CLIAMS:1. A process of preparing a solid oral dosage form of fingolimod or salts thereof, which process comprises steps of-
(a) dissolving or dispersing fingolimod or salt thereof and optionally one or more excipients in a pharmaceutically acceptable solvent or mixture of solvents;
(b) treating the solution or dispersion onto one or more excipients, and
(c) formulating the treated excipients into a solid oral dosage form.

2. The process of claim 1, wherein the treatment comprises adhering, adsorbing, absorbing, coating, spraying or combinations thereof.

3. The process of claim 1, wherein the pharmaceutically acceptable excipient comprises one or more non-hygroscopic bulking agents.

4. The process of claim 3, wherein the non-hygroscopic bulking agent comprises erythritol, trehalose, lactitol, tagatose, maltodextrin, lactose monohydrate, microcrystalline cellulose corn starch or mixtures thereof.

5. The process of claim 3 or 4, wherein the non-hygroscopic bulking agent is present in the amount of 50% to 99% by weight of the dosage form.

6. The process of claim 1, wherein the amount of fingolimod or salts thereof is present in the amount of 0.1% to 10% by weight of the composition.

7. The process of claim 1, wherein a pharmaceutically acceptable solvent selected from the group consisting of water, ethyl alcohol, isopropyl alcohol, methylene dichloride, chloroform or mixtures thereof.

8. A solid oral dosage form prepared by the process of claim 1.

9. A method of treating multiple sclerosis in a patient in need thereof, which method comprises of administering the solid oral dosage form of fingolimod or salts thereof prepared by the process of claim 1.
,TagSPECI:DESCRIPTION

The present invention relates to a process for preparing a solid oral dosage forms comprising effective amounts of fingolimod or salts thereof. In particular, the present invention relates to a process for preparing solid oral dosage forms comprising fingolimod or salts thereof, and other pharmaceutically acceptable excipients. The invention further relates to method of treating multiple sclerosis by using the composition fingolimod or salts thereof.

Multiple sclerosis, also known as disseminated sclerosis or encephalomyelitis disseminata, is an inflammatory disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate. The name multiple sclerosis refers to scars (plaques or lesions) in the white matter of the brain and spinal cord

Fingolimod is a sphingosine-1 phosphate (SIP) agonist, having immunosuppressive activity. Fingolimod reduces the rate of relapses in relapsing-remitting multiple sclerosis. Its chemical name is 2-amino-2-[2-(4-octylphenyl) ethyl] propan-1, 3-diol hydrochloride. Fingolimod in the form of its hydrochloride salt has following structural formula:

The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system. Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator.

Currently fingolimod is marketed as an immediate release capsule for the treatment of multiple sclerosis under brand name Gilenya™. This formulation contains 0.5 mg equivalent of fingolimod base in the form of the hydrochloride salt. The product is typically approved for treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

PCT Application No. WO2010/055028, WO2009/48993 and US Application No. 2010/0040678, US 2006/0275357, US2009/0203798, US2008/0311188, disclose formulations containing inter alia fingolimod or salts thereof.

U.S. Patent No. 8,324,283 & U.S. Patent Application No. 2013/0108675 discloses crystalline forms and hydrates of fingolimod hydrochloride and pharmaceutical formulations thereof. The solid pharmaceutical formulations comprise the crystalline fingolimod hydrochloride and a sugar alcohol. The sugar alcohol can be, e.g. mannitol, maltitol, inositol, xylitol or lactitol.

U.S. Patent No. 6,476,004 discloses pharmaceutical compositions comprising fingolimod, a cyclodextrin; and a pharmaceutically acceptable carrier or diluent.

US Application No. 2010/0040678 discloses rapidly disintegrating dosage forms of S1P agonists including FTY720 (fingolimod). The compositions comprise a coating, wherein the coating comprises one or more polymer resins and one or more metal oxides.

