FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION (SECTION 10 and Rule 13)
TITLE OF THE INVENTION "PHARMACEUTICAL FORMULATIONS OF FINGOLIMOD"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957 and having its
registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:

FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising a sphingosine-1 phosphate receptor agonist and processes for preparation thereof. Typically, the present invention relates to pharmaceutical compositions of fingolimod and processes for preparation thereof.
BACKGROUND OF THE INVENTION
Fingolimod or "FTY720", is a modulator of the sphingosine-1 phosphate receptor (hereinafter "SIP"), which, after phosphorylation, can bind SIP receptors, especially of T and B-lymphocytes. Inflammatory T-lymphocytes are possible triggers for the destruction of the neural myelin sheaths that are responsible for the typical symptoms of multiple sclerosis. Fingolimod inhibits the migration of lymphocytes from the lymph nodes into the blood and hence reduces their distribution in the central nervous system, evoking a generalized immmunosuppression. For this reason, in 2010, Fingolimod became the first oral disease-modifying drug approved for treating multiple sclerosis.
Fingolimod, chemically known as 2-amino-2-[2-(4-octylphenyl) ethyl] propane-1, 3-diol was first disclosed by Adachi et al in US 5,604,229. It is marketed worldwide under brand name "Gilenya® as an immediate release capsule formulation. This formulation contains 0.5 mg equivalent of fingolimod base in the form of hydrochloride salt and mannitol as excipient.
The poor physicochemical properties of fingolimod have vexed researchers involved in manufacturing of solid stable formulations of fingolimod. In particular, it has been found that fingolimod particles have a strong tendency to stick to surfaces and to each other. Moreover, it has found that there is a significant problem with achieving a desirable content uniformity in pharmaceutical formulations containing fingolimod. Further, aminopropane-1, 3-diol group of fingolimod can react with certain excipients to produce degradation products in the final formulation. Thus, it is very difficult to formulate the desired dosage form containing fingolimod.
Various approaches have been reported in the prior art to overcome abovementioned problems and are as follows:

Oomura et al in WO2004/089341 discloses a pharmaceutical composition of SIP agonist comprising a sugar alcohol, such as mannitol. The use of spray-dried sugar alcohol such as mannitol with high specific-surface area assists in promoting uniform distribution of fingolimod and improves compressibility and hardness of tablet composition. The sugar alcohol may act as a diluent, carrier, filler or bulking agent. Apparently, the innovator has performed drug-excipient compatibility studies and found that spray-dried mannitol was the only excipient that can provide uniform distribution of fingolimod and conferred good physicochemical and storage properties whereas microcrystalline cellulose, lactose & starch failed to obtain the desired profile.
WO 2008/037421 of Ambuhl et al discloses rapidly disintegrating dosage forms of SIP agonists including fingolimod. The composition comprises a taste masking coat of one or more polymer resins and metal oxides.
EP 1905434 provides a composition comprising an SIP receptor modulator and micronized microcrystalline cellulose in the absence of a sugar alcohol that result in better content uniformity of active ingredient.
Ruegger et al in WO 2009/048993 teaches that various SIP receptor modulators comprising an aminopropane-1, 3-diol group (such as, e.g., Fingolimod) are not easy to formulate in a solid oral formulation and only a limited number of excipients are potentially feasible with such amino diols. In particular, reducing sugars are not considered suitable due to danger of Maillard reaction with the amino-group. Though the document mentions that a fingolimod formulation requires judicious selection of the excipients, provides a long list of excipients which are normally employed as fillers, binders, disintegrants, lubricants, flow regulators, matrix formers, flavouring agents and sweeteners. The laundry list of excipients, which are mentioned as suitable, leaves the person bewildered about the judicious selection of the excipients.
WO2010/055028 discloses crystalline polymorphs and hydrates of fingolimod hydrochloride and pharmaceutical formulations thereof. The document discloses that these crystalline salts are more stable and better in quality than free base in terms of storage and distribution. The

