WO2016042493A1

WO2016042493A1 - Pharmaceutical compositions of fingolimod

Info

Publication number: WO2016042493A1
Application number: PCT/IB2015/057123
Authority: WO
Inventors: Pavan Kumar ALLURI; Subhash Chandra Bose MYLAMALA; Mastanaiah THUMMISETTY; Raghupathi Kandarapu; Varma S. Rudraraju
Original assignee: Aizant Drug Research Pvt. Ltd
Priority date: 2014-09-19
Filing date: 2015-09-16
Publication date: 2016-03-24

Abstract

The present invention relates to a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than about 0.5% concentration (w/w) of Impurity I after six months stability study at 40°C and 75% RH.

Description

Pharmaceutical Compositions of Fingolimod

Field of Invention

The invention relates to a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative as an active ingredient and its preparation, in particular having reduced levels of N-[l, l-bis-hydroxymethyl-3-(4- octyl-phenyl)-propyl]-acetamide (Impurity I) and total impurities.

Background of Invention

Fingolimod (2-amino-2-[2-(4-octylphenyl)ethyl]-propane-l,3-diol) is a sphingosine- 1 phosphate (SIP) receptor modulator. Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod phosphate. Chemically, it is know as (2-amino-2-[2-(4- octylphenyl)ethyl]-propane-l,3-diol) and is structurally represented as given below.

Fingolimod is currently approved for treating patients with relapsing forms of multiple sclerosis by reducing the frequency of clinical exacerbations and to delay the accumulation of physical disability.

Fingolimod is currently marketed as an immediate release capsule for the treatment of multiple sclerosis under the trade name Gilenya^® in the US (FDA NDA #02-2527). This formulation contains 0.5 mg equivalent of fingolimod base in the form of the hydrochloride salt and magnesium stearate, mannitol as inactive ingredients.

US 5,604,229 discloses fingolimod and its pharmaceutically acceptable salts and process for its preparation. US 6,004,565 discloses method of manipulating lymphocyte traffic in a mammal by administering fingolimod hydrochloride. US 8,324,283 discloses a solid pharmaceutical composition for oral administration comprising fingolimod and a sugar alcohol. The sugar alcohol may be mannitol, maltitol, inositol, xylitol or lactitol. US 2008/0096972 discloses a pharmaceutical organic concentrate formulation comprising fingolimod or a salt thereof in an organic solvent of ethanol in propylene glycol.

US 2010/0040678 & US 2012/288559 disclose a pharmaceutical composition comprising fingolimod with a coating comprising polymers resins and metal oxides. US 2010/0267675 discloses dosage forms containing fingolimod and one or more excipients selected from fillers, binders, disintegrants, lubricants, flow regulators, matrix formers, plasticizers, flavouring agents and sweeteners.

US 2011/0229501 discloses a pharmaceutical composition of hydrochloride salt of fingolimod in the form of a hydrate. US2013/0034603 discloses a process of preparing a pharmaceutical composition of fingolimod comprising preparing an intimate admixture of fingolimod and a solid surfactant and optionally combining the admixture with one or more excipients. US 2013/0095177 discloses a method of preparation of an intermediate containing fingolimod and excipients, having particles size of all the intermediate particles less than 250 μιτι and greater than Ο.όμιτι.

US 2013/0102682 discloses an intermediate containing fingolimod and matrix material, wherein the fingolimod is present in the matrix material in the form of a solid solution. US 2013/0102683 discloses a method of preparing an intermediate comprising melt processing fingolimod and a matrix former.

US 2012/0328664 discloses a concentrate for dilution comprising a SIP receptor modulator or agonist and propylene glycol. WO 2012/135561 discloses a solid oral pharmaceutical composition comprising fingolimod, a filler and a cyclodextrin as a stabilizer.

WO 2013/091704 discloses a pharmaceutical composition comprising fingolimod, calcium lactate pentahydrate and optionally a lubricant. WO 2013/190151 discloses a pharmaceutical composition comprising fingolimod or a pharmaceutically acceptable salt or ester thereof, tripotassium citrate and, optionally, a lubricant.

WO 2014/111955 discloses a pharmaceutical composition comprising fingolimod and a weak acid cation exchange resin in the form of an ion-exchange complex and pharmaceutically acceptable excipients.