U.S. Patent Application No. 2013/0034603 discloses pharmaceutical composition or dosage form comprising an intimate admixture of fingolimod or a pharmaceutically acceptable salt thereof, and a solid surfactant.

PCT Application No. WO2009/048993 discloses dosage forms containing S1P modulators and one or more excipients selected from fillers, binders, disintegrants, lubricants, flow regulators, matrix formers, plasticizers, flavouring agents and sweeteners.

PCT Application No. WO 2013/091704 discloses pharmaceutical composition comprising Fingolimod and/or a pharmaceutically acceptable salt or ester thereof, calcium lactate pentahydrate and, optionally, a lubricant.

Certain S1P agonist compounds, and in particular, fingolimod, possess properties that can cause processing problems when preparing pharmaceutical formulations. Particularly, fingolimod particles have a strong tendency to stick to surfaces and to each other. Moreover, because of a low dose there is a significant problem of achieving a desirable content uniformity in pharmaceutical formulations containing fingolimod.

It is also known in the art that to address the problems associated with formulation development of fingolimod or salts thereof, prior art suggests to incorporate various additional ingredients in the formulation, which may, however, compromise the stability of the formulation as fingolimod is known to interact with common excipients used to produce conventional solid oral dosage forms.

Thus there exists an enduring need to provide improved formulations of fingolimod or salts thereof which can address the aforesaid objective and also may exhibit excellent storage stability.

The present invention addresses this need by providing formulations of fingolimod that have a desirable content uniformity by a simplified process.

Inventors of the present invention have surprisingly found that the uniformity and optionally, stability of the pharmaceutical compositions containing fingolimod can be improved by adopting a special manufacturing process.

Particularly, the inventors have found that content uniformity of fingolimod in solid dosage forms is achieved by dissolving or dispersing fingolimod or its salt in suitable solvent or solvent mixtures, followed by processing the resulting solution in suitable solid dosage form. The solution may be subjected to granulation with intra-granular ingredients, then mixed with extra-granular ingredients and compressed into the desired dosage form.

In one general aspect, there is provided a solid oral dosage form comprising fingolimod or salts thereof, which composition is prepared by a process comprising a step of dissolving or dispersing fingolimod or salts thereof in a pharmaceutically acceptable solvent or mixture of solvents to form a solution or dispersion.

In another general aspect, there is provided a solid oral dosage form comprising fingolimod or salts thereof, which dosage form is prepared by a process comprising step of dissolving or dispersing fingolimod or salts thereof in a pharmaceutically acceptable solvent or mixture of solvents and treating the solution or dispersion onto one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a solid oral dosage form comprising fingolimod or salts thereof, which composition is prepared by a process comprising step of dissolving or dispersing fingolimod or salts thereof in a pharmaceutically acceptable solvent or mixture of solvents to form a solution or dispersion and treating the solution or dispersion with non-hygroscopic bulking agent.

In a further general aspect, the solution, which includes fingolimod or salt thereof, is treated with a pharmaceutical material or mixtures of pharmaceutical materials. This treatment can be mixing, adhering, adsorbing, absorbing, coating, spraying or combinations thereof. Pharmaceutical material means suitable pharmaceutically acceptable excipients or different physical forms thereof such as pellets, granules, active or non-active containing tablet cores or combinations thereof.

In a further general aspect, treatment of fingolimod solution with an excipient or mixtures of excipients may be performed to form intra-granular or extra-granular phases of the solid dosage form. The granulation may be carried out either by spraying a fingolimod solution or dispersion and excipients in a fluidization processor or in high mixture granulator to knead the mass to form granule. Optionally a binder solution can be used for granulation.

In a further general aspect, fingolimod or salt thereof dissolved or dispersing in a pharmaceutically acceptable solvent selected from the group consisting of water, ethanol or isopropyl alcohol or mixtures thereof and the like.

In a further general aspect, pharmaceutically acceptable solvents used for granulation process may be selected from aqueous or non-aqueous solvents. The solvents comprise, but not limited to, water, isopropyl alcohol, acetone, ethanol, methylene chloride or combination thereof.

