FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of sirolimus or pharmaceutically acceptable salts thereof for oral administration and process of preparation thereof.

BACKGROUND OF THE INVENTION

Sirolimus, which is also known as rapamycin, a macrolide antibiotic produced by Streptomyces hygroscopicus, is an immunosuppressant drug used to prevent rejection in organ transplantation.

U.S. Patent No. 3,929,992 discloses rapamycin, its preparation and its antibiotic activity for the first time. U.S. Patent No. 5,100,899 discloses the use of Rapamycin to inhibit transplantation rejection in mammals.

U.S. Patent Nos. 5,989,591 and 5,985,325 disclose a solid dosage unit of rapamycin comprising a core, which is over coated with rapamycin, and a sugar coat containing one or more surface modifying agents, one or more sugars and optionally one or more binders.

U.S. Patent No. 5,145,684 discloses a nanoparticulate composition comprising particles consisting of a poorly soluble drug having adsorbed onto the surface thereof a non-crosslinked surface stabilizer, wherein effective average particle size of drug substance is less than about 400 nm.

U.S. Patent Nos. 5,516,770 and 5,530,006 disclose intravenous sirolimus composition. U.S. Patent Nos. 5,536,729 and 5,559,121 disclose liquid oral sirolimus composition.

U.S. Patent Application No. 11/951,910 discloses a nanodispersion of Sirolimus comprising Sirolimus and a surface modifier, wherein the effective average particle size of Sirolimus is more than 400 nm.

U.S. Patent Application No. 12/127,130 discloses a pharmaceutical composition of sirolimus comprising an inert core and a sugar overcoat, wherein said sugar overcoat comprises a) sirolimus; b) poloxamer; c) microcrystalline cellulose; and d) a binder selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methyl cellulose or a mixture thereof; and wherein the poloxamer is not poloxamer 188.

U.S. Patent Application No. 12/578,776 discloses a pharmaceutical formulation, comprising a pharmacologically inert core having a coating comprising: (a) sirolimus or a derivative thereof; (b) at least one surface modifying agent; and (c) one or more sugars in an amount less than about 35% of the weight of the sugar overcoat.

PCT patent application WO 2011/135580 discloses stable solid pharmaceutical matrix composition comprising sirolimus or pharmaceutically acceptable salts thereof along with one or more sugars.

Sirolimus is marketed by Wyeth under the trade name Rapamune® as 0.5 mg, 1 mg and 2 mg oral tablets for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. It is also available as an oral solution containing 1 mg/ml sirolimus.

Sirolimus is poor oil and water solubility, poses a significant problems in formulating the drug into suitable dosage form. In addition, it has been reported that compositions of sirolimus with conventional excipients show unpredictable dissolution rates, irregular bioavailability profiles, as well as stability problems. There is therefore an existing and continual need for stable and therapeutically equivalent oral solid pharmaceutical compositions of sirolimus. The compositions of the invention overcome all the problems encountered during prior know formulation development process.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar.

In another aspect, a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and the inert core is a sugar sphere.

In another aspect, a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and the inert core is a mixture of sugar sphere and microcrystalline cellulose spheres.

In another aspect, a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar comprising sirolimus and an excipient.

In another aspect, a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat devoid of sugar comprises sirolimus and an excipient selected from the group consisting of a binder, a surface active agent and an antioxidant.

In another aspect, a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the inert core is a sugar sphere and the drug overcoat devoid of sugar comprises sirolimus, povidone, poloxamer and tocopherol.

In another aspect, a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,

a) preparing a drug overcoat by dispersing or dissolving sirolimus and an excipient in a solvent, wherein the overcoat is devoid of sugar,

b) spraying the drug overcoat onto a inert core and drying until the desired quantity of sirolimus has been sprayed onto the inert core.

In another aspect, a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and wherein the inert coat is a sugar sphere.

In another aspect, a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and wherein the drug overcoat is prepared by dispersing or dissolving sirolimus and an excipient in an organic solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present Invention relates to pharmaceutical compositions comprising sirolimus and pharmaceutically acceptable salts thereof, processes for preparing compositions comprising sirolimus, and their methods of use, treatment, and administration.

