DESC:FIELD OF THE INVENTION:
The present invention relates to compositions of tacrolimus or an analogue thereof and having enhanced bioavailability, more specifically stable extended release compositions comprising tacrolimus or an analogue thereof and pharmaceutically acceptable excipients and method of manufacturing thereof. The invention also relates to the use of said stable composition for the treatment of suppressing kidney rejection in a kidney transplant patient.

BACKGROUND OF THE INVENTION:
Tacrolimus is a macrolide lactone also known as FK506, fugimycin or tsukuba-enolide, which is a pharmaceutically active compound, i.e. a drug substance. Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)], 4S*,5R*,8S*, 9E,12R*, 14R*, 15S*, 16R* ,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16, 17,18,19, 24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy- 3-methoxycyclo-hexyl)-1-methylethenyl] -14,16-dimethoxy-4,10,12,18tetramethyl-8-(2- propenyl)-15,19-epoxy-3H -pyrido [2,1-c] [1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate. Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03 and has the chemical tricyclic structure shown below-

A number of tacrolimus formulations are marketed, e.g. under the tradenames Prograf®, Advagraf®, Protopic®, Envarsus® XR, and used as immunosuppressive agents to prevent allograft rejection, i.e. rejection of transplanted organs.

US patent no. 7,994,214 discloses a pharmaceutical composition comprising tacrolimus (FK-506) dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature have improved bioavailability. It also discloses a dosage forms such as solid oral unit dosage forms comprising the solid dispersion and/or solution of tacrolimus, pharmaceutically acceptable excipients and optionally pharmaceutically acceptable additive such as flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity- adjusting agents, surface-active agents, suspending agents, absorption enhancing agents and release modifying agents. It also discloses use of stabilizing agent in an amount of about 0.1% w/w to about 5% w/w.

US patent no. 9,549,918 discloses a stable pharmaceutical composition comprising a solid dispersion of tacrolimus in a vehicle further comprising a stabilizing agent capable of providing a pH below 7 in the composition, as measured after re-dispersion in water, and preventing or reducing the formation upon storage of major degradation products of tacrolimus, in particular the 8-epitacrolimus.

US patent application no. 2011/0142933 discloses a controlled release dosage form of tacrolimus, comprising a solid dispersion of tacrolimus, wherein a controlled release base, which is selected from the group consisting of a water-soluble macromolecule, a gum base, and a membrane forming agent and does not form the solid dispersion of tacrolimus, is further contained, is disclosed. The controlled release dosage form of tacrolimus has an excellent controlled release and shows a stable blood concentration.

Based on the above, there is requirement of addition of pH adjusting agent or stabilizer in the tacrolimus composition in order to control impurity and to ensure prolonged stability. Surprisingly, inventors of the present invention developed a stable composition comprising tacrolimus or analogue thereof which is substantially free of any pH adjusting agent or stabilizers and also convenient to manufacture at large scale.

SUMMARY OF THE INVENTION:
In one aspect, the present invention relates to a pharmaceutical composition comprising tacrolimus or an analogue thereof and one or more pharmaceutically acceptable excipient(s).
In another aspect, the present invention relates to a pharmaceutical composition comprising: a) Solid dispersion comprising tacrolimus or an analogue thereof and suitable pharmaceutically acceptable polymers or carriers; b) Pharmaceutically acceptable excipients comprising diluent, vehicles, release modifiers, lubricants, glidants.

In another aspect, the present invention relates to a pharmaceutical composition comprising solid dispersion comprising tacrolimus or an analogue thereof, hydroxypropyl methyl cellulose, croscarmellose sodium, and lactose.

In another aspect, the present invention relates to a pharmaceutical composition comprising: a) Solid dispersion comprising tacrolimus or an analogue thereof, hydroxypropyl methyl cellulose, croscarmellose sodium, and lactose; b) Pharmaceutically acceptable excipients comprising poloxamer, hydroxypropyl methyl cellulose, and magnesium stearate.

In another aspect, the present invention relates to a pharmaceutical composition comprising: a) Solid dispersion comprising tacrolimus or an analogue thereof, hydroxypropyl methyl cellulose, croscarmellose sodium, and lactose; b) Pharmaceutically acceptable excipients comprising lactose, poloxamer, hydroxypropyl methyl cellulose, and magnesium stearate; wherein said solid dispersion contains tacrolimus or an analogue thereof and hydroxypropyl methyl cellulose is in 1:1 w/w ratio.

In another aspect, the present invention relates to a pharmaceutical composition in the form of extended release tablet dosage form comprising: a) about 1 to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 75 to about 99% w/w of pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a pharmaceutical composition comprising solid dispersion of tacrolimus comprising: a) about 20% w/w of tacrolimus or an analogue thereof; b) about 20% w/w of hypromellose; c) about 20% w/w of croscarmellose; d) about 40% w/w of lactose anhydrous; and e) pharmaceutically acceptable solvent/vehicle.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising solid dispersion of tacrolimus comprising: a) about 15% to about 25 % w/w of tacrolimus or an analogue thereof; b) about 15% to about 25 % w/w of hydroxypropyl methyl cellulose; c) about 15% to about 25 % w/w of croscarmellose; d) about 30 % to about 50 % w/w of lactose; and e) pharmaceutically acceptable solvent/vehicle.