US 2014/0199382 discloses a stable pharmaceutical composition comprising an SIP receptor agonist and one or more pharmaceutically acceptable excipients, wherein the composition is free of a sugar alcohol. WO 2014/013090 discloses a pharmaceutical formulation comprising a solid composite of fingolimod base and a copolymer of methacrylic acid and divinylbenzene, and one or more pharmaceutically acceptable excipients. Preparation of pharmaceutical formulation of fingolimod is not an easy task as the drug itself either in its free form; in a pharmaceutically acceptable salt form or as a phosphate derivative possess properties that can cause processing problems during preparation. The stability and uniformity of pharmaceutical compositions containing fingolimod is heavily dependent on the choice of excipients used in the formulation, and the process by which the formulation is prepared. Fingolimod is unstable in presence of many excipients due to the reactivity of aminopropane-l,3-diol group and produce degradation products in the final formulation.

Even though the prior art teaches different fingolimod compositions, there still exists a need for stable pharmaceutical composition of the fingolimod. In particular, there is a need for a stable pharmaceutical composition of fingolimod, which is stable throughout the shelf life. The present invention relates to a stable pharmaceutical composition of fingolimod and its preparation.

The present invention provides a stable solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than about 0.5% concentration (w/w) of Impurity I and less than 5.0% concentration (w/w) of total impurities after six months stability study at 40°C and 75%RH (relative humidity). Another need exists for a stable pharmaceutical composition comprising fingolimod, wherein the total impurity of the composition is less than the total impurity of the composition containing sugar alcohol.

Summary of Invention

The present invention provides for a fingolimod composition in which the impurity profile of one or more impurities is less than the impurity profile of the marketed Gilenya® product. Accordingly, the present invention provides a stable solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than about 0.5% concentration (w/w) of Impurity I after six months stability study at 40°C and 75%RH. In yet another embodiment, the present invention provides a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 5.0% concentration (w/w) of total impurities after six months stability study at 40°C and 75%RH. In yet another embodiment, the present invention provides a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than about 0.5% concentration (w/w) of Impurity I and less than 5.0% concentration (w/w) of total impurities. In yet another embodiment, the present invention provides a stable pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion as a stabilizer. In yet another embodiment, the present invention provides a stable pharmaceutical composition having less than about 0.5% concentration (w/w) of Impurity I and less than 5.0% concentration (w/w) of total impuritiesafter six months stability study at 40°C and 75%RH,comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion as a stabilizer.

In yet another embodiment, the present invention provides a process for the preparation of stable pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion as a stabilizer. Detailed Description of the Invention

Fingolimod is unstable in the presence of many excipients due to the reactivity of aminopropane-l,3-diol group and produce degradation products in the final formulation. The major impurity produced is N-[l, l-bis-hydroxymethyl-3-(4-octyl-phenyl)-propyl]- acetamide (Impurity I). Other impurities produced during degradation are 2-Acetylamino- 2-[2-(4-octyl-phenyl)-2-oxo-ethyl]-malonic acid diethyl ester, N-[l-Hydroxymethyl-3-(4- octyl-phenyl)-propyl]-acetamide, l,3-diethyl-2-(acetamido)-2-(2-(4- octylphenyl)ethyl)propanedioate, l-(2-iodo ethyl) -4-octylbenzene, 4-octylphenetyl methansulfonate, 2-(4-octylphenyl)ethan-l-ol and a few unknown impurities. The present invention provides a stable solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than about 0.5% concentration (w/w) of Impurity I after six months stability study at 40°C and 75%RH. Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 5.0% concentration (w/w) of total impuritiesafter six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than about 0.5% concentration (w/w) of Impurity I and less than 5.0% concentration (w/w) of total impuritiesafter six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 0.4% concentration (w/w) of Impurity I after six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 0.3% concentration (w/w) of Impurity I after six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 0.2% concentration (w/w) of Impurity I after six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 0.1% concentration (w/w) of Impurity I after six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 3.5% concentration (w/w) of total impurities after six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 2.5% concentration (w/w) of total impurities after six months stability studyat 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 2.0% concentration (w/w) of total impurities after six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 1.0% concentration (w/w) of total impurities after six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 0.5% concentration (w/w) of Impurity I and less than 2.5% concentration (w/w) of total impurities after six months stability study at 40°C and 75%RH.

Another aspect of the invention is to provide a stable pharmaceutical composition of fingolimod, which comprises fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion.

