Efavirenz is effective in the treatment of the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system resulting in onset of AIDS. Efavirenz is a highly potent reverse transcriptase inhibitor and is effective against HIV reverse transcriptase resistance.

Efavirenz is commercially available as a capsule (SUSTIVA^®) for oral administration. SUSTIVA^® is supplied as capsules for oral administration containing either 50 mg or 200 mg of efavirenz and the following inactive ingredients: lactose monohydrate, magnesium stearate, sodium lauryl sulfate and sodium starch glycolate. The capsule shell contains the following inactive ingredients and dyes: gelatin, sodium lauryl sulfate, titanium dioxide and/or yellow iron oxide.

SUSTIVA^® is also available as film-coated tablets for oral administration containing 600 mg of efavirenz and the following inactive ingredients: croscarmellose sodium,

l hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The film coating contains Opadry Yellow and Opadry Clear.

The recommended dosage of SUSTIVA (efavirenz) is 600 mg orally and is administered once daily in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs).

Efavirenz is classified in Class ll/Class IV drug (low solubility, high permeability) of the Biopharmaceutical Classification System. Class II drugs like efavirenz demonstrate poor gastrointestinal (Gl) absorption due to inadequate drug solubility in Gl fluids.

Furthermore, efavirenz is a crystalline lipophilic solid with an aqueous solubility of 9.0 μg/mL and with a low intrinsic dissolution rate (IDR) of 0.037 mg/cm²/min. The drugs with less than 0.1 mg/cm²/min of IDR have dissolution as a rate-limiting step in absorption which is further affected by the fed/fasted state of the patient. This, in turn, can affect the peak plasma concentration making calculation of dosage and dosing regimens more complex. This suggests the importance of dissolution improvement for efavirenz. Moreover, most of these new chemical entities despite their high permeability exhibit first pass metabolism and are only absorbed in the upper small intestine. Consequently, if these drugs are not completely released in gastro intestinal tract area, they have low bioavailability. Thus, there is a need to increase the therapeutic dose of the drug in order to obviate this disadvantage; however increasing the dose may lead to increase in the side effects of the drug.

Various prior art formulations have been reported to improve the solubility of the efavirenz in the Gl tract.

One of the approaches used is encapsulation of drug in cyclodextrins using a 1 : 1 molar ratio as reported by Indrajit et al in Macromolecular symposia in 2010, 287, 51 -59.

Solid dispersion and PEGylation techniques have also been proposed by Madhavi et al in "Dissolution enhancement of efavirenz by solid dispersion and PEGylation techniques"; International Journal of Pharmaceutical Investigation, 201 1 (1 ) , 29-34, wherein the drug and the carrier are added to a common solvent followed by homogenization and evaporation of the solvent to form a solid dispersion of efavirenz.

WO99/61026 discloses a tablet dosage form of efavirenz wherein lactose is added extragranularly to obtain a stable tablet formulation which is bioequivalent to the capsule formulation of efavirenz.

US6555133 provides improved oral dosage forms of efavirenz containing one or more super disintegrants that enhance the dissolution rate of the drug in the gastrointestinal tract thereby improving the rate and extent of absorption of drug in the body.

WO201 1 131943 discloses efavirenz in the form of particles wherein substantially all the particles have a particle size less than or equal to 1 micrometre.

Development of solid self-emulsifying drug delivery Systems containing efavirenz: in vitro and in vivo evaluation, V. Kiran Kumar et al, Int J Pharm Bio Sci 2013 Jan; 4(1 ): (P) 869 - 882 which discloses a SEDDS formulation of efavirenz with enhanced solubility and dissolution. This document only discloses solid self-emulsifying drug delivery systems, and does not provide any teaching on how much efavirenz to include in the self-emulsifying drug delivery system formulations. Furthermore, it fails to provide any teaching on dosage regimes for treating patients with efavirenz.

Novel self-micro-emulsifying drug delivery systems of Efavirenz, Ashish Deshmukh et al, Journal of Chemical and Pharmaceutical Research, 2012, 4(8):3914 - 3919 discloses self-emulsifying drug delivery systems comprising efavirenz. However, the document does not provide any teaching about dosage regimes for treating patients with efavirenz.