In one embodiment of the invention relates to a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar.

The term "sirolimus" includes various forms of sirolimus such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art. Sirolimus can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "sirolimus" as used in the present invention.

The term "inert core" as used herein comprises a pharmacologically inactive tablet, core, or inert beads or spheres which comprise one or more of soluble or insoluble inert materials and the like, or mixtures thereof. The cores may be optionally seal coated to increase the strength of the core to withstand the mechanical pressures during processing.

The term "drug overcoat devoid of sugar" as used herein comprises a layer which coats the core. It comprises sirolimus, an excipient but devoid of any sugar. The coating can exist as one or more layers, optionally having one or more separating functional or non¬functional layers sandwiched between.

The term "pharmaceutical composition" as used herein refers to a solid dosage form suitable for administration, such as a tablet, capsule, granules, pill, etc.

The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The active ingredient, active agent and drug herein can be interchangeably used.

As used herein,"%" refers to the weight percent of a substance as it relates to the overall composition unless otherwise indicated.

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

In an aspect, the invention relates to pharmaceutical composition comprising sirolimus, wherein embodiments comprise: a) an inert core; b) a drug overcoat comprising sirolimus and an excipient surrounding the core, wherein the drug overcoat is devoid of sugar.

In an aspect, the invention relates to pharmaceutical composition comprising sirolimus, wherein embodiments comprise: a) an inert core, b) optionally, a barrier layer over the inert core, c) a drug overcoat comprising sirolimus and an excipient surrounding the core, wherein the drug overcoat is devoid of sugar.

In an aspect, the invention relates to pharmaceutical composition comprising sirolimus, wherein embodiments comprise: a) an inert core, b) optionally, a barrier layer over the inert core, c) a drug overcoat comprising sirolimus and an excipient surrounding the core, wherein the drug overcoat is devoid of sugar and d) optionally, a film coat over the drug overcoat.

"Sugar" as used herein includes but not limited to one or more of lactose, mannitol, sorbitol, starch, fructose, xylitol, and sucrose.

The inert cores are pharmacologically inert in nature and pharmaceutically compatible. An inert core may be spheres or a placebo tablet, prepared by compressing a mixture of excipients. The inert core is a sugar sphere. A mixture of different spheres with sugar sphere can be used in the present invention. The sugar sphere alone or a mixture of sugar sphere and microcrystalline cellulose sphere as inert core is the most preferred.

Non-limiting examples of various substances that can be used for inert cores along with sugar sphere include insoluble inert materials such as particles/beads of silicon dioxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, microcrystalline cellulose, cellulose derivatives, calcium carbonate, dibasic calcium phosphate anhydrous, dibasic calcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, and magnesium oxide, soluble cores such as sugar spheres having sugars like dextrose, lactose, anhydrous lactose, spray-dried lactose, lactose monohydrate, mannitol, starches, sorbitol, and sucrose, insoluble inert plastic materials such as spherical or nearly spherical core beads of polyvinylchloride or polystyrene, and any other pharmaceutically acceptable insoluble synthetic materials, and the like and mixtures thereof.

In another embodiment of the invention relates to pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat devoid of sugar comprises sirolimus and an excipient selected from the group consisting of a binder, a surface active agent and an antioxidant.

The composition according to the invention can comprise binders, such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. It is preferable to use a binder with good water solubility. In a preferred embodiment of the invention the excipients include at least one binder selected from hydroxypropyl cellulose and povidone. The binding agent is present in the composition in an amount of from about 0.1% to about 15%, preferably from about 0.1%, to about 10%, more preferably from about 0.5% to about 5%.

Surfactant otherwise called surface-active agents or solubilizing agents, used to disperse the drug in a particular solvent and also enhance wetting properties of the drug thereby helps either to lower the surface tension of a liquid, allowing easier spreading, and lower the interfacial tension between two liquids or to solubilize the active agent either in composition or in-situ at the site of absorption or action. They contain both hydrophobic groups and hydrophilic groups, thus being soluble in both organic solvents and water. Surface-active agents include but are not limited to surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination thereof. Non-limiting examples of surfactants include non-ionic, anionic, cationic, amphoteric or zwitterionic or any combination thereof. Non-ionic surfactant is preferable.