The intra and extra-granular excipients may comprise one or more fillers/diluents, disintegrants, binders, glidants, lubricants and optionally stabilizers (e.g. buffers or anti-oxidants or a mixture thereof).

In another general aspect, the process of preparing the solid oral dosage form of fingolimod or salt thereof further comprises steps of drying the granules, sizing the dried granules, optionally adding the extra-granular excipient(s), and formulating it further in a suitable solid oral dosage form.

In another general aspect, there is provided a process of preparing a solid oral dosage form of fingolimod or salts thereof, which process comprises steps of-
(a) dissolving or dispersing fingolimod or salt thereof and optionally one or more excipients in a pharmaceutically acceptable solvent or mixture of solvents,
(b) treating the solution or dispersion onto one or more excipients, and
(c) formulating the treated excipients into a solid oral dosage form.

In another general aspect, there is provided a method of treating multiple sclerosis by administering a solid oral dosage form comprising fingolimod or salts thereof, which composition is prepared by a process comprising a step of dissolving or dispersing fingolimod or salts thereof in a pharmaceutically acceptable solvent or mixture of solvents to form a solution or dispersion.

For active pharmaceutical ingredients, particle size is important to attain compressibility, proper content uniformity, bioavailability, compactness of the final dosage form. Proper content uniformity and release profiles are major concerns in the process development. Proper blending and prevention of segregation, especially when other techniques are not feasible, are required for a successful processing.

Most particularly for low dose drugs, active pharmaceutical ingredients' (API) particle size distribution is the most critical point impacting the uniformity of low dose solid dosage forms. In order to have a homogeneous distribution, API particle size can be reduced to below a certain size.

However, small particle size may cause manufacturing problems, hinder the processibility, thereby bringing about unnecessary delays in production. Other potential problems are related to reduce particle size include poor flowability and agglomeration which may result in segregation and poor blend uniformity.

Content uniformity of the fingolimod or salt thereof in suitable dosage form was determined using 10 random samples (for example capsules or tablets), by performing an HPLC assay to measure the amount of active ingredient in each samples, and comparing the amount of active ingredient in each samples to the labeled amount of active ingredient.

The manufacturing process of the invention may minimize the segregation potential by improving content uniformity across the granule particle size distribution, thereby improving content uniformity in the final solid dosage form.

Thus, according to the present invention, in order to eliminate the content uniformity problem, fingolimod or salt thereof is treated onto the surface of an excipient or mixtures of excipients. This method does not essentially require reducing of particle size of fingolimod or addition of specialized excipients. A particular advantage of the process is feasibility of using fingolimod of non-specific particle size. Thus, an additional advantage of the invention is that there is no need to take the particle size of fingolimod into account.

In an embodiment, the average particle size of fingolimod or its salt used in composition can be greater or lower than 250 µm, preferably lower than 250 µm. The term "average particle size" as used herein refers to the volume mean diameter of particles. The diameter and volume mean diameter can be determined by laser light scattering using e.g. a Malvern-Mastersizer Apparatus MS 2000. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogenous suspension of particles.

In another embodiment, the solid oral composition retains at least 90% by weight of the total content of fingolimod or salt thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

The term "content uniformity" as used herein, refers to the homogeneity of the fingolimod or salt thereof content among dosage forms.

The term “fingolimod” as used herein refers to fingolimod base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof. Particularly preferred salt of fingolimod is hydrochloride salt.

The improved solid oral dosage form of fingolimod or salts thereof is prepared by a process which comprises a step of dissolving or dispersing fingolimod or salts thereof in a solvent or mixture of solvents to form a solution. Alternatively, the solution is treated with non-hygroscopic bulking agent.

In a further embodiment, the aqueous solution of fingolimod or salts thereof is treated onto one or more pharmaceutically acceptable excipients. This treatment can be adhering, adsorbing, absorbing, coating, spraying mixtures thereof and the like. Pharmaceutical material means any kind of excipients, pellets, granules, active or non-active containing tablet cores or mixture thereof.