ENCORE1 is a randomized, double-blind, placebo controlled, non-inferiority trial which includes a daily dose of 400 mg efavirenz (EFV) which is non-inferior to the standard 600 mg dose. This study was presented at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) in Kuala Lumpur. Several strategies and formulations have been employed to overcome these limitations of solubility and poor bioavailability. Although existing 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.

The inventors of the present invention have appreciated the disadvantages and problems associated with efavirenz formulations and methods of administration discussed above, and sought ways of improving upon them. The inventors have appreciated that it would be beneficial to provide efavirenz in a formulation such that its solubility and bioavailability are improved. The inventors have also appreciated the need to provide an efavirenz formulation such that the daily dose of efavirenz administered to a patient can be reduced, minimizing undesirable side effects. The inventors have further appreciated the need to provide an efavirenz formulation such that it is only necessary to administer the formulation once a day for effective treatment.

OBJECT OF THE INVENTION:

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

Another object of the present invention is to provide a pharmaceutical composition comprising efavirenz with enhanced dissolution and solubility.

Another object of the present invention is to provide a pharmaceutical composition comprising efavirenz with improved bioavailability.

Another object of the present invention is to provide a pharmaceutical composition comprising efavirenz such that it is possible to administer the efavirenz in a daily dose which is less than the conventionally administered daily dose.

Another object of the present invention is to provide a pharmaceutical composition comprising efavirenz such that there are reduced side effects of the efavirenz. Another object of the present invention is to provide a pharmaceutical composition comprising efavirenz such that the composition only needs to be administered once a day.

SUMMARY OF THE INVENTION:

According to one aspect of the invention, there is provided a pharmaceutical composition comprising a self-emulsifying drug delivery system, wherein the self-emulsifying drug delivery system comprises efavirenz and one or more pharmaceutically acceptable excipients.

According to another aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising a self-emulsifying drug delivery system of efavirenz, wherein the process comprises dispersing or dissolving efavirenz with at least one or more pharmaceutically acceptable excipients.

According to another aspect of the invention, there is provided a pharmaceutical composition comprising a self-emulsifying drug delivery system of efavirenz for use in medicine. Preferably, the use is for the treatment of HIV or AIDS.

According to another aspect of the invention, there is provided a use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of HIV.

According to another aspect of the invention, there is provided a method of treating HIV by administering a pharmaceutical composition of the invention to a patient in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 - Mean Plasma Concentrations Vs Time Curve for Test Product (T1) and Reference Product (R) of Efavirenz. Figure 2 - Mean Plasma Concentrations Vs Time Curve for Test Product (T2) and Reference Product (R) of Efavirenz.

DETAILED DESCRIPTION OF THE INVENTION:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with a prolonged half-life allowing once-daily dosing and therefore presenting an advantage for treatment compliance and efficacy. However, 20% to 40% of patients receiving efavirenz exhibit central nervous system (CNS) side-effects. Such CNS disturbances range from dizziness to hallucinations including frequent nightmares and insomnia. These symptoms are usually mild to moderate in severity and are reported to subside progressively over a few weeks after the initiation of efavirenz therapy.

Nevertheless, efavirenz is discontinued in 4% of patients because of the severity or persistence of such adverse effects (Nelson M, Silleni M. Tolerability and efficacy of SUSTIVA in the European Expanded Access Programme. 7th European Conference on Clinical Aspects and Treatment of HIV-lnfection. Lisbon, October 1999 [Abstract 489]).

The inventors of the present invention have made an effort to formulate a pharmaceutical composition comprising a low dose self-emulsifying drug delivery system of efavirenz which can also be effectively administered for the treatment of HIV. Furthermore, the low dose self-emulsifying drug delivery system (SEDDS) compositions of the present invention have improved bioavailability due to enhanced solubility and dissolution properties.

The term 'low dose' as used herein refers to a therapeutically effective dose of efavirenz, which is less than the usual or the conventional dose required to produce the therapeutic effect.