Another aspect of the invention is to provide a stable pharmaceutical composition of fingolimod, having less than about 0.5% concentration (w/w) of Impurity I after sixmonths stability study at 40°C and 75%RH comprises fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion. Another aspect of the invention is to provide a stable pharmaceutical composition of fingolimod, having less than 5.0% concentration (w/w) of total impurities comprises fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion.

Another aspect of the invention is to provide a stable pharmaceutical composition of fingolimod, having less than about 0.5% concentration (w/w) of Impurity I and less than 5.0% concentration (w/w) of total impurities comprises fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion.

The zwitterion is used as a stabilizer in the composition and is present in an amount ranging from about 0.1 to 99.5 % by weight of total composition, preferably from 1 to 98.5 %, more preferably 5 to 98.5 % by weight of total composition. The weight ratio of fingolimod to zwitterion is from 90: 10 to 1:99.

The zwitterion according to the present invention is selected from an amino acid, a phospholipid, and a sulfobetaine (NS).

The non-limiting examples of amino acids as a zwitterion include but are not limited to glycine, arginine, histidine, alanine, isoleucine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, ornithine, proline, selenocysteine, serine, tyrosine or a combination thereof. The preferable amino acids are glycine, leucine or a mixture thereof. Zwitterion phospholipids constitute any phospholipid with ionizable groups where the net charge is zero. The non-limiting examples of a zwitterion phospholipid are phosphatidyl choline, phosphatidyl ethanolamine, sphingomyeline, lysophatidylethanolamine, cerebrosides, dimyristoylphosphatidyl choline, dipalmitotylphosphatidyl choline, distearyloylphosphatidyl choline, dielaidoylphosphatidyl choline, dioleoylphosphatidyl choline, dilauryloylphosphatidyl choline, 1 -myristoyl-2-palmitoyl phosphatidyl choline, 1 -palmitoyl-2-myristoyl phosphatidyl choline, 1 -palmitoyl -phosphatidyl choline, 1- stearoyl-2-palmitoyl phosphatidyl choline, dimyristoyl phosphatidyl ethanolamine, dipalmitoyl phosphatidyl ethanolamine, brain sphingomyelin, dipalmitoyl sphingomyelin, distearoyl sphingomyelin, and mixtures thereof. Preferably, the zwitterion phospholipid is phosphatidyl choline.

The non-limiting examples of amino acids of sulfobetaine are dimethylsulfonioacetate.

In another embodiment, the stable composition of fingolimod further comprises one or more pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, surafactant, glidant, lubricant and the like.

Fingolimod or its pharmaceutically acceptable salts or phosphate derivatives thereof, of the present invention may be in form of amorphous, crystalline or solvated form such as anhydrous, hydrate and the like.

The term "pharmaceutically acceptable salt" include inorganic or organic acids such as hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, oxalic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like.

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 a preferred embodiment, the present invention provides a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and glycine or leucine. The glycine used in the present invention is having a mean particle size less than 250μιτι, preferably less than Ιόθμιτι. The d90 of glycine particle size is less than 400μηι, preferably less than 350μιτι. The leucine used in the present invention is having a mean particle size less than 350μηι, preferably less than 250μιτι. The d90 of leucine particle size is less than όθθμιτι, preferably less than 500 μιτι.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion, wherein the total impurity of the composition is less than the total impurity of the composition containing only sugar alcohol.

It is a further embodiment that the impurity level of Impurity I is less than the impurity level of Impurity I in a composition containing a sugar alcohol. It is a further embodiment that the impurity level of Impurity I in a composition containing a zwitterion is less than the impurity level of Impurity I in a composition containing a sugar alcohol.

In another preferred embodiment, the present invention provides a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and glycine or leucine or a mixture thereof as a stabilizer, wherein the total impurity of the composition is less than the total impurity of the composition containing only a sugar alcohol. Suitable diluents according to the present invention are selected from 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 diluent is selected from microcrystalline cellulose, lactose monohydrate or mixture thereof. The diluent is present in amount from about 10% to about 80%, preferably from about 5%, to about 50%, by weight of the composition. Suitable binders according to the present invention are selected from 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. Preferably, the binder is selected from hydroxypropyl cellulose and povidone. The binding agent is present in the composition in an amount of from about 1% to about 25%, preferably from about 1%, to about 15%, more preferably from about 1% to about 10% by weight of the composition.

