Rilpivirine activity is mediated by noncompetitive inhibition of HIV- 1 reverse transcriptase.

Rilpivirine is commercially available as conventional tablet (EDURANT^®) for oral administration. EDURANT ^® is available as a tablet containing 25 mg of rilpivirine per tablet.

WO0316306 discloses compound TMC278, its pharmacological activity as well as a number of procedures for its preparation. Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions and injectable solutions are exemplified therein.

WO2007147882 discloses intramuscular or subcutaneous injection, comprising a therapeutically effective amount of TMC278 in micro- or nanoparticle form, having a surface modifier adsorbed to the surface thereof; and a pharmaceutically acceptable aqueous carrier; wherein the TMC278 active ingredient is suspended.

WO2012140220 discloses a freeze-dried nanosuspension comprising rilpivirine and a steric stabilizer which is a solid at room temperature.

WO2008110619 discloses a powder comprising TMC278, dispersed in a water-soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, a hydroxyalkyl alkylcellulose, and a poloxamer, to be mixed with water, for the manufacture of a medicament for the treatment of a subject infected with HIV.

Pharmacokinetics and disposition of rilpivirine (TMC278) nanosuspension as a long- acting injectable antiretroviral formulation; Antimicrob Agents Chemother. 2010 May; 54(5):2042-50. doi: 10.1128/AAC.01529-09. Epub 2010 Feb 16. This article discloses sustained plasma concentration-time profiles that were obtained for several months in rats and dogs after single dose of a nanosuspension of rilpivirine (200-nm particle size).

WO2006024668 discloses pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of rilpivirine.

Rilpivirine exhibits very poor 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. Further, the bioavailability of rilpivirine depends upon the meal content and the absorption is also pH dependent.

The pharmacokinetic properties of rilpivirine are affected by the prandial status of a patient receiving the treatment, i.e. it exhibits a "food effect". It has been observed that the exposure to rilpivirine was approximately 40% lower when it was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high -fat high-caloric meal (928 kcal). When rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.

As such, patients receive specific instructions to administer rilpivirine with a meal. Accordingly, rilpivirine is administered in a fed state in an attempt to minimize the food effect. Administration of a rilpivirine composition without food may change its bioavailability by affecting either the drug substance or the composition in which the drug substance is formulated.

This situation is unsatisfactory and inconvenient to the patients especially HIV patients since their medications usually consist of a multiple drug regimen demanding the administration of large numbers of tablets or capsules. Further, these HIV patients often suffer from nausea and lesions of the oral mucosa. Therefore the oral administration of rilpivirine may be hampered by factors such as emesis and ingestion and would ultimately lead to decreased bioavailability of rilpivirine.

Accordingly, there has been no prior art disclosing compositions of rilpivirine that are free of food effect and which thereby facilitate patient compliance and superior bioavailability. The currently commercialized dosage form and the recommended dose still do not address the tribulations of the rilpivirine therapy.

Attempts to overcome the prior art problems and food effect issues have led the inventors of the present invention to design formulations comprising rilpivirine which reduce or nullify the food effect to ensure better bioavailability. Such formulations of rilpivirine are patient compliant, robust, stable and further exhibit optimal dissolution properties.

In accordance, the inventors of the present invention have developed a patient compliant pharmaceutical composition of rilpivirine which addresses the food effects and bioavailability along with technical advancement and economic significance.

OBJECT OF THE INVENTION:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 rilpivirine.

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 rilpivirine.

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

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

According to one aspect of the present invention there is provided a pharmaceutical composition comprising nanosized rilpivirine, 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 rilpivirine 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 rilpivirine 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 nanosized pharmaceutical composition comprising rilpivirine.

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 rilpivirine 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 FHV infection, such method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising nanosized rilpivirine 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 rilpivirine 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 rilpivirine 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 a pharmaceutical composition comprising rilpivirine 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 a pharmaceutical composition comprising nanosized rilpivirine according to the present invention in treating 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 ΗΓν" 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.

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

Further, rilpivirine is noted to exhibit "food effect". It has been observed that the bioavailability of rilpivirine was substantially reduced when it was taken in a fasted condition as compared to a fed state.

Thus there is a dire need to develop suitable pharmaceutical compositions which address the bioavailability and food effect issues of rilpivirine.