Compositions of the invention preferably comprise low dose self-emulsifying drug delivery systems of efavirenz. Preferably, the efavirenz is present in the composition in an amount of from about 10 mg to about 500 mg. More preferably, the efavirenz is present in an amount of from about 25 mg to about 500 mg, from about 55 mg to about 500 mg, or from about 100 mg to about 500 mg. More preferably, the efavirenz is present in the compositions in an amount of from about 100 mg to about 450 mg, from about 150 mg to about 400 mg, from about 350 mg to about 450 mg, or from about 375 mg to about 425 mg.

Conventionally, it has been considered necessary to administer a daily dose of about 600 mg of efavirenz to achieve necessary therapeutic effects. Using pharmaceutical compositions of the invention, the inventors have found, surprisingly, that it has been sufficient to administer a total daily dose of less than 600 mg of efavirenz to achieve necessary therapeutic benefits.

Accordingly, the present invention also provides pharmaceutical compositions of the invention for use in the treatment of HIV or AIDS, wherein the use comprises administering a daily dose of less than 600 mg to a patient. Preferably, the total daily dose of efavirenz is from about 10 mg to about 500 mg, from about 25 mg to about 450 mg, or from about 55 mg to about 400 mg.

Preferably, the pharmaceutical composition of the present invention comprises from about 10 mg to about 500 mg, from about 25 mg to about 500 mg, from about 55 mg to about 500 mg, or from about 100 mg to about 500 mg of efavirenz, and is for use in the treatment of HIV or AIDS, wherein the use comprises administering a total daily dose of less than 600 mg of efavirenz, and preferably, from about 10 mg to about 500 mg, from about 25 mg to about 450 mg, or from about 55 mg to about 400 mg of efavirenz.

The pharmaceutical composition of the present invention can comprise from about 55 mg to about 400 mg of efavirenz, and is for use in the treatment of HIV or AIDS, wherein the use comprises administering a total daily dose of from about 55 mg to about 400 mg of efavirenz.

Preferably, the pharmaceutical composition comprises from 350 mg to 450 mg, more preferably from 375 mg to 425 mg and is for use in the treatment of HIV or AIDS, wherein the use comprises administering a total daily dose of from about 350 mg to about 450 mg of efavirenz. Preferably, there is provided the pharmaceutical composition of the present invention for use in the treatment of HIV or AIDS, wherein the use comprises administration of a pharmaceutical composition at least once a day to a patient in need thereof.

Preferably, there is provided a pharmaceutical composition comprising from about 55 mg to about 400 mg of efavirenz, for use in the treatment of HIV or AIDS, wherein the use comprises administering a total daily dose from about 55 mg to about 400 mg of efavirenz, and wherein the use comprises administration of the pharmaceutical composition at least once a day to a patient in need thereof.

The term "Efavirenz" is used in broad sense to include not only "Efavirenz" per se but also their pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable isomers, pharmaceutically acceptable esters, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers and/or pharmaceutically acceptable complexes thereof. Preferred derivatives are pharmaceutically acceptable salts, solvates and hydrates.

The present invention provides low dose self-emulsifying drug delivery systems of efavirenz pharmaceutical compositions comprising efavirenz or its pharmaceutically acceptable derivatives along with one or more pharmaceutically acceptable excipients.

Preferably, efavirenz may be present in an amount ranging from about 15% to about 50% by weight of the composition.

The pharmaceutical composition comprising a low dose self-emulsifying drug delivery system of efavirenz, according to the present invention, may exhibit bioavailability to an extent to produce the desired pharmacological effects along with reduced side effects after administration. The pharmaceutical composition comprising a low dose self-emulsifying drug delivery system of efavirenz, according to the present invention, may be used for the treatment of HIV.

The term "pharmaceutical composition" includes tablets (single layer, bilayer, multilayer, tablet in tablet and the like) which may be uncoated, film coated, sugar coated, powder coated, enteric coated, seal coated, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, microspheres , nanoparticles , and the like or combinations thereof), soft gelatin capsules, sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, film coated tablets, MUPS, film coated tablets MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, microspheres, nanoparticles and the like or combinations thereof) and sprinkles. However other dosage forms such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, micro emulsions, sprays, spot-on and the like), solid dispersion, injection preparations, gels, aerosols, ointments, creams, controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like or combinations thereof may also be envisaged under the ambit of the invention.