In another aspect, the present invention relates to a pharmaceutical composition in the form of extended release tablet dosage form wherein each tablet comprising: a) about 2 to about 25 mg of solid dispersion of tacrolimus or an analogue thereof; b) about 50 to about 200 mg of lactose; c) about 15 to about 50 mg of poloxamer; d) about 50 to about 150 mg of hydroxypropyl methyl cellulose; e) about 1.5 to about 6 mg of magnesium stearate; and f) Optionally other pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a pharmaceutical composition in the form of extended release tablet dosage form comprising: a) about 20 mg of solid dispersion of tacrolimus or an analogue thereof; b) about 150 mg of lactose; c) about 42 mg of poloxamer; d) about 132 mg of hydroxypropyl methyl cellulose; e) about 5 mg of magnesium stearate; and f) Optionally other pharmaceutically acceptable excipients; wherein the about 20 mg of solid dispersion contains about 4 mg of tacrolimus.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate and f) optionally other pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate; and f) optionally other pharmaceutically acceptable excipients; wherein solid dispersion of tacrolimus is obtained by dissolving tacrolimus in ethanol and dispersing the polymer in the obtained drug solution wherein lactose and croscarmellose sodium was further dispersed and the obtained dispersion involve evaporation and drying.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients; wherein the ratio of tacrolimus to hydroxypropyl methyl cellulose in a solid dispersion is between 0.5:2 w/w and 2:0.5 w/w.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which is substantially free of any pH adjusting agent or stabilizers i.e. contains less than or equal to 0.1% w/w of pH adjusting agent or stabilizers.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which is substantially free of any pH adjusting agent or stabilizers. Suitable pH adjusting agent or stabilizers selected from, but are not limited to, inorganic acids, inorganic bases, inorganic salts, organic acids, organic bases and pharmaceutically acceptable salts thereof. Preferred organic acids are selected from the group consisting of oxalic acid, tartaric acid and citric acid. The pharmaceutically acceptable salt of an organic acid or inorganic acid is preferably an alkali metal salt or an alkaline earth metal salt. Preferred examples of such salts are sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate.

In yet another aspect, the present invention relates to a stable pharmaceutical composition which is substantially free of any pH adjusting agent or stabilizers such as organic acid selected from succinic acid, citric acid, tartaric acid, oxalic acid, and mixtures thereof.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients; wherein the composition is substantially free of any impurity such as tacrolimus hydroxy acid, tacrolimus 8 epimer.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which is substantially free of impurity i.e. total impurity present in the composition in an amount of less than or equal to 1.5% w/w.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which contains less than or equal to 0.5% w/w of tacrolimus 8 epimers after at least 3 months of storage at 25° C and 60% relative humidity (RH), based upon 100% total weight of tacrolimus.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which contains nitrosamine impurity less than the FDA acceptable limit based on maximum daily dose of tacrolimus after at least 3 months of storage at 25° C and 60% relative humidity (RH), based upon 100% total weight of tacrolimus.

In another aspect, the present invention relates to a stable pharmaceutical composition in the form of extended release tablet dosage form wherein each tablet comprising: a) about 2 to about 25 mg of solid dispersion of tacrolimus or an analogue thereof; b) about 50 to about 200 mg of lactose; c) about 15 to about 50 mg of poloxamer; d) about 50 to about 150 mg of hydroxypropyl methyl cellulose; e) about 1.5 to about 6 mg of magnesium stearate; and f) Optionally other pharmaceutically acceptable excipients; wherein said composition exhibits a dissolution not more than 30% in 1 hour, not less than 80% in 10 hours using a paddle apparatus at a speed of about 100 rpm in dissolution medium 0.005% hydroxypropyl cellulose in water with 0.50% sodium lauryl sulfate adjusted to pH 4.5 and said composition contain less than or equal to 1.5% w/w of total impurity.

In another aspect, the dissolution medium used may contains varied amount of sodium lauryl sulfate is in the range of about 0.05 to 1%, preferably about 0.1 to 0.5%, more preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 3% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 35% w/w of lactose; c) about 15% w/w of poloxamer; d) about 45% w/w of hydroxypropyl methyl cellulose; e) about 1.2% w/w of magnesium stearate; and f) pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 2% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 35% w/w of lactose; c) about 15% w/w of poloxamer; d) about 45% w/w of hydroxypropyl methyl cellulose; e) about 1.2% w/w of magnesium stearate; and f) pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 6% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 42% w/w of lactose; c) about 12% w/w of poloxamer; d) about 38% w/w of hydroxypropyl methyl cellulose; e) about 1.4 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising tacrolimus and hydroxypropyl methyl cellulose in a solid dispersion form wherein ratio of tacrolimus to hydroxypropyl methyl cellulose is 0.5:2 w/w to 2:0.5 w/w.

In yet another aspect, the present invention relates to the process for preparation of a solid dispersion, wherein process comprises steps of: a) Dispensing of required raw material in appropriate quantities; b) Preparation of drug solution in ethanol; c) Dispersion of polymer in drug solution; d) Preparation of drug-polymer solution in methylene chloride; e) Dispersion of anhydrous lactose and croscarmellose sodium in drug-polymer solution; f) Solvent evaporation in rotary evaporator; and g) Drying in vacuum dryer.