In a further embodiment, the non-aqueous solution of fingolimod or salts thereof is treated onto one or more pharmaceutically acceptable excipients. This treatment can be adhering, adsorbing, absorbing, coating, spraying mixtures thereof and the like. Pharmaceutical material means any kind of excipients, pellets, granules, active or non-active containing tablet cores or mixture thereof.

In a further embodiment, treatment of solution or dispersion of fingolimod or salts thereof with an excipient or mixtures of excipients may be performed to form intra-granular or extra-granular phases. The granulation can be carried out either by spraying technology in a fluidization processor or in high mixture granulator to knead the mass to form granule. Optionally, a binder solution can be used for granulation.

In a further embodiment, fingolimod or salt thereof dissolved or dispersed in a pharmaceutically acceptable aqueous or non-aqueous solvent or mixture thereof and may be selected from the group consisting of water, ethanol or Isopropyl alcohol or mixtures thereof and the like.

In a further embodiment, pharmaceutically acceptable solvents used for granulation process may be selected from water, isopropyl alcohol, acetone, ethanol, methylene chloride or combination thereof.

In a further embodiment, there is provided an improved process of preparing solid pharmaceutical composition comprising fingolimod or salt thereof, which process comprises a step of dissolving or dispersing fingolimod or salt thereof in a solvent or mixture of solvents and a step of treating this solution onto one or more pharmaceutically acceptable excipients.

In a further embodiment, the process of preparing the solid oral dosage form of fingolimod or salt thereof further comprises steps of drying the granules, sizing the dried granules, optionally adding to the extra-granular excipient(s), and formulating in suitable solid oral dosage form.

In a further embodiment, the solid oral composition retains at least 90% by weight of the total content of fingolimod when stored at 40°C and 75% relative humidity over a period of at least 3 months.

The composition can be prepared by intra-granulation and/or extra-granulation steps. Intra and extra-granular ingredient(s) can be selected from the group consisting of diluents, binders, disintegrants, fillers, lubricants, glidants, antioxidants, surface active agents, chelating agents, mixtures thereof.

The term 'filler' and the term 'diluent' are herein used interchangeably. Suitable filler/diluent includes, but are not limited, to calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose (e.g. spray-dried lactose, a-lactose, [beta]-lactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), methyl cellulose polymers such as, e.g., Methocel A®, Methocel A4C®, Methocel A15C®, Metocel A4M®), hydroxyethylcellulose, hydroxypropylcellulose, L-hydroxypropyl- cellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E®, F and K, Metolose SH® of Shin-Etsu, grades of Methocel F® and Metolose 65 SH®, the 4,000, 15,000 and 100,000 cps grades of Methocel K®; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH®), sodium carboxymethyl cellulose, carboxymethylene, carboxy methyl hydroxyethyl cellulose and other cellulose derivatives, starches or modified starches (including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol, erythritol and the like.

The term “non-hygroscopic bulking agent” as used herein refers to the pharmaceutically acceptable excipients which do not absorb and/or adsorb atmospheric moisture. Suitable examples include erythritol, trehalose, lactitol, tagatose, maltodextrin, lactose monohydrate, microcrystalline cellulose corn starch and mixtures thereof.

The inventors of the present invention have also found that non-hygroscopic bulking agents are particularly advantageous for the present invention over the conventional excipients. Without binding to any particular theory, non-hygroscopic bulking agents may contribute in improving the content uniformity of fingolimod solid dosage forms.

Suitable binders include, but not limited to, microcrystalline cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (e.g. acacia, tragacanth sodium alginate, celluloses, and Veegum),and synthetic polymers such as polymetacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethyl cellulose, polyethylene oxide, mixtures thereof and the like.