Examples of suitable non-ionic surfactants include ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; alkyl polyglucosides; stearol ethoxylates; and alkyl polyglycosides.

Preferred non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.

More preferably, the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. The glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.

Also preferred are non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products. The polyol is preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

Examples of suitable anionic surfactants include alkylether sulfates; alkylether carboxylates; alkylbenzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffin sulfonates; secondary n-alkane sulfonates; alpha-olefin sulfonates; and isethionate sulfonates.

Examples of suitable cationic surfactants include fatty amine salts; fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; and sulfonxonium surfactants.

Examples of suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; and amidobetaines.

Mixtures of surface-active agents may be used. In such mixtures there may be individual components which are liquid, provided that the carrier material overall, is a solid. The concentration of surface-active agent in the composition is from range of about 0.01 to about 10.0% (based on the total mass of the pharmaceutical composition), preferably about 0.1 to about 5%, more preferably of about 0.1 to about 2%. The weight ratio of sirolimus to surfactant is from 10: 1 to 1: 1 (preferably 5: 1 to 1: 1).

Non limiting examples of surfactants are sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc. such as Span® or Arlacel®, Emsorb®, Capmul®, or Sorbester®, Triton X-200 etc.; or a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween®60), polyoxyethylene (20) sorbitan monopalmitate (Tween®40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20); or polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®); or hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH® 60); or sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate; or vitamin E and its derivatives such as Vitamin E-TPGS® (d-alpha-tocopheryl polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate; or bile acids and salts thereof; or ethoxylated triglycerides; or quaternary ammonium salts such as cetyl-trimethylammonium bromide, cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and triacetin; or triethanolamine, lecithin, monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol fatty acid esters such as mono-, di- and triglycerides and a cetylated mono- and di-glycerides; propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. l-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)- derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N, N- dimethylammonio-1-propanesulfonates, 3-cholamido-l-propyldimethylammonio-l- propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.), long-chain falty acids and salts thereof C6-C12 (eg. oleic acid and caprylic acid), acylcarnitines and derivatives, N-a-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N-ct-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N-a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surface-active agent constitutes an alternative embodiment of the invention.

The composition may further comprise antioxidant, to protect the drug from oxidative degradation. Antioxidants may be selected from group consisting of ascorbic acid, sodium pyrosulphite, glutathione or sorbic acid, tocopherol and the like, in particular tocopherol E-acetate. Weak organic acids like citric acid, tartaric acid, fumaric acid, maleic acid can be used in the drug overcoat to stabilize the formulation.

Various solvents used in processes for preparing the drug overcoat include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran, and mixtures thereof. Preferably organic solvents are used to prepare the drug overcoat.

In order to provide a barrier layer between inert core and drug overcoat or a final film coating drug overcoat, various film-forming coating composition are used. Film coating composition usually contains the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s). In film coating suspension the minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials.

Non limiting examples of cellulose ethers are methylcelluloses, hydroxymethylcelluloses, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethyl ethylcellulose, and sodium carboxymethyl celluloses; acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate trimellitates, hydroxypropylmethylcellulose phthalates, polyvinyl acetate phthalates, etc.; insoluble cellulose derivatives such as ethylcelluloses and the like; dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinylalcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (e.g., Eudragit®), and chitosan and derivatives thereof. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/dissolution of the film.

The commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol and macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil). A plasticizer is frequently present in amounts ranging from about 5% (w/w) to 30% (w/w) based on the total weight of the film coating. Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials from each group can be combined in defined ratios. Film coating suspensions can be used as ready-to-make preparations which are available on the market.

Film coating dispersion can be prepared by using different solvents water, alcohols, ketones, esters, chlorinated hydrocarbons or mixture thereof.