Preferably, the pharmaceutical composition comprising a low dose self-emulsifying drug delivery system of efavirenz is for oral administration.

The oral route has been the major route of drug delivery for the chronic treatment of human diseases. However, oral delivery of 50% of the drug compound is hampered because of the high lipophilicity of the drug itself. In drug discovery, about 40% of the new drug candidates display low solubility in water which leads to poor bioavailability, high intra subject/inter subject variability and lack of dose proportionality. Furthermore, oral delivery of numerous drugs is hindered owing to their high hydrophobicity. Therefore producing suitable formulations is very important to improve the solubility and bioavailability of such drugs. Self-emulsifying systems such as SEDDS are a useful means for improving the bioavailability of poorly water soluble drugs. Particularly the self-micro emulsifying drug delivery systems are well known for their potential as alternative strategies for delivery of hydrophobic drugs.

The average droplet size of the pharmaceutical composition comprising a low dose self- emulsifying drug delivery system of efavirenz was determined by using Malvern Zetasizer (Malvern Instrument UK) and is in the size range of 10 nm - 500 nm. Preferably, the average droplet size is in the size range of 20 nm - 200 nm. More preferably, the average droplet size is in the size range of 15 nm - 150 nm.

The pharmaceutical composition comprising a low dose self-emulsifying drug delivery system of efavirenz according to the present invention may comprise carriers/excipients suitable for formulating the same.

Suitable lipids or oils that may be used in the low dose self-emulsifying drug delivery system of efavirenz comprise, but are not limited to vegetable oils and vegetable oil derivatives. Vegetable oils may comprise mixtures of triglycerides (90 to 95% w w) but also free fatty acids, phospholipids, and non saponifiable products such as pigments and sterols or fat soluble vitamins like tocopherols, carotenoid, castor oil, coconut oil, corn oil, cotton seed oil, grape seed oil, olive oil and sesame oil and the like or combinations thereof.

Vegetable oil derivatives may comprise hydrogenated vegetable oils, partial glycerides, polyoxylglycerides, ethoxylated glycerides and esters of edible fatty acids and various alcohols. Hydrogenated vegetable oils such as hydrogenated castor oil (Lubritab^®, Akofine^®, Cutina HM) or hydrogenated soybean oil (Hydrocote^®). Medium-chain TAG (Miglyol 812, Tricaprylin), Caprylic/capric TG (Labrafac CC), Ethyl oleate, Glycerol caprylate caprate (Captex 355), FA ester (Isopropyl myristate), PG dicaprylocaprate (Labrafac PG), Glyceryl mono-oleate (Peceol), Glyceryl mono-linoleate (Maisine 35-1 ), Caprylic/capric glycerides (lmwitor 988, 191 , Akoline MCM, Capmul MCM, Capmul MCM C-8, Capmul MCM C-10) Glyceryl mono, di tri behenate (Compritol 888 ATO), Glyceryl tricaprylate/caprate/stearate (Softisan 378), Glyceryl monooleate (Capmul GMO) and the like or combinations thereof. Preferably, the lipid or oil used in the pharmaceutical composition of the present invention comprises hydrogenated castor oil, caprylic/capric glycerides, medium-chain triacylglycerols or any combinations thereof.

Preferably, the lipids or oils may be present in an amount ranging from about 5% to about 45% by weight of the composition.

Suitable surfactants that may be incorporated in the low dose self-emulsifying drug delivery system of efavirenz comprise, but are not limited to 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), Kolliphor^® 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 combinations thereof.

Preferably, the surfactant comprises D-alpha-tocopheryl PEG 1000 succinate, polyoxyl castor oils, hydrogenated polyoxylcastor oils, lauroyl macrogolglycerides, caprylocaproyl macrogol glycerides, diethylene glycol monoethyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil or any combinations thereof.

Preferably, the surfactants may be present in an amount ranging from about 15 % to about 55 % by weight of the composition. More preferably, the oil or lipid comprises a caprylic/capric glyceride and the surfactant comprises one or more of polyoxyl 35 castor oil, lauryl macrogol glyceride or caprylocaproyl macrogol glyceride.

Suitable co-solvents that may be incorporated in the low dose self-emulsifying drug delivery system of efavirenz comprise, but are not limited to, ethanol, PEG, Diethylene glycol monoethyl ether (Transcutol P, Transcutol HP) and the like or combinations thereof.