In yet another aspect, the present invention relates to the process for preparation of an extended release tablet dosage form, wherein process comprises steps of: a) Co-sifting of tacrolimus solid dispersion and poloxamer; b) Co-sifting of lactose, hydroxypropyl methyl cellulose; c) Sifting and addition of magnesium stearate in above material; d) Blending and lubrication of material obtained in step a) and b; e) Compression.

In yet another aspect, the blend or tablet composition obtained in present invention are subjected for tests such as dissolution, assay, impurity profiling, related Substances, content uniformity, Hardness, thickness, Friability, Bulk density, Tapped density, Hausner ratio (HR), Compressibility Index, Particle Size Distribution, Loss on drying (LOD), etc.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising tacrolimus used for the suppressing kidney rejection in a kidney transplant patient.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising tacrolimus used for the suppressing kidney rejection in a kidney transplant patient such as the prophylaxis of organ rejection in de novo kidney transplant patients in combination with other immunosuppressants and the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants.

In yet another aspect, the present invention relates to method of suppressing kidney rejection in a kidney transplant patient by a pharmaceutical composition comprising tacrolimus.

In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising tacrolimus for the suppressing kidney rejection in a kidney transplant patient.

DESCRIPTION OF THE INVENTION:
The present invention can be more readily understood by reading the following description of the invention and study of the included examples.

The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. tacrolimus and its salt, solvate, esters, isomers, polymorphs that induce a desired pharmacological or physiological effect.

As used herein, the term "analogue" means a chemical compound that is structurally similar to another.

By the term “pharmaceutical composition” or “solid oral pharmaceutical composition" or "composition" or "formulation" as used herein refers to a solid dosage form comprising tacrolimus suitable for administration such as a tablet, capsule, mini-tablets, pellets, granules, pills and the like.

The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.

The term "about" as used herein means a deviation within 10%, more preferably within 5%, and even more preferably, within 2% of the numbers reported.

The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug- related impurity contents in the formulations remain within acceptable limits.

The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.

As used herein, the term “substantially free of any impurity” means total impurity present in the composition in an amount of less than or equal to 1.5% w/w.

As used herein, the term “substantially free of any pH adjusting agent or stabilizers” means any pH adjusting agent or stabilizers present in the composition in an amount of less than or equal to 0.1% w/w.

The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response, when administered to the patient.

As used herein, the term "bioavailability" denotes the degree to which a drug or other substance becomes available to the target tissue after administration.

As used herein, the term “bioequivalency” denotes a scientific basis on which generic and brand drugs are compared with one another. For example, drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions. Parameters often used in bioequivalence studies are Tmax, Cmax, AUC0-8, AUC0-t.

The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

The term “solid dispersion of tacrolimus” is premix or dispersion/solid dispersion of tacrolimus with hydroxypropyl methyl cellulose and other suitable excipients. The content of tacrolimus in solid dispersion is from about 10% w/w to about 30% w/w, preferably from about 15% w/w to about 25% w/w, specifically about 20% w/w.

The term “dispersion or solid dispersion” is defined as dispersion or premix of one or more active ingredients in an inert carrier at solid state. Process for the preparation of dispersion of tacrolimus comprises dissolving tacrolimus in solvent to form a solution, adding pharmaceutically acceptable carriers like hydroxypropyl methyl cellulose. The solid dispersion may be obtained by techniques known in the art such as freeze-drying (lyophilization), distillation, evaporation, oven drying, tray drying, spray drying, fluid bed drying, flash drying, spin flash drying and agitated thin film dryer (ATFD), hot melt extrusion and the like. Particularly, the solution is evaporated in rotary evaporator to obtain solid dispersion.

The term modified-release drug product as used herein is to describe products that alter the timing and/or the rate of release of the drug substance.

The pattern of drug release from modified-release (MR) dosage forms is deliberately changed from that of a conventional (immediate-release) dosage formulation to achieve a desired therapeutic objective or better patient compliance. Types of MR drug products include delayed release (e. g, enteric coated), extended release (ER), and orally disintegrating tablets (ODT). Extended-release drug products is a dosage form that allows at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate-release (conventional) dosage form. Examples of extended-release dosage forms include controlled-release, sustained-release, long- acting drug products and the like. Delayed-release drug products is a dosage form that releases a discrete portion or portions of drug at a time other than promptly after administration. An initial portion may be released promptly after administration. Enteric-coated dosage forms are common delayed-release products. Targeted-release drug products is a dosage form that releases drug at or near the intended physiologic site of action. Targeted-release dosage forms may have either immediate- or extended- release characteristics.

In one aspect, the present invention relates to a pharmaceutical composition comprising tacrolimus or an analogue thereof and one or more pharmaceutically acceptable excipient(s).

In another aspect, the present invention relates to a pharmaceutical composition comprising: a) Solid dispersion comprising tacrolimus or an analogue thereof and suitable pharmaceutically acceptable polymers or carriers; b) Pharmaceutically acceptable excipients comprising diluent, vehicles, release modifier, water-miscible polymer, lubricants, glidants.

In another aspect, the present invention relates to a pharmaceutical composition comprising solid dispersion comprising tacrolimus or an analogue thereof, hydroxypropyl methyl cellulose, croscarmellose sodium, and lactose.