Suitable polishing agents include polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax). In embodiments, polyethylene glycols having molecular weights about 3,000-20,000 are employed.

Optionally, cores/tablets can be coated with conventional materials used for film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995, edited by Graham Cole.

Another embodiment of the invention relates to a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,

a) preparing a drug overcoat by dispersing or dissolving sirolimus and an excipient in a solvent, wherein the overcoat is devoid of sugar,

b) spraying the drug overcoat onto a inert core and drying until the desired quantity of sirolimus has been sprayed onto the inert core.

Another embodiment of the invention relates to a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,

a) preparing a drug overcoat by dispersing or dissolving sirolimus and an excipient in a solvent, wherein the overcoat is devoid of sugar,

b) optionally, a barrier layer over the inert core,

c) spraying the drug overcoat onto a inert core and drying until the desired quantity of sirolimus has been sprayed onto the inert core.

Another embodiment of the invention relates to a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,

a) preparing a drug overcoat by dispersing or dissolving sirolimus and an excipient in a solvent, wherein the overcoat is devoid of sugar,

b) optionally, a barrier layer over the inert core,

c) spraying the drug overcoat onto a inert core and drying until the desired quantity of sirolimus has been sprayed onto the inert core,

d) optionally, a film coat over the drug overcoat.

Another embodiment of the invention relates a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat devoid of sugar, wherein the inert coat is a sugar sphere.

Another embodiment of the invention relates a process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar and wherein the drug overcoat is prepared by dispersing or dissolving sirolimus and an excipient in an organic solvent.

The coating steps comprise drug layering techniques or coating techniques known to the skilled artisan. For example, the drug layering or coating techniques may include, but are not limited to, powder coating, spray coating, dip coating, fluidized bed coating with Wurster or top spray or side spray techniques, and modifications thereof.

Another embodiment of the invention relates to a pharmaceutical composition comprising sirolimus, wherein the composition may be in a monolithic form, multiparticulate form, or a combination of both.

In one embodiment, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, soft and hard gelatin capsules, suppositories etc. The preferred dosage form is tablet. The dosage form is preferably suitable for oral application.

The present pharmaceutical compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of sirolimus, the active ingredient i.e. drug coated spheres will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the sirolimus.

The composition preparations of the invention can be produced by compressing a mixture of the drug substance of the invention with excipients. For example, one method for the production includes mixing the sirolimus coated spheres with one or more excipients for the preparation by a suitable mixer, and directly compressing the mixture to tablets. Other methods include a dry granulating step to produce granules for tablets using dry granulating machines or roller compacters, and a wet granulating step to produce granules for tablets using water, ethanol and solutions containing binders. In another embodiment of the invention relates to a pharmaceutical composition of sirolimus comprising an inert core coated with a drug overcoat devoid of sugar and one or more excipients such as binders, diluents, lubricant/glidants, disintegrating agents, surfactants, solvents, and coloring agents.

Excipients such as diluents, lubricants and glidants commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe, Paul J Sheskey & Sian C Owen (2006)] the content of which is incorporated herein by reference.

Other excipients are also used in the preparation of the pharmaceutical composition like diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof. A preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica. Preferably, the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.

Non-limiting examples of binders include one or more of gum acacia, cholesterol, tragacanth, stearic acid, gelatin, casein, lecithin (phosphatides), carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcelluloses, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalates, microcrystalline celluloses, noncrystalline celluloses, polyvinylpyrrolidones (povidones or PVP), cetostearyl alcohol, cetyl alcohol, cetyl esters wax, dextrates, dextrin, lactose, dextrose, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyoxyethylene alkyl ethers, polyethylene glycols, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyvinylalcohols, and mixtures thereof.

Non-limiting examples of disintegrants include starches, modified starches, croscarmellose sodium, crospovidones, and sodium starch glycolate.

The composition according to the invention can also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof. It is preferred that the excipients include at least one lubricant, selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate. The composition can also comprises glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

Useful coloring agents include FDA approved colorants and examples are iron oxides, lake of tartrazine, allura red, lake of quinoline yellow, and lake of erythrosine.