The recommended dosage of rilpivirine is about 25 mg once daily and which dose needs to be administered along with food.

The inventors of the present invention have found ways to address the solubility problems of rilpivirine. In particular, the inventors have found that the solubility properties of rilpivirine were improved and food effect was nullified by using nanosized rilpivirine and thus leading to better bioavailability of the drug.

The term "rilpivirine" is used in broad sense to include not only "rilpivirine" 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 rilpivirine in the form of rilpivirine hydrochloride or rilpivirine fumarate.

The term "low dose" as used herein refers to a therapeutically effective dose of rilpivirine, 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 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.

The low dose of the pharmaceutical composition may be less than 25 mg, preferably from about 3 mg to about 20 mg, more preferably from about 5 mg to about 15 mg. The conventional dose of EDU ANT^®, the current trade name for rilpivirine, is 25 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 rilpivirine in the form of nanoparticles.

The term "nanosize" as used herein refers to rilpivirine 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 less than or equal to about 700 nm, optionally less than or equal to about 500 nm, optionally less than or equal to about 250 nm, optionally less than or equal to about 150 nm.

The rilpivirine particles may have a particle size distribution with a D90 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 rilpivirine wherein rilpivirine is in the nanosize range.

The term "particle" as used herein refers to an individual particle of rilpivirine, or particles of rilpivirine, or rilpivirine granules and/or mixtures thereof. In addition, the particles of the present invention may comprise rilpivirine 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 rilpivirine 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 rilpivirine.

Preferably, the pharmaceutical composition comprising rilpivirine 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), sprinkles and the like. Preferably, the solid oral dosage forms comprise nanosized rilpivirine.

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, coloring agents and the like.

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, Ν,Ν,Ν,Ν tetrakis substituted ethylenediamines 2- alkyl 1- hydroxy ethyl 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 rilpivirine range from about 2 % to about 10 % of the total weight of the composition, wherein the rilpivirine 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 rilpivirine range from about 4 % to about 20 % of the total weight of the composition, wherein the rilpivirine 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 rilpivirine range from about 2 % to about 15 % of the total weight of the composition, wherein the rilpivirine 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 rilpivirine range from about 5 % to about 30 % of the total weight of the composition, wherein the rilpivirine 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., Piano, 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 rilpivirine range from about 0.5 % to about 5 % of the total weight of the composition, wherein the rilpivirine 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 rilpivirine range from about 2 % to about 10 % of the total weight of the composition, wherein the rilpivirine 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.

The amount of binder in the pharmaceutical composition comprising rilpivirine range from about 5 % to about 20 % of the total weight of the composition, wherein the rilpivirine 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, β-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), hydroxy ethylcellulose, 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 rilpivirine range from about 15 % to about 60 % of the total weight of the composition, wherein the rilpivirine 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 rilpivirine, wherein the rilpivirine is preferably in a nanosized form.

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

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

The rilpivirine 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 rilpivirine particles may be compressed into unit dosage forms. Optionally, the rilpivirine particles are lubricated before being compressed into unit dosage forms. The unit dosage forms may be coated. The rilpivirine 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 rilpivirine 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 blend 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 rilpivirine range from about 2 % to about 15 % of the total weight of the composition, wherein the rilpivirine 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 rilpivirine range from about 1 % to about 4 % of the total weight of the composition, wherein the rilpivirine 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, wherein the rilpivirine present in the pharmaceutical composition is preferably in a nanosized form.

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

The pharmaceutical composition comprising rilpivirine may further comprise at least one additional active ingredient selected from nucleoside reverse transcription inhibitors (NRTIs), nucleotide reverse transcription inhibitors (NtRTIs), NNRTIs, protease inhibitors (Pis), and maturation inhibitors (Mis) and any combination thereof, wherein the rilpivirine 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, 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-2-fluoro-P-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 NNRTIs 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 -methyl ethyl)-6- (phenylmethyl)-(2,4(lH,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-(l- hydroxy-quinolin-4-yloxy)-ethyl]-5-methyl-l l,12-dihydro~5H-l,5,10,12-tetraaza- dibenzo[a,e]cycloocten-6-one; PHI-236 (7-bromo-3-[2-(2,5-dimethoxy-phenyl)-ethyl]- 3,4-dihydro-lH-pyndo[l ,2-a][- l,3,5]tnazine-2-thione) and PHI-443 (TMC-278, l-(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-y-[[(carbocyclic- or heterocyclic-substituted) amino) carbonyl]alkanamide derivatives; y-hydroxy-2- (fluoroalkylaminocarbonyl)-l-piperazinepentanamides; dihydropyrone derivatives and a- and β-amino acid hydroxy ethylaminosulfonamides; and N-aminoacid substituted L-lysine derivatives.