Preferably, the co-solvent comprises ethanol, polyethylene glycol, diethylene monoethyl ether, or any combinations thereof.

Preferably, the co-solvents may be present in an amount ranging from about 5% to about 30% by weight of the composition.

Further, the pharmaceutical composition comprising a self-emulsifying drug delivery system of efavirenz is free of PEG-6 Caprylic/Capric Glycerides (Softigen^® 767).

The pharmaceutical composition comprising a low dose self-emulsifying drug delivery system of efavirenz is provided as a liquid and/or semi-solid optionally filled in a hard or soft gelatin capsule.

Soft gelatin capsules are a suitable dosage form for the administration of liquids, suspensions, pastes and the like. Soft gelatin capsules are an effective delivery system, especially for poorly soluble drugs because the capsules can contain liquids and/or semi-solid ingredients that help increase solubility or permeability of the drug across the membranes in the body. Also the soft gelatin capsules ease the ingestion process and exhibit uniform drug distribution at the site of action where the active ingredient is released, thus improving the bioavailability.

Further, the pharmaceutical composition comprising a low dose self-emulsifying drug delivery system of efavirenz of the present invention may also comprise one or more pharmaceutically acceptable ingredients, such as, but not limited to polymers, carriers, diluents or fillers, binders, lubricants, plasticizers, glidants, antiadhereants, colourants, flavourants and disintegrants, or any combination thereof.

The pharmaceutical composition according to the present invention may also optionally be coated, i.e. seal coated, enteric coated or film coated.

The pharmaceutical composition may be film coated with, but not limited to, colour mix systems and polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol.

In one embodiment the pharmaceutical composition comprising a low dose self- emulsifying drug delivery system of efavirenz can be formulated in a suitable liquid oral dosage form, including but not limited to emulsions, solutions, suspensions, syrups, and elixirs.

The pharmaceutical composition may be prepared by admixing a low dose self- emulsifying drug delivery system of efavirenz obtained according to the present invention with other suitable pharmaceutically acceptable excipients such as sweeteners, vehicle/wetting agents, coloring agents, flavoring agents, preservatives, viscosity enhancing/thickening agents, film formers, plasticizers, opacifiers and the like or combinations thereof.

Accordingly, the pharmaceutical composition of the invention may further comprise other suitable pharmaceutically acceptable excipients such as sweeteners, vehicle/wetting agents, coloring agents, flavoring agents, preservatives, viscosity enhancing/thickening agents, film formers, plasticizers, opacifiers, and the like or combinations thereof.

Suitable viscosity enhancing/thickening agents which may be used, include, but are not limited to methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy ethyl propyl cellulose, starches (such as maize or corn starch, potato starch, rice starch, tapioca starch, and wheat starch), carboxyvinyl polymers (carbomers such as Carbopol®), carboxymethyl cellulose and salts thereof, microcrystalline cellulose and arabic gum, guar gum, and xanthan gum, and the like or combinations thereof. Suitable vehicle/wetting agents which may be used, include, but are not limited to glycerol, propylene glycol, liquid polyethylene glycols, sorbitol, water and the like or combinations thereof.

Suitable flavouring agents which may be used include, but are not limited to cherry, raspberry, pineapple, black currant, strawberry flavour, caramel chocolate flavour, mint cool flavour, fantasy flavour, meat flavours and the like or combinations thereof.

Suitable sweeteners which may be used include, but are not limited to, saccharin, aspartame, acesulfame, cyclamate, alitame, a dihydrochalcone sweetener, monellin, neohesperidin, neotame, stevioside and sucralose, the pharmaceutically acceptable salts and the like or combinations thereof.

Suitable colouring agents which may be used include, but are not limited to quinoline yellow and the like or combinations thereof.

Suitable preservatives which may be used include, but are not limited to, sodium benzoate, benzoic acid, potassium sorbate, sorbic acid, methyl p-hydroxibenzoate, ethyl p-hydroxibenzoate, propyl p-hydroxibenzoate, butyl p-hydroxibenzoate, sodium methyl p-hydroxibenzoate, sodium ethyl p-hydroxibenzoate, sodium propyl p-hydroxibenzoate, sodium butyl p-hydroxibenzoate, domiphen bromide, sodium propionate, propylene glycol and the like or combinations thereof.