solid pharmaceutical formulations comprise the crystalline fingolimod hydrochloride and a sugar alcohol.
WO2014111955 discloses pharmaceutical composition comprising fingolimod and a weak acid cation exchange resin in the form of an ion-exchange complex and pharmaceutically acceptable excipients.
US2014199382 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.
In summary, the prior art teaches that the poor physicochemical properties of fingolimod and its incompatibility with commonly employed excipients make it very difficult to formulate fingolimod stable solid dosage forms for oral administration.
Thus, there exists a need for an alternate and/or improved solid oral composition of Fingolimod, which is stable and has good handling properties.
OBJECT OF THE INVENTION
It is therefore an object of the present invention to provide an alternate and/or improved stable solid oral dosage form of SIP receptor modulator.
Another object of the present invention is to provide an alternate and/or improved solid oral composition of Fingolimod which is stable and has good handling properties.
Yet another object of the present invention is to provide a simple, economically viable process for preparation of solid oral dosage form of Fingolimod.
SUMMARY OF THE INVENTION
The present inventors have surprisingly found that the stability and uniformity of pharmaceutical compositions containing fingolimod is heavily dependent on the choice of excipients used in the formulation, their ratio and the process by which the formulation is prepared.

The solid oral pharmaceutical composition of the present invention comprises of fingolimod or pharmaceutically acceptable acid addition salt thereof and pharmaceutically acceptable compatible excipients, such as binders, disintegrants, lubricants, glidants, anti-adherents and combinations thereof.
Thus, in one aspect, present invention provides judicious selection of excipients compatible with fingolimod as well as their ratio and the process of preparation of formulation that result in stable solid oral dosage form of fingolimod.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to stable solid oral pharmaceutical compositions comprising a sphingosine-1 phosphate receptor agonist (typically fingolimod).
Fingolimod comprises a basic amino-group and may accordingly form acid addition salts with organic or inorganic acids. In accordance with its intended use, pharmaceutically acceptable acids are preferred. Examples of pharmaceutically acceptable acids are, without limitation, a hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, formic, acetic, propionic, oxalic, malonic, maleic, fiimaric, lactic, citric, malic, tartaric, methane sulfonic, benzene sulfonic, naphthalene disulfonic acid, etc. Preferred pharmaceutically acceptable salt is fingolimod hydrochloride. The composition of the present invention typically includes the micronized fingolimod hydrochloride.
The composition of the invention preferably contains 0.01 to 20% by weight of SIP receptor agonists -fingolimod, more preferably 0.1 to 10%, e.g. 0.5 to 5% by weight, based on the total weight of the composition.
In contrast to above mentioned prior art, present inventors have found that the stable solid oral composition of fingolimod can be formed with excipients other than sugar alcohol. Because of the nucleophilic amino group of fingolimod, which has ability to undergo Maillard's reaction, resulting in degradation of fingolimod, a limited number of excipients are potentially feasible with such amino diols. Therefore, for preparation of solid oral compositions of such amino diols, the various excipients requires judicious selection.

Thus, typically, the composition of the invention contains pharmaceutical^ acceptable compatible excipients such as dibasic calcium phosphate, microcrystalline cellulose, amberlite and mixtures thereof.
The amount of dibasic calcium phosphate is in the range of 75 to 99% by weight; more preferably 85 to 95% by weight, e.g. 90 to 95% by weight based on the total weight of the composition.
The amount of microcrystalline cellulose is in the range of 80 to 99% by weight; more preferably 85 to 95% by weight, e.g. 90 to 95% by weight based on the total weight of the composition.
The amount of amberlite is in the range of 1 to 10% by weight; more preferably 2 to 8% by weight, e.g. 3 to 7% by weight based on the total weight of the composition.
The composition further comprises a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, zinc stearate,. glyceryl palmitostearate, hydrogenated vegetable oil such as hydrogenated castor oil, mineral oil, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol or a mixture of any of the above. Preferably the lubricant comprises magnesium stearate, hydrogenated castor oil or mineral oil.
The composition preferably contains 1 to 10%o by weight of the lubricant, more preferably 3 to 7% by weight, e.g. about 5% by weight, based on the total weight of the composition.
The composition may further comprise excipients to ease the manufacturing process as well as to improve the performance of the dosage form. Common excipients include disintegrants, glidants etc. Such excipients are well known and routinely used for such oral dosage forms.
Examples of suitable disintegrants include croscarmellose sodium, starch, crospovidone, sodium starch glycolate, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, powdered cellulose, chitosan, guar gum, magnesium aluminium silicate, methylcellulose, and sodium alginate, and mixtures thereof.
Examples of suitable glidants include talc, silicon dioxide and cornstarch.