Suitable lubricants according to the present invention are selected from stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof. Preferably, the lubricant is selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate. The lubricant is present in an amount from about 0.5% to about 5% by weight of the composition. Suitable disintegrants according to the present invention are selected from crospovidone, modified starches especially sodium starch glycolate, carmellose especially croscarmellose sodium, carboxymethylcellulose calcium and the mixture thereof. The disintegrant is present in the composition in an amount of from about 1% to about 20 %, preferably from about 1% to about 15%, more preferably from about 1% to about 10% by weight of the composition. The composition can also comprises glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

Suitable surfactants according to the present invention are selected from 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.

In another embodiment, the stable composition of the present invention is free of sugar alcohol.

In a preferred embodiment, the present invention provides a stable pharmaceutical composition comprising fingolimod or a pharmaceutically acceptable salt thereof or a phosphate derivative, 5 to 98.5% by weight of a zwitterion and one or more pharmaceutically acceptable excipients.

In another preferred embodiment, the present invention provides a stable pharmaceutical composition comprising fingolimod or a pharmaceutically acceptable salt thereof or a phosphate derivative, 5 to 98.5% by weight of a zwitterion selected from glycine, arginine, histidine, alanine, isoleucine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, valine, ornithine, proline, selenocysteine, serine, tyrosine or a combination thereof and one or more pharmaceutically acceptable excipients. In yet another preferred embodiment, the present invention provides a stable pharmaceutical composition comprising fingolimod or a pharmaceutically acceptable salt thereof or a phosphate derivative, 5 to 98.5% by weight of a zwitterion and at least one pharmaceutically acceptable excipient comprising:

a) diluent for example microcrystalline cellulose, lactose monohydrate or mixture thereof; b) binder for example hydroxypropyl cellulose or povidone;

c) lubricants for example stearic acid, magnesium stearate or calcium stearate. d) disintegrant for example crospovidone, sodium starch glycolate, croscarmellose sodium,

e) glidant for example colloidal silica or talc. In one embodiment, the compositions of the present invention may be in the form of capsules, powders, granules, tablets, pills, lozenges, sachets, suppositories etc. The dosage form is preferably suitable for oral application. The compositions are preferably formulated in a unit dosage form, each dosage containing about 0.05 to about 20 mg, more usually about 0.1 to about 10 mg of fingolimod, most preferably about 0.2 to about 5mg of fingolimod. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of fingolimod calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The pharmaceutical composition of the present invention is preferably a capsule, powder or granules in sachets.

Optionally, powder, 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. Film coating formulations usually contain 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 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.

Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. 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, and triacetin), oils/glycerides (castor oil, acetylated monoglycerides, and fractionated coconut oil).

Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials form 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 using solvents selected from water, alcohols, ketones, esters, chlorinated hydrocarbons and the like or mixture thereof.

A composition of coating suspension (calculated on dry material) is particularly preferred which comprises: 1-99% by weight of polymer, preferably 1- 95% of polymer; 1-50% by weight of plasticizer, preferably 1-40% of plasticizer; 0.1-20% of colourant/opacifier, preferably 0.1- 10% of colourant/opacifier, all the percentage are based on the total weight of coating material. The present pharmaceutical compositions are prepared by known technological procedures, e.g. direct blending and capsule filing, direct compression, dry granulation or wet granulation. In the preparation of the compositions of fingolimod, the active ingredient 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 fingolimod.

The composition 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 fingolimod with the materials for the preparation by a suitable mixer, and followed by capsule filing or directly compressing the mixture to tablets. Other methods include a dry granulating step to produce granules using dry granulating machines or roller compacters, and a wet granulating step using water, ethanol and solutions containing binders, to produce granules for filling into capsules or compressing into tablets.

In one aspect, the present invention relates to a process for producing a pharmaceutical composition, comprising:

(a) mixing fingolimod or a pharmaceutical acceptable salts or a phosphate derivative thereof with a zwitterion;

(b) optionally, granulating the mixture obtained in the step (a); and (c) mixing the mixture from the step (a) or, optionally, from the step (b) with a lubricant,

(d) finally filing the mixture of step (c) to capsules or compressing into tablets. In another aspect, the present invention relates to a process for producing a pharmaceutical composition, comprising:

(b) optionally, granulating the mixture obtained in the step (a); and (c) optionally, mixing the mixture from the step (a) or (b) with one or more additional excipients like diluents, disintegrants, surfactants;

(d) lubricating the mixture of step (c); and

(e) finally filing the mixture of step (d) to capsules or compressing into tablets. In another embodiment, at least 75% of fingolimod is dissolved from the pharmaceutical composition in a 0.1N HC1 + 0.2% sodium lauryl sulphate in 30 minutes, when dissolution is performed using USP apparatus I (basket), at a temperature of the dissolution medium of 37±0.5°C, speed of rotation of the basket 100 rpm and volume of the dissolution medium 500 ml. Preferably the drug release rate of the composition of the invention is more than 70% in 15 minutes, above 80%, e. g. 90%, over 30 minutes, and above 95% over 45 minutes. The composition of the invention containing fingolimod is preferably administered once daily in an amount of 0.1 to 5 mg/day.

