FORM 2
THE PATENTS ACT. 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See Sections 10 and rule 13]
Title: Stable pharmaceutical composition of fingolimod Applicant: (a) Astron Research Ltd
(b) Company Registered under Indian Company ACT
(c) 10th Floor. Premier House Bodakdev. Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
Gujarat. India.
The following specification particularly describes the invention and the manner in which it is to be preformed describes the invention:

FIELD OF THE INVENTION
This present invention relates to stable pharmaceutical composition of fingolimod or its pharmaceutically acceptable salts thereof and process for preparation of the same. The pharmaceutical compositions as disclosed in the present invention can be dispensed as an oral dosage form, which are bioequivalent to the marketed Fingolimod product.
BACKGROUND OF THE INVENTION
Fingolimod is a sphingosine-1 phosphate (SIP) agonist, having immunosuppressive activity. Chemically, fingolimod is 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l .3-diol hydrochloride. Its structure is shown:

Fingolimod hydrochloride is a white to practically white powder that is freely soluble in water and alcohol and soluble in propylene glycol. It has a molecular weight of 343.93.

WO2004/089341 discloses the solid pharmaceutical composition suitable for oral administration comprising mannitol and 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salts thereof.
US20110105620 also discloses the solid pharmaceutical composition suitable for oral administration; comprising: (a) a SIP receptor agonist: and (b) a sugar alcohol. The sugar alcohol can be. e.g. mannitol, maltitol. inositol, xylitol or lactitol.
US20I00040678 discloses rapidly disintegrating dosage forms of SIP agonists including FTY720 (fingolimod). The compositions comprise a coating, wherein the coating comprises one or more polymer resins and one or more metal oxides.
WO2009/048993 discloses dosage forms containing SIP modulators and one or more excipients selected from fillers, binders, disintegrants. lubricants, flow regulators: matrix formers, plasticizers. flavouring agents and sweeteners.
The applicant has discovered that fingolimod. possess properties that can cause several processing problems like content uniformity as fingolimod particles have strong tendency to stick surfaces and each other. Further fingolimod can react with certain excipients to produce degradation products in the final composition.

Moreover, the applicant has found that there are significant problems in pharmaceutical composition containing fingolimod. The present invention addresses the need to provide stable composition of fingolimod to overcome the above mentioned problems.
The inventors of the present invention have found a stable pharmaceutical composition of fingolimod or its pharmaceutical!}' acceptable salts.
OBJECTS OF THE INVENTION
The object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, which can be dispensed as an oral dosage form.
Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, saccharide and/or its derivatives, and optionally at least one pharmaceutically acceptable excipient

Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable sail thereof, polysaccharide and/or its derivatives, and optionally at least one pharmaceutically acceptable excipient.
Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, maltodextrin, and optionally at least one pharmaceutically acceptable excipient.
Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, pullulan, and optionally at least one pharmaceutically acceptable excipient.
Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, pregelatinized starch, and optionally at least one pharmaceutically acceptable excipient.
Another object of the present invention is to provide a stable composition of fingolimod comprising: (a) a core; (b) dry coating on the said core, wherein the drug coating comprises of fingolimod or its pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable excipient.

Another object of the present invention is to provide a method for the preparation of a stable composition of fingolimod comprising fingolimod or its pharmaceutically acceptable salt thereof, polysaccharide and optionally at least one pharmaceutically acceptable excipient.
Another object of the present invention is to provide a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof for the treatment of multiple sclerosis, preferably relapsing-remitting multiple sclerosis
SUMMARY OF THE INVENTION
This present invention relates to stable pharmaceutical composition of fingolimod or its pharmaceutically acceptable salts thereof, polysaccharide and/or its derivatives and optionally at least one pharmaceutically acceptable excipient. Said composition can be dispensed as an oral dosage form to overcome the several processing problem associated with the fingolimod composition. Further, the present invention provides a method for the preparation of said fingolimod composition which is bioequivalent to the marketed Fingolimod product.
Preferably, the polysaccharide and/or its derivatives are selected form maltodextrin. pullulan or pregelatinized starch.

DETAILED DESCRIPTION
Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.
This present invention relates to stable pharmaceutical composition comprising fingolimod or its pharmaceutically acceptable salts thereof, polysaccharide and/or its derivatives and optionally at least one pharmaceutically acceptable excipient.
Fingolimod is marketed by Novartis under the brand name Gilenya ' for the treatment of multiple sclerosis' Gilenya is presented as immediate-release hard gelatin capsules containing 0.56 mg of fingolimod hydrochloride as the active substance corresponding to 0.5 mg of fingolimod base.
The proportion of the active agent in the total weight of the formulation in the case of formulations for oral administration is typically in the range of only a few percent by weight, such as 0.25 to 4 % by weight. This small proportion of active agent can lead to considerable problems during the manufacture of the formulation with regard to the uniformity of the content of active agent in the individual formulation units.