The composition may be in the form of a powder, granule or pallets or a unit dosage form, for example as a tablet or capsule. 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 compositions of the invention show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to one, two or three years, and even longer. Stability characteristics are determined, e.g. by measuring decomposition products by HPLC analysis after storage for particular times, at particular temperatures, e.g. 20 °C, 40 °C or 60 °C.
The pharmaceutical compositions of the present invention are produced by standard processes, for instance by conventional mixing, granulating, sugar-coating, dissolving processes. Procedures which may be used are well known in the art, e.g. those described in L. Lachman et al, The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986 or Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or later editions.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.

Illustrative Examples:
Example 1:
Fingolimod capsules were prepared by following formula summarised in Table - 1. Both micronized fingolimod hydrochloride and excipients were pre-screened and later blended together in geometric mixing sequence. The blend was further lubricated with pre-screened magnesium stearate. Final lubricated blend was then filled in capsules using automatic capsule filling machine.
Table 1: Fingolimod Capsule formulation

Sr.
No. Ingredients % w/w

Exampl e-1 Exampl
e-2 Exampl
e-3 Exampl
e -4 . Exampl e -5 Exampl e -6
1 Fingolimod HC1 0.5-5 0.5-5 0.5-5 0.5-5 0.5-5 0.5-5
2 Dicalcium Phosphate Anhydrous 90-95 90-95 90-95 - - -
3 Amberlite IRP 64 - 1.5-4 - - 1.5-4 1.5-4
4 Microcrystalline Cellulose - - - 90-95 85-95 -
5 Crospovidone - - 3-7 - - 85-95
6 Magnesium Stearate 3-7 3-7 3-7 3-7 3-7 3-7
7 Water - QS QS QS QS QS

CLAIMS:
1. A stabilized solid pharmaceutical composition for oral administration comprising fingolimod or pharmaceutically acceptable salts thereof and pharmaceutically acceptable compatible excipients.
2. The composition of claim 1 comprises from about 0.5 to about 5 % by weight of Fingolimod or pharmaceutically acceptable salts thereof.
3. The composition of claim 1 wherein the pharmaceutically acceptable compatible excipients are selected from dibasic calcium phosphate, microcrystalline cellulose, amberlite and mixtures thereof.
4. The composition of claim 3 wherein the amount of dibasic calcium phosphate is in the range of from about 75 to about 99 % by weight of total composition.
5. The composition of claim 3 wherein the amount of microcrystalline cellulose is in the range of from about 80 to about 99 % by weight of total composition
6. The composition of claim 3 wherein the amount of Amberlite is in the range of from about 1 to about 10 % by weight of total composition.
7. The composition of claim 1 may further comprise additional excipients such as disintegrant, glidant, lubricant.
8. The composition of claim 7 wherein disintegrants are selected from croscarmellose sodium, starch, crospovidone, sodium starch glycolate, alginates, chitosan, guar gum and mixtures thereof.

9. The composition of claim 7 wherein lubricants are selected from stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, hydrogenated vegetable oil magnesium oxide, colloidal silicon dioxidel or mixtures thereof.
10. The composition of claim 1 is in the form of tablet or capsule.