Field of invention:

The present invention is directed to oral solid pharmaceutical dosage form comprising 2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-diol hydrochloride and method of making thereof.

Background of invention:

2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-diol hydrochloride is generically known as Fingolimod (Formula-I) with an empirical formula of C19H33NO2 and a molecular weight of 343.93.

Fingolimod is a sphingosine 1-phosphate receptor modulator resulting in inhibition of the egress of lymphocytes from lymph nodes and Peyer's patches, and thereby reduces the recirculation of lymphocytes to blood and tissues including the Central Nervous System. 2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-diol hydrochloride has demonstrated significant and consistent effects on Magnetic Resonance Imaging (MRI) measures of inflammation and relapses in study performed in adult patients with relapsing MS (Kappos, et al 2006], Oral 2-amino->2-[2-(4-octylphenyl)ethyl]propane-l,3-diol hydrochloride for relapsing multiple sclerosis.(N Engl J Med; 355(11 ): 1124-1140).

Fingolimod HC1 is commercially available as a capsule for oral administration (Gilenya®, marketed by Novartis). Fingolimod HC1 is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

As the pharmaceutical compositions comprising, an active ingredient, Fingolimod HC1 or its salt the following literatures have been known so far.

Fingolimod or its salt was disclosed in US5604229. Fingolimod HC1 is sold by

Novartis in capsules under the commercial name of Gilenya® as in the treatment of multiple sclerosis.
International Publication No. WO2010055028A2 discloses polymorphs of fingolimod HC1 referred as form I, II & III and also disclosed the pharmaceutical composition thereof.

International Publication No. WO2004089341A1 discloses the pharmaceutical composition comprising fingolimod HC1 combination with sugar alcohol.

International Publication No. WO2008037421A2 discloses the pharmaceutical composition comprising SIP receptor modulator, wherein the composition comprises a coating comprising one or more polymer resin and one or more metal oxides.

Fingolimod HC1 is soluble (>10%) in water, 0.9% saline and aqueous buffers at a pH~2.0. It is very soluble or practically insoluble in aqueous buffer at or above pH~3.0.

Henceforth, there is a need in the art to develop a pharmaceutical composition, which enhances the solubility of the API in the stomach.

Advantages of the present Invention:

> Pregelatinized starch used as capsule binder and diluent. Preferably as diluent.
> Pregelatinized starch is used along with stearic acid to enhance the compatibility of the final dosage form.
> Pregelatinized starch also enhances the flow properties of blend during capsule filling.
> The present invention reduces the filled blend weight and capsule size as well. This gives more patient compliance.
> Optionally tricalcium phosphate can also be used as diluent, glidant and buffering agent.

Optionally sodium lauryl sulphate may used to increase the solubility, finally it leads to increase in the bioavailability of fingolimod HC1 (in vitro and in vivo release profile)

Summary of Invention:

In an aspect of the present invention provides a pharmaceutical composition comprising fingolimod HC1, diluent & lubricant and optionally other pharmaceutically acceptable carrier.

In an aspect of the present invention provides a pharmaceutical composition comprising fingolimod HC1, pregelatinized starch and stearic acid, wherein the pharmaceutical composition is a solid oral dosage form.

In an aspect of the present invention provides a pharmaceutical composition comprising fingolimod HCI, pregelatinized starch and stearic acid, wherein the % of the drug content in the composition is about 0.1% to about 2.0%.

In an aspect of the present invention provides a solid oral dosage form comprising fingolimod HCI, pregelatinized starch and stearic acid, wherein the dosage form is in the form of a tablet, capsule, powder, pellets, granules etc., preferably the dosage form is a capsule and more preferably the capsule size is 3 to 4.

In an aspect of the present invention provides a solid oral dosage form is preferably a capsule dosage form, wherein the weight of the filled blend in the capsule is about 30 mg to about 200 mg.

In an aspect of the present invention provides a process for preparing a pharmaceutical composition comprising fingolimod HCI, pregelatinized starch and stearic acid.

In an aspect of the present invention provides a process for preparing a pharmaceutical composition comprising (a) co-sifting fingolimod & pregelatinized starch and stearic acid separately; (b) blending fingolimod & pregelatinized starch; (c) blending stearic acid with step (b); (d) filling the blend into hard gelatin capsules.

In an aspect of the present invention provides a process for manufacturing the oral solid pharmaceutical composition of fingolimod or its salts, particularly hydrochloride salt.

In an aspect of the present invention provides a method of treating multiple sclerosis in a subject in need thereof, said method comprising administration of fingolimod composition.

Detailed Description of the Invention:

The present invention relates to a novel process for the preparation of 2-amino-2-2-(4-octylphenyl)ethyl]propane-l,3-diol hydrochloride compound of formula-1 and its pharmaceutical composition. Hereinafter formula-1 is also referred as fingolimod or its salt.

Fingolimod HC1 is commercially available as a capsule for oral administration (Gilenya®, marketed by Novartis). Fingolimod HC1 is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

By "salt" or "pharmaceutically acceptable salt", it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for oral use for humans to commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, and bisulphate. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts. The term "pharmaceutically acceptable" as used in connection with components includes those components approved by a governmental regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, such as humans.