Suitable disintegrants include, but not limited to, cross linked polyvinylpyrolidone (crospovidone, polyplyplasdone XL(R), kollidon CL(R)); starches such as maize starch and dried sodium starch glycolate; gums such as maize starch and dried sodium starch glycolate; gums such as alginic acid, sodium alginate, guar gum; croscarmellose sodium; cellulose products such as microcrystalline cellulose and its salts, microfine cellulose, low-substituted hydroxypropylcellulose, mixtures thereof and the like.

Suitable lubricants include, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like.

Suitable glidants include, but not limited to, colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, mixtures thereof and the like

Suitable solid oral dosage form include, but are not limited to, capsules, tablets, granules, powders and unit dose pockets. Preferably oral pharmaceutical formulation is capsule.

Solid oral composition of the present invention is prepared by dissolving fingolimod or salt thereof in a solution. Solution may include an aqueous solvent or a non-aqueous solvent of mixture thereof or the like.

The invention further provides a method of treating multiple sclerosis by administering a solid oral dosage form comprising fingolimod or salts thereof of administering the solid oral composition of fingolimod or salts thereof in accordance with the present invention.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

Example 1:
Table 1
Sr. No. Ingredients Quantity (mg/Cap)
A Intragranular
1 Fingolimod HCl 0.50
2 Trehalose 23.50
3 PVP K30 2.50
4 Purified water q.s.
B Extragranular
5 Microcrystalline cellulose (MCC 102) 23
6 Magnesium stearate 0.50
Total 50

Process: Trehalose (non-hygroscopic bulking agent) was loaded into a FBP bowl and was sprayed with aqueous solution of fingolimod HCl and PVP K30 as a binder. After complete spray coating and drying of granules, microcrystalline cellulose (MCC 102) was mixed with granules as extragranular portion and lubricated with magnesium stearate. The lubricated blend was formulated into a suitable dosage form.

Example 2:
Table 2
Sr. No. Ingredients Quantity (mg/Cap)
A Intragranular
1 Fingolimod HCl 0.50
2 Maltodextrin 23.50
3 PVP K30 2.50
4 Purified water q.s.
B Extragranular
5 Microcrystalline cellulose (MCC 102) 23
6 Magnesium stearate 0.50
Total 50

Process: Maltodextrin (non-hygroscopic bulking agent) was loaded into a FBP bowl and was sprayed with aqueous solution of fingolimod HCl and PVP K30 as a binder. After complete spray coating and drying of granules, microcrystalline cellulose (MCC 102) was mixed with granules as extragranular portion and lubricated with magnesium stearate. The lubricated blend was formulated into a suitable dosage form.

Example 3:
Table 3
Sr. No. Ingredients Quantity (mg/Cap)
A Intragranular
1 Fingolimod HCl 0.50
2 Lactose monohydrate 23.50
3 PVP K30 2.50
4 Purified water q.s.
B Extragranular
5 Microcrystalline cellulose (MCC 102) 23
6 Magnesium stearate 0.50
Total 50

Process: Lactose monohydrate (non-hygroscopic bulking agent) was loaded into a FBP bowl and was sprayed with aqueous solution of fingolimod HCl and PVP K30 as a binder. After complete spray coating and drying of granules, microcrystalline cellulose (MCC 102) was mixed with granules as extragranular portion and lubricated with magnesium stearate. The lubricated blend was formulated into a suitable dosage form.

Example 4:
Table 4
Sr. No. Ingredients Quantity (mg/Cap)
A Intragranular
1 Fingolimod HCl 0.50
2 Maltodextrin 23.50
3 PVP K30 2.50
4 Purified water q.s.
B Extragranular
5 Microcrystalline cellulose (MCC 102) 23
6 Magnesium stearate 0.50
Total Tablet Weight 50

Process: Maltodextrin (non-hygroscopic bulking agent) was granulated in rapid mixer granulator with aqueous solution of fingolimod HCl and PVP K30 as a binder. Microcrystalline cellulose (MCC 102) was mixed granules as extragranular portion and lubricated with magnesium stearate. The lubricated blend was formulated into a suitable dosage form.