Further, fingolimod can react with certain excipients lo produce degradation products in the final formulation. The compatibility studies showed that the active substance interacts with several excipients. It reflects that content uniformity & product degradation play important role in the bioavailability of the drug,
The present invention is based on the findings that pharmaceutical compositions and dosage forms comprising fingolimod having improved stability and/or content uniformity by using the excipients like polysaccharide and/or its derivatives, chosen based on compatibility studies and experience from development of similar formulations.
In one embodiment the present invention provides a stable composition comprising fingolimod or its pharmaceutical!}' acceptable salt thereof polysaccharide and/or its derivatives, and optionally at least one pharmaceutically acceptable excipient.
In preferred embodiments, the polysaccharide and/or its derivatives are selected from maltodextrin. pullulan, pregelatinized starch or mixtures thereof. The composition of the present invention preferably contains 0.01 to 20% by weight of fingolimod or its pharmaceutically acceptable salts, more preferably 0.1 to 10%, e.g. 0.5 to 5% by weight, based on the total weight of the composition.

According to present invention, the 90% by volume or more of the particles (d90) of fingolimod or its pharmaceutical!)' acceptable salts have not more than 30μ particle size, more preferably not more than 20μ. In addition, according to the present invention the average particle size (d50) of fingolimod or its pharmaceutical!}' acceptable salt is not more than lOμ.
In another embodiment, the present invention provides a stable composition comprising fingolimod or its pharmaceutical^ acceptable salt thereof, maltodextrin. and optionally at least one pharmaceutical!}' acceptable excipient.
As described herein, maltodextrin is a nonsweet nutritive saccharide mixture of polymer that consists of D-glucose unit, with a dextrose equivalent (DE) of less than .20.
Optionally the composition may comprise at least one pharmaceutically acceptable excipients selected form binders, diluents, lubricants.
The composition preferably comprises a lubricant. Suitable lubricants selected from magnesium stearate. talc, stearic acid, zinc steartc, calcium stearate. sodium stearyl fumarate, hydrogenated vegetable oil such as hydrogenated castor oil or a mixture of any of the above. Preferably the lubricant is magnesium stearate.

Preferably: the composition consists of fingolimod or its pharmaceutically acceptable salts thereof, maltodextrin and magnesium slearate.
In another embodiment, the present invention provides a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, pulluian. and optionally at least one pharmaceulicafly acceptable excipient.
As described herein. Pulluian is a polysaccharide produced by yeast like fungus Aureobasidium pullulans. Pulluian is an essentially linear glucan consisting mainly of 1,6-linked maltotriose and some interspersed maltotetraose units.
The composition preferably comprises a lubricant, more preferably lubricant is magnesium stearate.
Preferably, the composition consists of fingolimod or its pharmaceutically acceptable salts thereof pulluian and magnesium stearate.
In another embodiment, the present invention provides a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, pregelatinized starch, and optionally at least one pharmaceutically acceptable excipient.

In a particularly preferred embodiment, pregelatinized starch is a pharmaceutical grade of partially pregelatinized maize starch. Pregelatinized starch, also called modified starch or starch derivatives that has been chemically and/or mechanically processed to rupture all or part of the native starch and so render the starch flow able and directly compressible. Further starch is a polysaccharides consisting of large number of glucose units joined by glycosidic bonds.
Pregelatinized starch is a unique pharmaceutical excipient combining several properties in a single product: binder, disintegranl, filler and flow-aid while having lubricant properties.
Preferably in this invention, pregelatinized starch used in the present invention is commercially available Starch 1500® Partially Pregelatinized Maize Starch by Colorcon. More preferably, the pregelatinized starch is Starch 1500® LM of Colorcon.
Most preferably, in this invention pregelatinized starch works is used in the range of 5% to 75% by weight based on the total weight of the composition, more preferably 10% to 70%. most preferably 20% to 60% by weight based on the total weight of the composition.

The composition preferably comprises a lubricant, more preferably lubricant is magnesium stearate.
More preferably, the composition consists of fingolimod or its pharmaceutical!)' acceptable salts thereof, pregelatinized starch and magnesium stearate.
In another embodiment the present invention provides a stable composition comprising: (a) a core: (b) drug coating on the said core, wherein the said drug layer comprising fingolimod or its pharmaceutical!)' acceptable salts and optionally at least one pharmaceutically acceptable excipient.
In a particularly preferred embodiment, a core is inert microcrystallinc cellulose core unit. The microcrystalline cellulose core unit of the beads is any core or seed that contains microcrystalline cellulose and is typically a commercially available microcrystalline cellulose sphere such as Celfets® or Celpheres®.
In most preferred embodiment, the drug coating consists essentially of fingolimod or its pharmaceutically acceptable salts, preferably fingolimod HCI. together with a pharmaceutically acceptable binder.