One or more of these additives may be selected and used by the skilled artisan having regard to the particular desired properties of the pharmaceutical composition by routine experimentation and without any undue burden. The absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the pharmaceutical composition and may also be chosen by the skilled artisan by routine experimentation without undue burden.

The composition prepared can be packaged using appropriate packaging materials such as containers and closures composed of polyethylene (high density polyethylene or low density polyethylene), polypropylene, glass, stainless steel, etc. Also useful are various blisters or strips composed of aluminum or high-density polypropylene, or polyvinyl chloride, or polyvinyl chloride (PVC) coated with polyvinylidene dichloride (PVDC), generally termed PVC/PVDC.

In another embodiment, at least 60 % of drug are dissolved from the pharmaceutical composition in a 0.4% SLS in water in 30 minutes, when dissolution is performed using a basket apparatus according to Ph. Eur. or an apparatus I according to USP, at a temperature of the dissolution medium of 37±0.5°C, speed of rotation of the paddle 150 rpm and volume of the dissolution medium 500 ml. Preferably the drug release rate of the composition of the invention is more than 40% in 15 minutes, above 60% in 30 minutes, and above 75% in 45 minutes.

The exact dose of active agent and the particular formulation to be administered depend on a number of factors, e. g. the condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect. Another embodiment of the invention relates to methods of using pharmaceutical compositions of the present invention for the known indications of the particular active agent incorporated therein including prophylaxis of organ rejection especially in renal transplantation.

Another embodiment of the invention relates to methods of using pharmaceutical composition of the present invention may include co-administration of cyclosporine and/or corticosteroids, as required for particular patients.

In one embodiment, a pharmaceutical composition comprising sirolimus or a pharmaceutically acceptable salt thereof of the invention has a comparable bioavailability to commercial form of sirolimus.

The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.

Procedure: Sirolimus poloxamer, tocopherol, povidone, were added to acetonitrile while stirring on a magnetic stirrer. The drug overcoat dispersion was coated on to weighed quantities of sugar spheres using fluid bed processor. Drug coated beads were mixed with microcrystalline cellulose, mannitol followed by magnesium stearate. The blend was compressed into tablet and coated with Opadry orange and finally dried.

We Claim:

1. A pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar.

2. The pharmaceutical composition of claim 1, wherein the inert core is a sugar sphere.

3. The pharmaceutical composition of claim 1, wherein the inert core is a mixture of sugar sphere and microcrystalline cellulose spheres.

4. The pharmaceutical composition of claim 1, wherein the drug overcoat comprises sirolimus and an excipient.

5. The pharmaceutical composition of claim 4, wherein the excipient is selected from the group consisting of a binder, a surface active agent and an antioxidant.

6. The pharmaceutical composition of claim 1, wherein the inert core is a sugar sphere and the drug overcoat comprises sirolimus, povidone, poloxamer and tocopherol.

7. A process for preparing a pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar by employing to the following steps,

a) preparing a drug overcoat by dispersing or dissolving sirolimus and an excipient in a solvent, wherein the overcoat is devoid of sugar,

b) spraying the drug overcoat onto a inert core and drying until the desired quantity of sirolimus has been sprayed onto the inert core.

8. The process for preparing a pharmaceutical composition of sirolimus of claim 7, wherein the inert coat is a sugar sphere.

9. The process for preparing a pharmaceutical composition of sirolimus of claim 7, wherein the drug overcoat is prepared by dispersing or dissolving sirolimus and an excipient in an organic solvent.
10. A pharmaceutical composition of sirolimus comprising an inert core and a drug overcoat, wherein the drug overcoat is devoid of sugar, wherein the composition comprises

a) about 0.55% w/w of sirolimus

b) about 0.3 % of poloxamer

c) about 0.1 % of tocopherol

d) about 0.7% of povidone

e) about 27.5% of sugar sphere

f) about 66.5% of microcrystalline cellulose

g) about 0.5% of mannitol

h) q.s. of organic solvent