In another aspect, the present invention relates to a pharmaceutical composition comprising solid dispersion of tacrolimus comprising: a) about 20% w/w of tacrolimus or an analogue thereof; b) about 20% w/w of hypromellose; c) about 20% w/w of croscarmellose; d) about 40% w/w of lactose anhydrous; and e) pharmaceutically acceptable solvent/vehicle.

In another aspect, the present invention relates to a pharmaceutical composition comprising: a) solid dispersion comprising tacrolimus or an analogue thereof, hydroxypropyl methyl cellulose, croscarmellose sodium, and lactose; b) Pharmaceutically acceptable excipients comprising poloxamer, hydroxypropyl methyl cellulose, and magnesium stearate.

In another aspect, the present invention relates to a pharmaceutical composition comprising: a) solid dispersion comprising tacrolimus or an analogue thereof, hydroxypropyl methyl cellulose, croscarmellose sodium, and lactose; b) Pharmaceutically acceptable excipients comprising lactose, poloxamer, hydroxypropyl methyl cellulose, and magnesium stearate; wherein said solid dispersion contains tacrolimus or an analogue thereof and hydroxypropyl methyl cellulose is in 1:1 w/w ratio.

In another aspect, the present invention relates to a pharmaceutical composition in the form of extended release tablet dosage form comprising: a) about 1 to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 75 to about 99% w/w of pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a pharmaceutical composition comprising solid dispersion of tacrolimus comprising: a) about 20% w/w of tacrolimus or an analogue thereof; b) about 20% w/w of hypromellose; c) about 20% w/w of croscarmellose; d) about 40% w/w of lactose anhydrous; and e) pharmaceutically acceptable solvent/vehicle.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising solid dispersion of tacrolimus comprising: a) about 15% to about 25 % w/w of tacrolimus or an analogue thereof; b) about 15% to about 25 % w/w of hydroxypropyl methyl cellulose; c) about 15% to about 25 % w/w of croscarmellose; d) about 30 % to about 50 % w/w of lactose; and e) pharmaceutically acceptable solvent/vehicle.

In another aspect, the present invention relates to a pharmaceutical composition in the form of extended release tablet dosage form wherein each tablet comprising: a) about 2 to about 25 mg of solid dispersion of tacrolimus or an analogue thereof; b) about 50 to about 200 mg of lactose; c) about 15 to about 50 mg of poloxamer; d) about 50 to about 150 mg of hydroxypropyl methyl cellulose; e) about 1.5 to about 6 mg of magnesium stearate; and f) optionally other pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a pharmaceutical composition in the form of extended release tablet dosage form comprising: a) about 20 mg of solid dispersion of tacrolimus or an analogue thereof; b) about 150 mg of lactose; c) about 42 mg of poloxamer; d) about 132 mg of hydroxypropyl methyl cellulose; e) about 5 mg of magnesium stearate; and f) optionally other pharmaceutically acceptable excipients; wherein the about 20 mg of solid dispersion contains about 4 mg of tacrolimus.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate and f) optionally other pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate; and f) optionally other pharmaceutically acceptable excipients; wherein solid dispersion of tacrolimus is obtained by dissolving tacrolimus in ethanol and dispersing the polymer in the obtained drug solution wherein lactose and croscarmellose sodium was further dispersed and the obtained dispersion involve evaporation and drying.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients; wherein the ratio of tacrolimus to hydroxypropyl methyl cellulose in a solid dispersion is between 0.5:2 w/w and 2:0.5 w/w.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which is substantially free of any pH adjusting agent or stabilizers i.e. contains less than or equal to 0.1% w/w of pH adjusting agent or stabilizers.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which is substantially free of any pH adjusting agent or stabilizers. Suitable pH adjusting agent or stabilizers selected from, but are not limited to, inorganic acids, inorganic bases, inorganic salts, organic acids, organic bases and pharmaceutically acceptable salts thereof. Preferred organic acids are selected from the group consisting of oxalic acid, tartaric acid and citric acid. The pharmaceutically acceptable salt of an organic acid or inorganic acid is preferably an alkali metal salt or an alkaline earth metal salt. Preferred examples of such salts are sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate.

In another aspect, the present invention relates to a stable pharmaceutical composition which is substantially free of any pH adjusting agent or stabilizers such as organic acid selected from succinic acid, citric acid, tartaric acid, oxalic acid, and mixtures thereof.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients; wherein the composition is substantially free of any impurity such as tacrolimus hydroxy acid, tacrolimus 8 epimer.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which is substantially free of impurity i.e. total impurity present in the composition in an amount of less than or equal to 1.5% w/w.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which contains less than or equal to 0.5% w/w of tacrolimus 8 epimers after at least 3 months of storage at 25° C and 60% relative humidity (RH), based upon 100% total weight of tacrolimus.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of tacrolimus or an analogue thereof which contains nitrosamine impurity less than the FDA acceptable limit based on maximum daily dose of tacrolimus after at least 3 months of storage at 25° C and 60% relative humidity (RH), based upon 100% total weight of tacrolimus.