In a particular preferred embodiment, drug layer comprises a binder which is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose polyvinylpyrrolidone, starch or a combination thereof, more preferable the binder is a low viscosity of hydroxypropyl methylcellulose.
In a particular preferred embodiment, the drug layer solution comprises the fingolimod HC1, a binder and a suitable solvent, most preferably purified water. The drug layer solution is applied on to the MCC core by any method known in the art.
In another embodiment, the present invention provides a method for the preparation of a stable composition comprising fingolimod or its pharmaceutically acceptable salt thereof, polysaccharide and optionally at least one pharmaceutically acceptable excipient
In a particular preferred embodiment, the composition according to the present invention can be dispensed as a dosage form for oral administration. The compositions of the present invention are well-adapted for encapsulation into an orally administrable capsule shelf, particularly a hard gelatin shell. Alternatively the compositions may be compacted into tablets. The tablets may optionally be coated.

The pharmaceutical compositions of the present invention may be produced by standard processes, for instance by mixing, granulating, sugar-coating, dissolving or lyophilizing processes.
In a particular preferred embodiment, the present invention provides a method for the preparation of a stable composition comprising mixing the fingolimod or its pharmaceutical!)/ acceptable slats thereof, with polysaccharide and/or its derivatives and sifted through mesh screen. Further the above sifted mixture is blended with suitable blender. Then lubricated the above mixture with magnesium stearate and blended to produce a product composition showing a substantially uniform distribution of fingolimod throughout the blend, The product composition is then filled into size 3 hard gelatin capsule shell.
Alternatively, a wet granulation process is employed. In this embodiment, the fingolimod is dissolved in purified water followed by wet granulation with polysaccharide and/or its derivatives.
Further, the composition according to present invention optionally comprises one or more ingredients selected from fillers, diluents, binders, disinlegrants, lubricants. glidants, surfactants, stabilizers and other suitable excipients or mixture thereof.

In another embodiment, the present invention provides a stable composition comprising fmgolimod or its pharmaceutically acceptable salt thereof for the treatment of multiple sclerosis, preferably relapsing-remitting multiple sclerosis
EXAMPLES
The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The scope of the invention is in no manner limited by the disclosed example. Example I:

Ingredients Function Qry/cap (mg)
Fingolimod HC1 Active 0.56
Maltodextrin Filler 46.48
Magnesium stearate Lubricant 0.96
Dry Mix weight 48.00
H.G.Capsule Shell (Size 3) 48 mg
Capsule Fill Weight 96.00 mg
Brief Manufacturing Process:
0.56mg of fmgolimod is mixed with 46.48 mg of maltodextrin and then screened through 30 mesh screen. Magnesium stearate separately screened and blended with

the fmgolimod/maltodextrin mixture. The above lubricated mixture further screen through 40 mesh screen and blended to produce a product composition showing a substantially uniform distribution of fingolimod throughout the maltodextrin in the blend. The product composition is then filled into size 3 hard gelatin capsule shell.
Example 2:

Ingredients Function Qry/cap(mg)
Fingolimod HC1 Active 0.56
Pullulan Filler 46.48
Magnesium stearale Lubricant 0.96
Dry Mix weight 48.00
H.G.Capsule Shell (Size 3) 48 mti
Capsule Fill Weight 96.00 mg
Brief Manufacturing Process:
0.56 mg of Fingolimod is mixed with 46.48 nig of pullulan and then screened through 30 mesh screen. Magnesium stearate separately screened and blended with the fingolhnod/pullulan mixture. The above lubricated mixture further screen through 40 mesh screen and blended to produce a product composition showing a substantially uniform distribution of Fingolimod throughout the pullulan in the blend. The product composition is then Filled into size 3 hard gelatin capsule shell.