The pharmaceutical compositions of the present invention are useful in: (a) treatment and prevention of organ or tissue transplant rejection, for example for the treatment of the recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants, and the prevention of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation; particularly in the treatment of acute or chronic alio- and xenograft rejection or in the transplantation of insulin producing cells, e.g. pancreatic islet cells; (b) treatment and prevention of autoimmune disease or of inflammatory conditions, e.g. chronic long term diseases, e.g. multiple sclerosis, arthritis (for example rheumatoid arthritis), inflammatory bowel disease, hepatitis, etc.; treatment and/or prevention of viral myocarditis and viral diseases caused by viral myocarditis, including hepatitis and AIDS. Multiple sclerosis takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Multiple sclerosis refers to, but is not limited to, relapsing remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS), e.g. RRMS. In one embodiment, a pharmaceutical composition comprising fingolimod or a pharmaceutically acceptable salt thereof of the invention has a comparable bioavailability to the commercial form of fingolimod. In one preferred embodiment, a pharmaceutical composition comprising fingolimod is bioequivalent to commercial dosage form of fingolimod. The term bioequivalent is used to mean a "generic" version of a reference drug, and includes but is not limited to the definition provided in the commonly known "Orange Book", the official title being the Approved Drug Products With Therapeutic Equivalence Evaluations, 34th Edition, Sept. 2014.

The impurities or decomposition products can be measured by HPLC analysis or any other suitable method, after storage at 40°C/75%RH, (accelerated stability studies) as specified by the regulatory authorities or as per ICH guidelines. The following experimental details are set forth to aid in 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.

Example 1

Procedure: Fingolimod HC1, a part of glycine were mixed in water followed by addition of polyvinylpyrrolidone and remaining part of glycine. The wet mass was kept for drying at 50°C in oven for about 9hrs. The obtained dried granules were sized, mixed with talc and finally filled into capsule or compressed into tablet.

Example 2

Ingredients Example 2a Example 2b Example 2c

%w/w %w/w %w/w

Fingolimod HC1 1.14 1.14 1.14

Mannitol SD 200 61.15 83.16 75.83

Glycine 36.69 14.68 22.01

Magnesium stearate 1.02 1.02 1.02 Procedure: Mannitol SD-200 and glycine were mixed together, followed by co-shifting with fingolimod HCl and mixing. The drug mixture was lubricated with magnesium stearate and filled into capsule or compressed into tablet. Example 3

Comparative Example:

Procedure: Fingolimod HCl and mannitol SD-200 co-shifted and mixed well followed by lubricating with magnesium stearate and then filled into capsule or compressed into tablet as described in US 8,324,283.

Stability Study: Stability study was conducted for active ingredient, compositions of the present invention and comparative composition. The study was conducted at 40°C/75%RH for one week.

API Example 1

Impurities

Initial After one week

Sample Blend Capsules

(% w/w) (% w/w) (% w/w)

Impurity 1 0.03 0.04 0.04

Impurity 2 ND ND ND Impurity 3 ND ND ND

Impurity 4 ND ND ND

Total Impurities 0.13 0.12 0.14

API Comparative Example

Impurities Initial After one week Initial After one week

Sample Sample Sample Blend Capsules

(% w/w) (% w/w) (% w/w) (% w/w) (% w/w)

Impurity 1 0.05 0.05 0.05 0.05 0.08

Impurity 2 ND ND 0.40 0.84 0.47 Impurity 3 ND ND ND 0.08 0.19

Impurity 4 ND ND ND 0.05 0.09

Total Impurities 0.05 0.05 0.45 1.02 0.84

ND: Not Detected

Example 4

Procedure: Fingolimod HCl, a part of leucine were mixed in water followed by polyvinylpyrrolidone and remaining part of glycine. The wet mass was kept for drying at 50°C in oven for about 9hrs. The obtained dried granules were sized, mixed with talc and finally filled into capsule as well compressed into tablet. Example 5

Procedure: Mannitol SD-200 and leucine were mixed together, followed by co-shifting with fingolimod HCl and mixing well. The drug mixture was lubricated with magnesium stearate and filled into capsule as well compressed into tablet. Example 6

Procedure: Fingolimod HCl and leucine were co-shifted and mixed well. The drug mixture was mixed well with talc and then filled into capsule as well compressed into tablet.