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 rilpivirine to a patient in need thereof, wherein the rilpivirine is preferably in a nanosized form.

The present invention also provides the use of a pharmaceutical composition comprising rilpivirine 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 rilpivirine is preferably in a nanosized form.

The present invention also provides a pharmaceutical composition comprising rilpivirine 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 rilpivirine 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

Process:

1. Docusate sodium, hydroxy propyl methyl cellulose, sodium lauryl sulphate and lactose were solubilized in water.

2. Rilpivirine 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 croscarmellose sodium to produce the granules. 5. The dried granules obtained in step (4) were blended with sodium chloride, mag stearate, silicified microcrystalline cellulose and croscarmellose sodium.

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

Process:

2. Rilpivirine 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 croscarmellose sodium to produce the granules.

5. The dried granules obtained in step (4) were blended with sodium chloride, magnesium stearate, silicified microcrystalline cellulose and croscarmellose sodium.

6. The blend obtained in step (5) was lubricated by magnesium stearate.

8. The tablets obtained in step (7) were then film coated.

Example 3

Total Weight 100.0

Coating

14. Opadry White 3.0

15. Purified Water q.s.

Total weight 103.0

Process:

1. Docusate sodium, hydroxy propyl methyl cellulose, sodium lauryl sulphate, lactose and cremophor ELP were solubilized in water.

2. Rilpivirine was dispersed in the solution obtained in step (1).

3. The dispersion obtained in step (2) was homogenized and then nanomilled.

6. The blend obtained in step (5) was lubricated by magnesium stearate.

8. The tablets obtained in step (7) were then film coated.

Example 4

8. Lactose Monohydrate 10.0

9. Croscarmellose Sodium 5.0

Blending & Lubrication

10. Sodium Chloride 3.0

11. Croscarmellose Sodium 2.0

12. Silicified Microcrystalline Cellulose 36.32

13. Magnesium Stearate 0.8

Total Weight 100.0

Coating

14. Opadry White 3.0

15. Purified Water q.s.

Total weight 103.0

Process:

1. Docusate sodium, hydroxy propyl methyl cellulose, sodium lauryl sulphate, lactose and labrasol were solubilized in water.

2. Rilpivirine was dispersed in the solution obtained in step (1).

3. The dispersion obtained in step (2) was homogenized and then nanomilled.

6. The blend obtained in step (5) was lubricated by magnesium stearate.

8. The tablets obtained in step (7) were then film coated.

Example 5

1. Rilpivirine Hydrochloride 11.0

2. Sodium Lauryl Sulphate 1.38

3. Hypromellose 5.0

4. Docusate Sodium 0.5

5. Polysorbate 80 20.0

6. Lactose Monohydrate 5.0

7. Purified water q.s

Dry Mix

8. Lactose Monohydrate 10.0

9. Croscarmellose Sodium 5.0

Blending & Lubrication

10. Sodium Chloride 3.0

11. Croscarmellose Sodium 2.0

12. Silicified Microcrystalline Cellulose 36.32

13. Magnesium Stearate 0.8

Total Weig tit 100.0

Coating

14. Opadry White 3.0

15. Purified Water q.s.

Total weight 103.0

Process:

1. Docusate sodium, Hypromellose, sodium lauryl sulphate, lactose and polysorbate 80 were solubilized in water.

2. Rilpivirine was dispersed in the solution obtained in step (1).

3. The dispersion obtained in step (2) was homogenized and then nanomilled.

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

CLAIMS:

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

2. The pharmaceutical composition according to claim 1 comprising rilpivirine 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 rilpivirine 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.

1 1. 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 a day administration.

13. The pharmaceutical composition claim 1 1 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, micropellets, 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 25 mg of rilpivirine.

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 rilpivirine.

17. A 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.