In another aspect, the present invention relates to a stable pharmaceutical composition in the form of extended release tablet dosage form wherein each tablet comprising: a) about 2 to about 25 mg of solid dispersion of tacrolimus or an analogue thereof; b) about 50 to about 200 mg of lactose; c) about 15 to about 50 mg of poloxamer; d) about 50 to about 150 mg of hydroxypropyl methyl cellulose; e) about 1.5 to about 6 mg of magnesium stearate; and f) Optionally other pharmaceutically acceptable excipients; wherein said composition exhibits a dissolution not more than 30% in 1 hour, not less than 80% in 10 hours using a paddle apparatus at a speed of about 100 rpm in dissolution medium 0.005% hydroxypropyl cellulose in water with 0.50% sodium lauryl sulfate adjusted to pH 4.5 and said composition contain less than or equal to 1.5% w/w of total impurity.

In another aspect, the dissolution medium used contains varied amount of sodium lauryl sulfate is in the range of about 0.05 to 1%, preferably about 0.1 to 0.5%, more preferably 0.1%, 0.2%, 0.3%, 0.4%, 0.5%.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 3% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 35% w/w of lactose; c) about 15% w/w of poloxamer; d) about 45% w/w of hydroxypropyl methyl cellulose; e) about 1.2% w/w of magnesium stearate; and f) pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 2% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 35% w/w of lactose; c) about 15% w/w of poloxamer; d) about 45% w/w of hydroxypropyl methyl cellulose; e) about 1.2 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a stable pharmaceutical composition comprising: a) about 6% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 42% w/w of lactose; c) about 12% w/w of poloxamer; d) about 38% w/w of hydroxypropyl methyl cellulose; e) about 1.4 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising tacrolimus and hydroxypropyl methyl cellulose in a solid dispersion form wherein ratio of tacrolimus to hydroxypropyl methyl cellulose is 0.5:2 w/w to 2:0.5 w/w.

“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but are not limited to, diluents, release modifiers, vehicles, lubricants/glidants, and any other excipient known to the art for making pharmaceutical composition for oral administration, e. g. such as a tablet, capsule, mini-tablets, pellets, granules, pills and the like.

Diluents according to the present invention are selected from, but are not limited to, Light magnesium oxide, silicon dioxide, titanium dioxide, talc, celluloses, microcrystalline cellulose, and as well as soluble materials such as mannitol, sorbitol or other sugar alcohols, sucrose, lactose, and the like used either alone or in combinations thereof and the most preferably used diluent is lactose. Diluent may be present in an amount of about 25 % w/w to about 70 % w/w, preferably about 25 % w/w to about 50% w/w, more preferably about 35.8, 36.5, 42.7 % w/w of the composition.

Release modifiers according to the present invention are selected from, but are not limited to, water soluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts of polysaccharide gums such as sodium alginate, sodium tragacanth, and sodium gum ghattate; water-soluble hydroxyalkylcellulose wherein the alkyl member is straight or branched of 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; synthetic water-soluble cellulose-based lamina formers such as methyl cellulose and its hydroxyalkyl methylcellulose cellulose derivatives such as a member selected from the group consisting of hydroxypropyl methylcellulose (Hypromellose) such as e.g. Methocel®. E, F and K, the 4,000 cps grades of Methocel E, Methocel E 6 PREMIUM LV, the 4,000 cps grades of Methocel® F, the 4,000, 15,000 and 100,000 cps grades of Methocel® K; and the Metho.K100 PREM.L VCR, Methocel K4M PREM. CR or mixture thereof, hydroxyethyl methylcellulose, and hydroxybutyl methylcellulose; other cellulose polymers such as sodium carboxymethylcellulose, cellulose acetate, cellulose acetate butyrate and ethyl cellulose; and other materials known to those of ordinary skill in the art. Other suitable release modifiers that can be used for this purpose include poly(vinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a blend of gelatin and polyvinylpyrrolidone, gelatin, glucose, saccharides, povidone, copovidone, poly(vinyl)pyrrolidone)-polyvinyl acetate) copolymer, Acryl-EZE®, Eudragit® NE, RL and RS, hydroxypropylcellulose, microcrystalline cellulose, polyethylene-vinyl acetate copolymer, 2-hydroxyethylmethacrylate (HEMA), methyl methacrylate (MMA), calcium pectinate and the like used either alone or in combinations thereof and the most preferably used release modifier is hypromellose selected from Metho.K100 PREM.L VCR, Methocel K4M PREM. CR, Methocel E 6 PREMIUM LV or mixture thereof. Composition according to the present invention are either mixed or coated with above release modifiers. Release modifier may be present in an amount of about 1 % w/w to about 50 % w/w, preferably about 30 % w/w to about 50% w/w, more preferably about 38, 45.7, 45.8% w/w of the composition.

Vehicles according to the present invention are selected from, but are not limited to polyethylene glycols, polyoxyethylene oxides, poloxamers, polyoxyethylene stearates, poly-epsilon caprolactone, polyglycolized glycerides such as Gelucire® and mixtures thereof and the most preferably used vehicle is poloxamer. Vehicle may be present in an amount of about 5 % w/w to about 20 % w/w, preferably about 7 % w/w to about 20% w/w, more preferably about 12.03 or 14.11 % w/w of the composition. Lubricants according to the present invention are selected from, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, and the like used either alone or in combinations thereof and the most preferably used lubricant is magnesium stearate. Lubricant may be present in an amount of about 0.5 % w/w to about 3 % w/w, preferably about 1 % w/w to about 2% w/w, more preferably about 1.2, 1.23, or 1.43% w/w of the composition.