Example 3:

Ingredients Function Qry/cap (mg)
Drug Layering
MCC spheres Inert Pellet 44.00
Fingoimod HCl Active 0.56
HPMC E-5 Binder 2.48
Purified water Vehicle q.s.
Lubrication
Talc Glidant 0.96
Pellets weight 48.00
H.G.Capsuie Shell (Size 3) 48.00
Capsule Fill Weight 96.00
Brief Manufacturing Process:
Prepare a drug layer solution by dissolving the fingolimod MCI & HPMC in purified water. Coat the MCC sphere with above prepared drug layer solution in FBD or suitable granulator and then lubricated the above drug coated core with talc. The above lubricated drug coated core further screen through 40 mesh screen and blended to produce a drug pellets. The drug pellets is then filled into size 3 hard gelatin capsule shell. Example 4:

Ingredients Function Qrv/cap (mg)
Fingolimod HC1 Active 0.56
Starch 1500 Filler 46.48
Magnesium stearate Lubricant 0.96
Dry Mix weight 48.00
H.G.Capsuie Shell (Size 3) 48 mg
Capsule Fill Weight 96.00 mg

Brief Manufacturing Process:
0.56 mg of fingolimod is mixed with '16.48 my of starch 1500 and then screened through 100 mesh screen. Magnesium stearate separately screened and blended with the fingolimod/starch 1500 mixture. The above lubricated mixture further screen through 40 mesh screen and blended to produce a product composition showing a substantially uniform distribution of fingolimod throughout the starch 1500 in the blend. The product composition is then filled into size 3 hard gelatin capsule shell.
Stability Data
The capsule of the example 4 composition were filed in PVC/PVDC- Alu blister and subjected to stability testing at 25°C/60%RH: and 40°C/75%RH. The results of stability study were as follows:
Tabic 1: Stability data under different time interval at stress condition of 40°C / 75 % RH

Time Periods
(Months) Condition: 40°C / 75 % RH

Assay (%) Impurity (%)
Initial 99.70% 0.2
1 97% 0,4
2 99.70% 0.5
99.00% 1.1
6 97.90% 1.3

The above data shows a total impurity of 1.3% in the formulation indicative of
stability of fingolimod HC1 in the drug product.
Total impurity describes herein the degradation product of fingolimod produce
during the manufacturing process of pharmaceutical composition.
Tabic 2; Stability data under 6 month time interval at condition of 25°C / 60% RH

Time Periods (Month) Condition: 2 5°C/60%RH

Assay (%) Impurity (%)
6 99.90 0.2
The above data shows a total impurity of 0.2% in the formulation indicative of stability of fingolimod HCI in the drug product.
Above stability data indicates that the stable composition of fingolimod comprising fingolimod or its pharmaceutically acceptable salts can be obtained by using polysaccharides.
The composition of the present invention overcomes the problem associated with the content uniformity related with fingolimod composition.
Dissolution study
Dissolution study of the example 4 were carried with USP dissolution apparatus I at lOOrpm using 1000 ml in 0.IN HCI with 0.2% SLS.

Table 3: Dissolution profile in 0.1 N HCI with 0.2% SLS, USP dissolution apparatus I at 100 rpm using 1000 ml at 40°C/75%RH.

Time(Min) % Drim Release
5 71
10 86
15 92
20 94
30 96
45 96
Table 4: Dissolution profile in 0.1 N HCI with 0.2% SLS, USP dissolution apparatus I at 100 rpm using 1000 ml at 25°C/60% RH.

Time (Min) % Drug Release
5 79
10 89
15 95
20 96
30 98
45 98
The above dissolution study data comply with the dissolution testing requirements of immediate release solid oral dosage forms.

We claim;
1. A stable pharmaceutical composition of fingolimod comprising fingolimod or its pharmaceutically acceptable salt thereof, polysaccharide and at least one pharmaceutically acceptable excipient.
2. The stable pharmaceutical composition of fingolimod according to claim I, wherein the polysaccharide is maltodextrin.
3. The stable pharmaceutical composition of fingolimod according to claim I. wherein the polysaccharide is pullulan.
4. The stable pharmaceutical composition of fingolimod according to claim I. wherein the polysaccharide is pregelatinized starch.
5. A stable pharmaceutical composition of fingolimod comprising: (a) a core: (b) drug coating on the said core, wherein the drug coating comprises of fingolimod or its pharmaceutically acceptable salts and optionally at least one pharmaceutically acceptable excipient.
6. The stable pharmaceutical composition according to any preceding claim, wherein pharmaceutically suitable excipients are selected from binder, diluent, lubricant, fillers, disintegrates, glidanls, surfactants, stabilizers and mixtures thereof.
7. A process for preparation of a stable pharmaceutical composition of fingolimod comprising the steps of

a) mixing fingolimod or its pharmaceutically acceptable salts with polysaccharides selected form maltodextrin. pullulan or pregelatinized starch or mixture thereof.
b) mixing the mixture obtained from step (a) with a lubricant.
c) formulate the above lubricated mixture obtain form step (b) into final dosage form.
8. A process for preparation of a stable pharmaceutical composition comprising:
(a) a core; (b) drug coating on the said core, wherein the drug coating
comprises of fingolimod or its pharmaceutically acceptable salts and
optionally at least one pharmaceutically acceptable excipient,