Suitable opacifiers which may be used include, but are not limited to titanium dioxide.

Suitable plasticizers which may be used include, but are not limited to, glycerin or polyhydric alcohols such as, but are not limited to glycerol, propylene glycol, polyvinyl alcohol, sorbitol and maltitol.

Suitable film forming materials, which may be used include, but are not limited to gelatin.

The present invention also provides a process to manufacture the pharmaceutical composition comprising a low dose self-emulsifying drug delivery system of efavirenz according to the present invention. Accordingly, the present invention provides a process which process comprises dispersing or dissolving efavirenz along with pharmaceutically acceptable excipients and further formulating to a desired dosage form.

The present invention also provides a process which process comprises dispersing or dissolving efavirenz along with pharmaceutically acceptable excipients, optionally followed by encapsulation in soft or hard gelatin capsules.

The pharmaceutical composition of the invention can thus be filled into soft or hard gelatin capsules, by being subjected to suitable filling and sealing techniques.

Further, the low dose self-emulsifying drug delivery system of efavirenz according to the present invention may further comprise at least one additional active ingredient such as but not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors and integrase inhibitors and the like or combinations thereof.

Suitable integrase inhibitors include but are not limited to dolutegravir, raltegravir, MK- 2048, JTK-656, elvitegravir.

Suitable nucleoside reverse transcriptase inhibitors (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, -L-FD4 (also called -L-D4C and named -L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, the purine nucleoside, (-)- -D-2,6-diamino-purine dioxolane; and lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro- - D-threo-pentofuranosyl)adenine

Suitable nucleotide reverse transcriptase inhibitors (NtRTIs) that may be employed in the pharmaceutical composition of the present invention may comprise tenofovir or its prodrug thereof, and adefovir. Suitable non-nucleotide reverse transcriptase inhibitors (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-1 153 or AG-1 549; 5-(3,5-dichlorophenyl)-thio- 4-isopropyl-1-(4-pyridyl)methyl-1 H-imidazol-2- -ylmethyl carbonate); emivirine [MKC- 442; (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1 H,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- 1 1 ,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-1 H-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 protease inhibitors (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; TMC1 14; 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; ohydroxy-γ- [[(carbocyclic- or heterocyclic-substituted) amino) carbonyl] alkanamide derivatives; γ- hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides; dihydropyrone derivatives and a- and β-amino acid hydroxyethylamino sulfonamides; 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 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; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

Specifically, the low dose self-emulsifying drug delivery system of efavirenz may further comprise at least one additional active ingredient such as emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, lamivudine, stavudine, zidovudine and the like or combinations thereof.

The present invention further provides a self-emulsifying drug delivery system of efavirenz for use in medicine, wherein the use is for the treatment of HIV and which use comprises administering a daily dose of less than 600 mg of efavirenz to a patient in need thereof.

The present invention also provides a method of treating HIV comprising administering self-emulsifying drug delivery system of efavirenz wherein the method comprises administering a daily dose of less than 600 mg of efavirenz to a patient in need thereof.

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) Cremophor ELP and Capmul MCM were added in a container and stirred to form a mixture.

2) Efavirenz was added to the mixture obtained in step (1) to form a solution.

3) The solution obtained in step (2) was filled in soft or hard gelatin capsule.

Example 2

Process:

2) Ethanol was added to the mixture obtained in step (1).

3) Efavirenz was added to the mixture obtained in step (2) to form a solution.

3) The solution obtained in step (3) was filled in soft or hard gelatin capsule.

Example 3

Process:

1) Cremophor ELP and Capmul MCM were added in a container, heated and stirred to form a mixture.

2) Efavirenz was added to the mixture obtained in step (1) to form a solution.

Example 4

Process:

2) Efavirenz was added to the mixture obtained in step (1) to form a solution.

Example 5

Process:

1) Efavirenz was added to Phosal under sonication

2) The solution obtained in step (1) was filled in soft or hard gelatin capsule. Example 6

Process:

2) Vitamin E TPGS was heated and added to the solution obtained in step (1).