Glidants according to the present invention are selected from, but are not limited to, colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, and the like used either alone or in combinations thereof.

Tablet coating refers to the phenomenon of application of coating to the tablet, which involves some coating agents like plasticizer, polymers, colorants and solvent.

Colorants is a substance that is preferably added to the coating agent for coating of the tablet. Pharmaceutically acceptable colorants include but are not limited to red iron oxide, non-irradiated, iron oxide black, Ferrosoferric oxide, tartrazine, erythrosine, amaranth lake, opadry systems, titanium dioxide, and iron oxide yellow.

Solid dispersion or premix of tacrolimus comprises pharmaceutically acceptable polymer or carrier, disintegrants, diluent and solvent/vehicle.

In another aspect, the present invention relates to a pharmaceutical composition in the form of extended release tablet dosage form comprising about 1 to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof, based upon 100% total weight of composition, preferably about 2 to about 10 % w/w, more preferably about 2.2, 3 or 5.8% w/w of the composition.

Suitable pharmaceutically acceptable polymer or carrier that may be used to form dispersion/solid dispersion or premix with tacrolimus includes but not limited to water soluble as well as water insoluble carriers, disintegrant, diluent and solvents/vehicles.

Pharmaceutically acceptable water-soluble carriers according to the present invention are selected from Hypromellose i.e. Methocel®. E, F and K, the 4,000 cps grades of Methocel E, Methocel E 6 REMIUM LV, the 4,000 cps grades of Methocel® F, the 4,000, 15,000 and 100,000 cps grades of Methocel® K; and the Metho.K100 PREM.L VCR, Methocel K4M PREM. CR), polyvinylpyrrolidone (povidone), polyvinylpyrrolidone-vinyl acetate copolymer (copovidone), polyvinyl alcohol, hydroxypropylcellulose, polyvinyl caprolactam- polyvinyl acetate- polyethylene glycol graft co-polymer (Soluplus™), sugar and its derivatives, organic amines and similar. Typical water insoluble polymers are methylcellulose, ethylcellulose, microcrystalline celluloses, polymethacrylates, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate phthalate, carboxymethyl ethyl cellulose and crospovidone. Sugar and its derivatives mannitol, lactose, sorbitol, xylitol, dextrins and like. The preferable pharmaceutically acceptable carriers include but not limited to hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone-vinyl acetate copolymer or mixture thereof and the most preferably used carrier is hypromellose. Carrier may be present in an amount of about 1 % w/w to about 40 % w/w, preferably about 10 % w/w to about 30% w/w, more preferably about 20 % w/w of the dispersion.

Disintegrants according to the present invention are selected from, but are not limited to, L-HPC (Low-Substituted Hydroxy propyl Cellulose), croscarmellose sodium, crospovidone, sodium starch glycolate, polacrilin potassium, microcrystalline cellulose, starches, etc. or mixture thereof and the most preferably used disintegrant is croscarmellose sodium. Disintegrant may be present in an amount of about 1 % w/w to about 40 % w/w, preferably about 10 % w/w to about 30% w/w, more preferably about 20 % w/w of the dispersion.

Diluent according to the present invention are selected from, but are not limited to calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol or other sugar alcohols, sucrose, starch, pregelatinized starch, sugar etc. or mixture thereof and the most preferably used diluent is lactose. Diluent may be present in an amount of about 1 % w/w to about 60 % w/w, preferably about 30% w/w to about 50% w/w, more preferably about 40 % w/w of the dispersion.

A solvent/vehicle is a substance that dissolves a solute. Solid dispersions are prepared by dissolving a physical mixture of the active substance (e.g., a drug substance) and the solvent/vehicle or carrier in a common organic solvent, followed by evaporation of the solvent. Suitable organic solvents include pharmaceutical acceptable solvent in which the active substance is soluble such as methanol, ethanol, methylene chloride, chloroform, ethylacetate, dichloromethane, ketones such as acetone, propanone, or mixtures thereof. Preferred solvents/vehicle used in the dispersion selected from ethanol, methylene chloride or mixture thereof.

In yet another aspect, the present invention relates to the process for preparation of a solid dispersion, wherein process comprises steps of: a) Dispensing of required raw material in appropriate quantities; b) Preparation of drug solution in ethanol; c) Dispersion of polymer in drug solution; d) Preparation of drug-polymer solution in methylene chloride; e) Dispersion of anhydrous lactose and croscarmellose sodium in drug-polymer solution; f) Solvent evaporation in rotary evaporator; and g) Drying in vacuum dryer.

In yet another aspect, the present invention relates to the process for preparation of an extended release tablet dosage form, wherein process comprises steps of: a) Co-sifting of tacrolimus solid dispersion and poloxamer; b) Co-sifting of lactose, hydroxypropyl methyl cellulose; c) Sifting and addition of magnesium stearate in above material; d) Blending and lubrication of material obtained in step a and b; e) Compression.