Example 7

Procedure: Part of Glycine and PVP was loaded in a rapid mixer granulator (RMG), and mixed well followed by granulation with fingolimod HCl and small amount of glycine dissolved in water. The wet mass was dried to obtain granule, mixed well with talc and then filled into capsule or compressed into tablet.

Example 8

Ingredients Mg/Tablet %W/W

Intragranular material

Fingolimod HCl 0.56 0.86 Glycine 22.72 34.95

Micro crystalline cellulose (MCC) 101 22.72 34.95

Polyvinyl pyrrolidone (PVP) k29/32 1.5 2.31

Plasdone XI 10 7.5 11.54

Purified water q.s. q.s.

Extra granular material

Micro crystalline cellulose (MCC) 101 9 13.85

Talc 1 1.54

Total 65 100

Procedure: Fingolimod HCl and small amount of glycine was dissolved in water. The remaining amount of glycine, PVP K, MCC, Plasdone XL 10 was loaded in a RMG and mixed followed by granulating the step-2 materials by using step-1 solution. The wet mass was dried to obtain granule, mixed well with extragranular MCC and talc and then filled into capsule or compressed into tablet.

Example 9

Procedure: Fingolimod HCl and small amount of glycine was dissolved in water. The remaining amount of glycine, PVP K, MCC, was loaded in a RMG and mixed followed by granulating the step-2 materials by using step-1 solution. The wet mass was dried to obtain granule, mixed well with extragranular MCC and talc and then filled into capsule or compressed into tablet. Example 10

Procedure: Part of the glycine and PVP was loaded in a RMG, and mixed well followed by granulation with fingolimod HCl dissolved in water. The wet mass was dried to obtain granule, mixed well with talc and then filled into capsule or compressed into tablet.

In an open-label, balanced, randomized, two-treatment, two-period, two-sequence, single- dose, crossover, oral bioequivalence study of the composition of example 10 as a test product and a commercially available fingolimod oral capsule of strength 0.5 mg (GILENYA^®) as a reference product in normal healthy adult human subjects under both fasting and fed conditions. Data was determined experimentally by HPLC analysis. Both fingolimod and its active metabolite fingolimod phosphate is measured and compared for test and reference product.

C_max, T_max, AUCo-72: The values are presented as mean value of human subjects (n=23)

Claims

We Claim:

1. A stable solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than about 0.5% concentration (w/w) of Impurity I after six months stability studyat 40°C and 75%RH.

2. The solid dosage form according to claim 1, having less than 0.3% concentration (w/w) of Impurity I.

3. The solid dosage form according to claims 2, having less than 0.1% concentration (w/w) of Impurity I.

4. A solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than 5.0% concentration (w/w) of total impurities.

5. The solid dosage form according to claim 4, having less than 3.5% concentration (w/w) of total impurities.

6. The solid dosage form according to claim 4, having less than 2.5% concentration (w/w) of total impurities.

7. The solid dosage form according to claim 4, having less than 1.0% concentration (w/w) of total impurities.

8. A solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having less than about 0.5% concentration (w/w) of Impurity I and less than 5.0% concentration (w/w) of total impurities.

9. The solid dosage form according to claim 8, having less than 0.5% concentration (w/w) of Impurity I and less than 2.5% concentration (w/w) of total impurities.

10. The solid dosage form according to claim 8, having less than 0.3% concentration (w/w) of Impurity I and less than 2.0% concentration (w/w) of total impurities.

11. A stable solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, having an impurity level of Impurity I that is less than the impurity level of Impurity I in a composition containing a sugar alcohol when measured after a six months stability study at 40°C and 75% RH.

12. A stable solid dosage form comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative, and a zwitterion, the dosage form further having an impurity level of Impurity I that is less than the impurity level of Impurity I in a composition containing a sugar alcohol when measured after a six months stability study at 40°C and 75% RH.