Pharmaceutical Composition 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.
Background of Invention
Fingolimod (2-amino-2-[2-(4-octylphenyl)ethyl]-propane-l,3-diol) is a sphingosine-1 phosphate (SIP) agonist, having immunosuppressive activity. It is approved for treating multiple sclerosis by reducing the rate of relapses in relapsing-remitting multiple sclerosis by over half. Fingolimod sequesters lymphocytes in lymph nodes, preventing them from moving to the central nervous system for autoimmune responses in multiple sclerosis.
Fingolimod is currently marketed as an immediate release capsule for the treatment of multiple sclerosis. This formulation contains 0.5 mg equivalent of fingolimod base in the form of the hydrochloride salt.
US 5604229 first discloses fingolimod and different salts of it, its process of preparation. US 6004565 discloses method of manipulating lymphocyte traffic in a mammal by administering fingolimod hydrochloride.
US 8324283 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 20080096972 discloses a pharmaceutical organic concentrate formulation comprising fingolimod or a salt thereof in an organic solvent of ethanol in propylene glycol.
US 20100040678 & US 2012288559 discloses a pharmaceutical composition comprising fingolimod with a coating comprising polymers resins and metal oxides.

US 20100267675 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 20110229501 discloses a pharmaceutical composition of hydrochloride salt of fingolimod in the form of a hydrate.
US20130034603 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 20130095177 discloses a method of preparation of an intermediate containing fingolimod and excipients, having particles size of all the intermediate particles less than 250 μm and greater than 0.6μm.
US 20130102682 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 20130102683 discloses a method of preparing an intermediate comprising melt processing fingolimod and a matrix former.
US 20120328664 discloses a concentrate for dilution comprising a SIP receptor modulator or agonist and propylene glycol.
WO 2013091704 discloses a pharmaceutical composition comprising fingolimod, calcium lactate pentahydrate and optionally a lubricant.
WO2012135561 discloses a solid oral pharmaceutical composition comprising fingolimod, a filler and a cyclodextrin as a stabilizer.

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 there are prior art teaches about different way of making fingolimod composition, there still exists a need for preparing an improved pharmaceutical composition of the drug. In particular, there is a need for preparing a stable pharmaceutical composition of fingolimod. The present invention relates to a stable pharmaceutical composition of fingolimod and its preparation.
Summary of Invention
It is an object of the invention to provide a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion as a stabilizer. The pharmaceutical composition comprising zwitterion is an amino acid, preferably glycine, leucine or a mixture thereof.
It is another object of the invention is to provide a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and glycine, wherein glycine is present in the range of about 5% to about 95% by weight of the total composition.
It is another object of the invention is to provide a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and glycine, wherein the glycine is having a mean particle size of less than 250 μm preferably less than 160μm.

It is another object of the invention is to provide a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and glycine, wherein the d90 glycine particle size is less than 400μm preferably less than 350 μm.
It is another object of the invention to provide a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion as a stabilizer and optionally one or more pharmaceutically acceptable excipients.
It is another object of the invention to provide a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion as a stabilizer, wherein the total impurity of the composition in less than the total impurity of the composition containing sugar alcohol.
It is another object of the invention to provide a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and glycine as a stabilizer, wherein the total impurity of the composition in less than the total impurity of the composition containing sugar alcohol.
Detailed Description of the Invention
The present invention relates to a stable pharmaceutical composition of fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and its preparation. The present invention provides an improved pharmaceutical composition of fingolimod wherein the composition comprises fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion. The invention also relates to administration of stable pharmaceutical composition of fingolimod to patients who are in need of the drug for the treatment of multiple sclerosis.

In one aspect, a pharmaceutical composition of fingolimod comprises fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion. The composition may further comprise other additives for the preparation of the composition.
The term "fingolimod" includes various forms of fingolimod such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art. Fingolimod can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "fingolimod" as used in the present invention.
The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
The active ingredient, active agent and drug herein can be interchangeably used.
As used herein,"%" refers to the weight percent of a substance as it relates to the overall composition unless otherwise indicated.
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.
The zwitterion used in the composition as a stabilizer. Zwitterion can be used from 0.1 to 95% by weight of total composition, preferably from 5 to 95% by weight of total

composition. The mass ratio of drug to zwitterion is from 90:10 to 1:99. The zwitterion may comprise at least one entity chosen, for example, from amino acids, phosphorylcholine (PC), and sulfobetaine (NS).
The non-limiting examples of amino acids are 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.
The non-limiting examples of zwitterion phospholipid are phosphatidyl choline,
phosphatidyl ethanolamine, sphingomyeline, lysophatidylethanolamine, cerebrosides,
dimyristoylphosphatidyl choline, dipalmitotylphosphatidyl choline,
distearyloylphosphatidyl choline, dielaidoylphosphatidyl choline, dioleoylphosphatidyl choline, dilauryloylphosphatidyl choline, l-myristoyl-2-palmitoyl phosphatidyl choline, l-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. Zwitterion phospholipids constitute any phospholipid with ionizable groups where the net charge is zero.
One of the embodiments of the invention relates a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and glycine as a stabilizer. The glycine used in the present invention is having a mean particle size less than 250μm, preferably less than 160μm. The d90 of glycine particle size is less than 400μ.m, preferably less than 350|im.
One of the embodiments of the invention relates a pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate

derivative and a zwitterion as a stabilizer, wherein the total impurity of the composition in less than the total impurity of the composition containing only a sugar alcohol.
One of the embodiments of the invention relates 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 in less than the total impurity of the composition containing only a sugar alcohol.
According to the invention, the composition can also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof. It is preferred that the excipients include at least one lubricant, selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate.
According to the invention, the composition can also comprise a disintegrant. The non limiting examples of disintegrants are 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%.
According to the invention, the composition can also comprise a surfactant. Surface-active agents include but are not limited to surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination thereof. Non-limiting examples of surfactants include non-ionic, anionic, cationic, amphoteric or zwitterionic or any combination thereof. Non-ionic surfactant is preferable.
According to the invention, the composition can also comprise a binder. The composition according to the invention can comprise binders, such as polyvinyl pyrollidone,

polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. It is preferable to use a binder with good water solubility. In a preferred embodiment of the invention the excipients include at least one binder selected from hydroxypropyl cellulose and povidone. The binding agent is present in the composition in an amount of from about 1% to about 25%, preferably from about 1%, to about 15%, more preferably from about 1% to about 10%.
According to the invention, other excipients are also used in the preparation of the pharmaceutical composition like diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof. A preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica. Preferably, the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.
The composition can also comprises glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
Other excipients commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe, Paul J Sheskey & Sian C Owen (2006)] the content of which is incorporated herein by reference.

One or more of these additives may be selected and used by the skilled artisan having regard to the particular desired properties of the pharmaceutical composition by routine experimentation and without any undue burden. The absolute amounts of each additive and the amounts relative to other additives is similarly dependent on the desired properties of the pharmaceutical composition and may also be chosen by the skilled artisan by routine experimentation without undue burden.
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 majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials.
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 by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.
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.
In one embodiment, the compositions can 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.
The present pharmaceutical compositions are prepared by known technological procedures, e.g. direct blending and capsule filing, direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. 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 preparations of the invention can be produced by compressing a mixture of the drug substance of the invention with excipients. For example, one method for the production includes mixing the 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 for capsules to tablets using dry granulating machines or roller compacters, and a wet granulating step to produce granules for capsules or tablets using water, ethanol and solutions containing binders.
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 zwitterion;
(b) Optionally, screening, milling and/or 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. In another 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 zwitterion;
(b) Optionally, screening, milling and/or 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 drug 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 exact dose of active agent and the particular formulation to be administered depend on a number of factors, e. g. the condition to be treated, the desired duration of the treatment and the rate of release of the active agent. For example, the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein including: (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). As herein defined, multiple sclerosis refers, 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 form of fingolimod.
The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.
Example 1
Procedure: Fingolimod HC1, a part of glycine 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 2
Procedure: Mannitol SD-200 and glycine were mixed together, followed by co-shifting with Fingolimod HC1 and mixing well. The drug mixture was lubricated with magnesium Stearate and filled into capsule as well compressed into tablet.
Example 3
Procedure: Fingolimod HC1 and glycine were co-shifted and mixed well. The drug mixture was mixed well with talc and then filled into capsule as well compressed into tablet.
Comparative Example:

Procedure: Fingolimod HC1 and Mannitol SD-200 co-shifted and mixed well followed by lubricating with magnesium stearate and capsule filing or compressing to tablet as described in US 8324283.
Stability Study: Stability study was conducted for active ingredient, compositions of the invention and comparative composition. The study was conducted at 40°C/75% RH for one week.

i i i
ND: Not Detected
Example 4
Procedure: Fingolimod HC1, a part of glycine 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 HC1 and mixing well. The drug mixture was lubricated with magnesium Stearate and filled into capsule as well compressed into tablet.
Example 6
Procedure: Fingolimod HC1 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.

We claim
1. A pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion as a stabilizer.
2. The pharmaceutical composition according to claim 1, wherein the zwitterion is an amino acid.
3. The pharmaceutical composition according to claim 2, wherein the amino acid is selected from the group consisting of glycine, leucine or a mixture thereof.
4. The pharmaceutical composition according to claim 3, wherein the amino acid is glycine.
5. The pharmaceutical composition according to claim 4, wherein glycine is present in the range of about 5% to about 95% by weight of the total composition.
6. The pharmaceutical composition according to claim 3, wherein the glycine is having a mean particle size of less than 250 um.
7. The pharmaceutical composition according to claim 3, wherein the glycine is having a mean particle size of less than 160 um.
8. The pharmaceutical composition according to claim 1, wherein the composition may optionally comprises other pharmaceutically acceptable excipients.
9. A pharmaceutical composition comprising fingolimod, a pharmaceutically acceptable salt thereof or a phosphate derivative and a zwitterion as a stabilizer, wherein the total impurity of the composition in less than the total impurity of the composition containing only a sugar alcohol.