3) Efavirenz was added to the mixture obtained in step (2) to form a solution.

4) The solution obtained in step (3) was filled in soft or hard gelatin capsule.

Example 7

Process:

2) Labrasol was heated and added to the solution obtained in step (1).

3) Efavirenz was added to the mixture obtained in step (2) to form a solution. 4) The solution obtained in step (3) was filled in soft or hard gelatin capsule.

Example 8

Process:

2) Labrasol was heated and added to the solution obtained in step (1).

3) Efavirenz was added to the mixture obtained in step (2) to form a solution.

Example 9

Process:

1) Gelucire was added in a container and heated.

2) Efavirenz was added to the liquid obtained in step (1).

3) This mass obtained in step (2) was then filled in soft or hard gelatin capsules. Example 10

Process:

2) Efavirenz was added to the mixture obtained in step (1) to form a solution.

Example 11

Process:

2) Efavirenz was added to the mixture obtained in step (1) to form a solution.

Example 12 Sr. No. Ingredients mg/unit

1 Efavirenz 400

2 Capmul MCM 315

3 Cremophor ELP 438.75

4 Labrasol 146.25

Total 1300

Process:

2) Labrasol was heated and added to the solution obtained in step (1).

3) Efavirenz was added to the mixture obtained in step (2) to form a solution.

Example 13

Process:

2) Kolliphor TPGS was heated and added to the solution obtained in step (1).

3) Efavirenz was added to the mixture obtained in step (2) to form a solution.

4) The solution obtained in step (3) was filled in soft or hard gelatin capsule. Example 14

Process:

2) Labrasol was heated and added to the solution obtained in step (1).

3) Efavirenz was added to the mixture obtained in step (2) to form a solution.

Example 15

* Formula for Gelatin Shell:

* Inclusive of 2% extra water to be used to compensate the loss during processing of capsule preparation. Example 16 - Pilot study I

A single-dose, randomized, open-label, crossover, pilot, comparative bioavailability study of Efavirenz 300 mg capsules (Cipla Limited, India), Efavirenz 400 mg capsules (Cipla Limited, India), and Sustiva^® 600 mg tablets (Bristol-Myers Squibb Company, USA) in healthy male and female volunteers under fasting conditions was performed.

Test Product (T1): Efavirenz 300 mg Capsules manufactured by Cipla Limited, India.

Test Product (T2): Efavirenz 400 mg Capsules manufactured by Cipla Limited, India.

Reference Product (R): Sustiva^® 600 mg Tablets marketed by Bristol-Myers Squibb Company, USA.

When the Test Product (T1) was compared with the Reference Product (R) the C_maxand AUC of the Test Product (T1) was less than the C_max and AUC of the Reference Product (R) - see Figure 1.

When the Test Product (T2) was compared with the Reference Product (R) the C_max and AUC the Test Product (T2) was approximately equal to the C_max and AUC of the Reference Product (R) - see Figure 2.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein. 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 "an excipient" includes a single excipient as well as two or more different excipients, and the like.

Claims

1. A pharmaceutical composition comprising a self-emulsifying drug delivery system, wherein the self-emulsifying drug delivery system comprises efavirenz and one or more pharmaceutically acceptable excipients.

2. A pharmaceutical composition according to claim 1 , wherein the efavirenz is in the form of a pharmaceutically acceptable derivative thereof.

3. A pharmaceutical composition according to claim 2, wherein the wherein the pharmaceutically acceptable derivative thereof is a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug.

4. A pharmaceutical composition according to any preceding claim, wherein said pharmaceutical composition is for oral administration.

5. A pharmaceutical composition according to any preceding claim, wherein said pharmaceutical composition is for once a day administration.

6. A pharmaceutical composition according to any preceding claim, wherein said pharmaceutical composition is provided as a liquid and/or semi-solid optionally filled in a capsule.

7. A pharmaceutical composition according to any preceding claim, wherein the efavirenz is present in an amount of from about 15% to about 50% by weight of the composition.

8. A pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprise at least one lipid or oil, optionally in an amount of from about 5% to about 45% by weight of the composition.