In yet another aspect, the blend or tablet composition obtained in present invention are subjected for tests such as dissolution, assay, impurity profiling, related Substances, content uniformity, Hardness, thickness, Friability, Bulk density, Tapped density, Hausner ratio (HR), Compressibility Index, Particle Size Distribution, Loss on drying (LOD), etc.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising tacrolimus used for the suppressing kidney rejection in a kidney transplant patient.

In yet another aspect, the present invention relates to a pharmaceutical composition comprising tacrolimus used for the suppressing kidney rejection in a kidney transplant patient such as the prophylaxis of organ rejection in de novo kidney transplant patients in combination with other immunosuppressants and the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants.

In yet another aspect, the present invention relates to method of suppressing kidney rejection in a kidney transplant patient by a pharmaceutical composition comprising tacrolimus. In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising tacrolimus for the suppressing kidney rejection in a kidney transplant patient.

The composition of the tacrolimus extended release tablet can be packed into suitable packaging system e.g. Blister packs, strip packs, alu-alu packs, bottles such as glass and plastic bottles, etc.

EXAMPLES:
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example - 1: Solid dispersion/Pre-mix composition of tacrolimus (Table 1)

Sr. No. Ingredient Ex. 1A Ex. 1B Ex. 1C
mg/100 mg mg/100 mg mg/100 mg
1. Tacrolimus 20 20 20
2. Hydroxypropyl methylcellulose
(Hypromellose) 18 20 22
3. Croscarmellose Sodium 22 20 20
4. Anhydrous Lactose 40 40 38
5. Ethanol Absolute q. s. q. s. q. s.
Dehydrated Alcohol
6. Methylene Chloride q. s. q. s. q. s.
q. s.: Quantity sufficient.
Manufacturing process (Example 1):
a) Requisite raw materials were taken in appropriate quantities; b) Tacrolimus was added in ethanol to form drug solution; c) Hydroxypropyl methylcellulose (Hypromellose) polymer was dispersed in drug solution obtained in step b); d) Drug-polymer solution obtained in step c) was added in methylene chloride; e) Anhydrous lactose and croscarmellose sodium were dispersed in drug-polymer solution obtained in step d); f) Dispersion obtained in step e) was subjected to solvent evaporation by using rotary evaporator; and g) Material obtained in step f) subjected to drying by using vacuum dryer.

Example - 2: Extended-release tablet 4 mg (Table 2)
Sr. No. Ingredient Ex.2A Ex.2B Ex.2C
mg/tab mg/tab mg/tab
1. Tacrolimus Premix* 20.40 20.40 20.40
2. Lactose 150.10 149.10 148.10
3. Poloxamer 41.00 42.00 43.00
4. Hypromellose 133.5 132.5 135
5. Magnesium Stearate 5.00 5.00 4.50
Total tablet weight 350.00 349.000 351.00

*Standard quantity is based on the 100% assay on as is basis as Tacrolimus 20.400 mg of Tacrolimus Premix is equivalent to 4.0 mg of Tacrolimus.

Manufacturing process (Example 2):
a) Tacrolimus solid dispersion obtained in example 1 and poloxamer was sifted through sieve #60; b) Lactose and hydroxypropyl methyl cellulose were sifted through sieve #40; c) Magnesium stearate was sifted through sieve #60; d) Material obtained in step a) and b) were blended followed by lubrication with magnesium stearate; e) Lubricated blend obtained in step d) was compressed to form tablets.

Example - 3: Extended-release tablet 1 mg (Table 3)
Sr. No. Ingredient Ex.3A Ex.3B Ex.3C
mg/tab mg/tab mg/tab
1. Tacrolimus Premix * 5.10 5.10 5.10
2. Lactose 60.90 60.90 61.90
3. Poloxamer 26.00 24.00 24.00
4. Hypromellose 76.90 77.90 79.50
5. Magnesium Stearate 2.100 2.10 2.00
Total tablet weight 171.00 170.00 172.50

*Standard quantity is based on the 100% assay on as is basis as Tacrolimus 5.100 mg of Tacrolimus Premix is equivalent to 1 mg of Tacrolimus.

Manufacturing process for example 3: As described above in example 2.

Example - 4: Extended-release tablet 0.75 mg (Table 4)
Sr. No. Ingredient Ex.4A Ex.4B Ex.4C
mg/tab mg/tab mg/tab
1. Tacrolimus Premix * 3.83 3.83 3.83
2. Lactose 62.17 62.17 63.17
3. Poloxamer 23.00 24.00 24.80
4. Hypromellose 76.90 77.90 79.90
5. Magnesium Stearate 2.10 2.10 2.30
Total tablet weight 168.00 170.00 174.00

* Standard quantity is based on the 100% assay on as is basis as Tacrolimus 3.830 mg of Tacrolimus Premix is equivalent to 0.75 mg of Tacrolimus.

Manufacturing process for example 4: As described above in example 2.

Example - 5: Extended-release tablet % w/w composition (Table 5)
Sr. No. Ingredient % w/w per tab
1. Tacrolimus Premix 1-25 %
2. Lactose 25-50 %
3. Poloxamer 5-20 %
4. Hypromellose 1-50 %
5. Magnesium Stearate 0.5-3 %

Manufacturing process for example 5: As described above in example 2.