9. A pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprise at least one surfactant, optionally in an amount of from about 15% to about 55% by weight of the composition.

10. A pharmaceutical composition according to any preceding claim, wherein the at least one or more pharmaceutically acceptable excipients comprises at least one co- solvent, optionally in an amount of from about 5% to about 30% by weight of the composition.

1 1 . A pharmaceutical composition according to any one of claims 8 to 10, wherein the lipid or oil comprises hydrogenated castor oil, caprylic/capric glycerides, medium- chain triacylglycerols, or any combination thereof.

12. A pharmaceutical composition according to any one of claims 9 to 1 1 , wherein the surfactant comprises D-alpha-tocopheryl PEG 1000 succinate, polyoxyl castor oils, hydrogenated polyoxylcastor oils, lauroyl macrogolglycerides, caprylocaproyl macrogol glycerides, diethylene glycol monoethyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil or any combination thereof.

13. A pharmaceutical composition according to any one of claims 10 to 12, wherein the cosolvent comprises ethanol, polyethylene glycol, diethylene monoethyl ether, or any combination thereof.

14. A composition according to any preceding claim, wherein the composition is free of PEG-6 Caprylic/Capric Glycerides (Softigen^®767).

15. A pharmaceutical composition according to any preceding claim, wherein the excipients comprise one or more of the following: a viscosity enhancing agent or thickening agent, a vehicle or wetting agent, a flavouring agent and/or a sweetener, a colouring agent, a preservative, an opacifier, a plasticiser, or any combination thereof.

16. A pharmaceutical composition according to any preceding claim, wherein efavirenz is present in an amount of from about 10 mg to about 500 mg.

17. A pharmaceutical composition according to any preceding claim, wherein the efavirenz is present in an amount of from 25 mg to 500 mg.

18. A pharmaceutical composition according to any preceding claim, wherein the efavirenz is present in an amount of from 55 mg to 500 mg.

19. A pharmaceutical composition according to any preceding claim, wherein the efavirenz is present in an amount of from 100 mg to 500 mg.

20. A pharmaceutical composition according to any preceding claim, wherein the efavirenz is present in an amount of from 100 mg to 450 mg.

21 . A pharmaceutical composition according to any preceding claim, wherein the efavirenz is present in an amount of from 150 mg to 400 mg.

22. A pharmaceutical composition according to any preceding claim, wherein the efavirenz is present in an amount of from 350 mg to 450 mg, optionally 375 mg to 425 mg.

23. A pharmaceutical composition according to any preceding claim, further comprising at least one additional active ingredient such as protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, integrase inhibitors, or any combination thereof.

24. A pharmaceutical composition according to claim 23, wherein the at least one additional active ingredient comprises emtricitabine, tenofovir disproxil fumarate, tenofovir alafanamide fumarate, lamivudine, stavudine, zidovudine, or any combination thereof.

25. A process for preparing a pharmaceutical composition according to any one of claims 1 to 24, wherein the process comprises dispersing or dissolving efavirenz with at least one or more pharmaceutically acceptable excipients.

26. A capsule comprising a pharmaceutical composition according to any one of claims 1 to 24.

27. A pharmaceutical composition according to any one of claims 1 to 24, or a capsule according to claim 25, for use in medicine.

28. A pharmaceutical composition for use or capsule for use according to claim 27, for use in the treatment of HIV.

29. A pharmaceutical composition for use according to claim 28, wherein the use comprises administering a daily dose of less than 600 mg of efavirenz to a patient in need thereof.

30. Use of a pharmaceutical composition according to any one of claims 1 to 24 or a capsule according to claim 26 in the manufacture of a medicament for the treatment of HIV.

31 . Use according to claim 30, wherein the use comprises administering a daily dose of less than 600 mg of efavirenz to a patient in need thereof.

32. A method of treating HIV comprising administering a pharmaceutical composition according to any one of claims 1 to 24, or a capsule according to claim 26 to a patient in need thereof.

33. A method of treating HIV according to claim 32, wherein the method comprises administering a daily dose of less than 600 mg of efavirenz to a patient in need thereof.

34. A pharmaceutical composition substantially as described herein.

35. A process for preparing a pharmaceutical composition substantially as described herein.