Dissolution testing: The dissolution test is performed in accordance with general rules of USP for dissolution testing and results given in table 6 below. The dissolution test parameters were: dissolution apparatus- USP II (paddle apparatus); dissolution media- 0.005% hydroxypropylcellulose in water with 0.50% sodium lauryl sulfate adjusted to pH 4.5; dissolution volume- 900mL; paddle rotation speed- 100 RPM.
Table 6: In-vitro dissolution results of example 2 measured at initial and 3 months:
Time point
(Hours) % release
Initial 3 Month
1Hr 17 % 17 %
3.5Hr 53 % 48 %
10Hr 103 % 109 %

Stability Study: Stability study conducted on compositions in order to ensure the stable composition for longer period of time and data is given in Table- 7 below:
Table 7: Stability study results of example 2 at 25°C / 60% RH:
Test/Parameter Initial 3 months
Assay of tacrolimus 102.7% 104.3%
Tacrolimus hydroxy acid BLQ BLQ
Tacrolimus 8 epimers ND 0.17
Any individual unspecified impurity ND ND
Total impurities BLQ 0.2

NMT: Not More Than; BLQ: Below the Limit of Quantitation; ND: Not Detected.

Bioequivalence study (BE study): Bioequivalence (BE) assessment is essential for generic drug development and availability of any interchangeable product. An open label, balanced, pivotal, laboratory blind, randomized, four period, two treatment, two sequence, single dose, fully replicated, crossover, bioequivalence study was conducted on test/generic product i.e. example 2 with comparison to reference product i.e. ENVARSUS® XR (Tacrolimus extended-release tablets) as given below in table 8 (under fasting condition) and table 9 (under fed condition).
Table 8: Results of BE study of example 2 under fasting condition full Replicate (N =28-1)
Parameter LSMT LSMR ratio ISVR ISVT Lower Upper
LCmax 15.30 16.74 91.39 32.79 20.47 81.37 102.63
LAUC0-t 323.94 315.36 102.72 36.83 16.03 93.41 112.95
LAUC 0-8 354.80 346.80 102.31 35.36 15.43 93.40 112.06

Table 9: Results of BE study of example 2 under fed condition full Replicate (N =28-1)
Parameter LSM-T LSM-R ratio ISV-R ISV-T Lower Upper
LCmax 14.53 16.37 88.76 25.13 20.77 82.33 95.69
LAUC0-t 203.38 193.30 105.22 13.15 12.34 100.98 109.63
LAUC 0-8 227.38 215.74 105.39 12.43 10.92 101.49 109.45

LSM: Least Square Mean; ISV: Intra-Subject Variability; R: Reference; T: Test; L: Least.
Cmax: Maximum Measured whole blood Concentration.
AUC0-t: Area under the whole blood concentration curve from administration to the last observed concentration at time t.
AUC0-8: Area under the whole blood concentration curve extrapolated to infinite time

Based on the above BE results, it was concluded that the test product is bioequivalent to reference product i.e. ENVARSUS® XR.
Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.
,CLAIMS:1. A stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients.

2. The stable composition of claim 1, wherein the solid dispersion of tacrolimus or an analogue thereof comprises: a) about 20% w/w of tacrolimus or an analogue thereof; b) about 20% w/w of hypromellose; c) about 20% w/w of croscarmellose; d) about 40% w/w of lactose anhydrous; and e) pharmaceutically acceptable solvent/vehicle.

3. The stable composition of claim 2, wherein, the ratio of tacrolimus to hydroxypropyl methyl cellulose in a solid dispersion is between 0.5:2 w/w and 2:0.5 w/w.

4. The stable composition of claim 1, wherein the process for preparation comprises a) co-sifting of tacrolimus solid dispersion, lactose, hydroxypropyl methyl cellulose and poloxamer in one or more steps b) mixing magnesium stearate in step a; and c) compressing to obtain the compressed tablets.

5. A stable pharmaceutical composition comprising: a) about 6% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 42% w/w of lactose; c) about 12% w/w of poloxamer; d) about 38% w/w of hydroxypropyl methyl cellulose; e) about 1.4 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients; wherein the composition is substantially free of impurity such as tacrolimus hydroxy acid, tacrolimus 8 epimer.

6. The stable composition of claim 5, wherein the composition is substantially free of any pH adjusting agent or stabilizers.

7. The stable composition of claim 5, wherein the composition remains stable for at least 3 months when stored at 25°C and 60% relative humidity.

8. The stable composition of claim 5, wherein composition exhibits dissolution not more than 30% in 1 hour, not less than 80% in 10 hours using a paddle apparatus at a speed of about 100 rpm in dissolution medium 0.005% hydroxypropyl cellulose in water with sodium lauryl sulfate.

9. The stable composition of claim 5, wherein the composition used for the prophylaxis of organ rejection in a kidney transplant patient.

10. A stable pharmaceutical composition comprising: a) about 1% to about 25% w/w of solid dispersion of tacrolimus or an analogue thereof; b) about 25% to about 50 % w/w of lactose; c) about 5% to about 20 % w/w of poloxamer; d) about 1% to about 50 % w/w of hydroxypropyl methyl cellulose; e) about 0.5% to about 3 % w/w of magnesium stearate; and f) pharmaceutically acceptable excipients, wherein the composition is substantially free of any pH adjusting agent or stabilizers selected from the group consisting of succinic acid, citric acid, tartaric acid, oxalic acid, and mixtures thereof.