The present invention relates to a pharmaceutical composition comprising fingolimod HC1, diluent & lubricant and optionally other pharmaceutically acceptable carrier.

In the present invention relates to an oral solid pharmaceutical composition comprising one or more of:

a) fingolimod HC1,
b) at least one diluent,
c) at least one surfactant,
d) at least one binder,
e) at least one glidant,
f) at least one lubricant.

The term "solid oral dosage form" (synonymously, "dosage form") is used herein to refer to a pharmaceutical preparation intended for oral administration, includes such dosage forms as tablets, capsules, minitablets, pellets, granules & spheroids. Preferably, solid oral dosage form is in the form of a tablet or a capsule.

In an aspect of the present invention provides a pharmaceutical composition comprising fingolimod HC1, pregelatinized starch and stearic acid, wherein the pharmaceutical composition is a solid oral dosage form.

In an aspect of the present invention provides a pharmaceutical composition comprising fingolimod HC1, pregelatinized starch and stearic acid, wherein the % drug content in the composition is about 0.1% to about 2.0%.

In an aspect of the present invention provides a solid oral dosage form comprising fingolimod HC1, pregelatinized starch and stearic acid, wherein the dosage form is in the form of a tablet, capsule, powder, pellets, granules etc., preferably the dosage form is a capsule and more preferably the capsule size is 3 to 4.

In an aspect of the present invention relates to an oral solid composition of fingolimod, wherein the said oral solid dosage form has a drug release is not less than 75% with in 5 minutes by using USP apparatus 1 (basket) at 100 rpm in 0.1 N HC1 + 0.5 % SLS.

The excipients are selected to ensure the delivery of consistent amount of fingolimod HC1 and also should contain a convenient unit dosage form to optimize the cost, ease and reliability of the manufacturing process. All the excipients must be inert, organoleptically acceptable, and compatible with the fingolimod HC1. Generally the excipients used in the solid dosage form include diluents or fillers, binders, surfactants, lubricants, glidants and coating agents.

In an aspect of the present invention provides a solid oral dosage form is preferably a capsule dosage form, wherein the weight of the filled blend in the capsule is about 30 mg to about 200 mg.

In an aspect of the present invention provides a process for preparing a pharmaceutical composition comprising fingolimod HC1, pregelatinized starch and stearic acid.

Diluents are included to increase the bulk of the capsule. The various types of diluents are tricalcium phosphate, lactose and microcrystalline cellulose, pregelatinized starch and the like. Preferably the diluent is pregelatinized starch.

Optionally surfactants are included to increase the solubility of the drug that finally leads to increase in the bioavailability of the drug. Surfactants may be ionic or nonionic. Ionic surfactants may be anionic, cationic and zwitter ionic. Non-limiting examples include sodium lauryl sulphate, sodium cholate hydrate, poloxomers and docusate sodium and the like.

Binders may be used as a wet granulation excipient to agglomerate the powder mixture of active pharmaceutical ingredient and the other excipients. The binder is selected to improve the flow properties of powder and to improve compatibility. The most commonly used binders are pregelatinized starch, hydroxypropylcellulose, hydroxypropyl methylcellulose and povidone.

Glidants or flow regulators may be included to increase the flow properties of the blend. The various types of glidants are dried starch, colloidal silicon dioxide and talc.

Lubricants are used in the tablet formulation to reduce the friction during the compression stages and to prevent the sticking of the tablet to the punch faces. Lubricant is selected from stearic acid, vegetable oils(corn oil), mineral oils, polyethylene glycol, inorganic salts(such as sodium chloride), organic salts (sodium benzoate, sodium acetate), and polyvinyl alcohols. Preferably the lubricant is stearic acid.
In an aspect of the present invention provides a process for preparing a pharmaceutical composition comprising (a) co-sifting fingolimod & pregelatinized starch and stearic acid separately; (b) blending fingolimod & pregelatinized starch; (c) blending stearic acid with step (b); (d) filling the blend into hard gelatin capsules.

In an aspect of the present invention provides a process for manufacturing the oral solid pharmaceutical composition of fingolimod or its salts, particularly hydrochloride salt.

In an aspect of the present invention provides a method of treating multiple sclerosis in a subject in need thereof, said method comprising administration of fingolimod composition.

The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the invention.

Example-1:
Table-1
S No Components Mg /Cap
1 Fingolimod HC1 0.5
2 Tricalcium phosphate 281.9
3 Sodium lauryl sulphate 3
4 Pregelatinized starch 7.5
5 Purified water qs
6 Dried starch 3
7 Stearic acid 4.5 Total Weight 300

Procedure: Dispense fingolimod HC1, tricalcium phosphate, sodium lauryl sulphate, pregelatinized starch, dried starch and stearic acid were passed through an appropriate mesh. The fingolimod HC1, tricalcium phosphate, sodium lauryl sulphate and pregelatinized starch were mixed for 15min. A sufficient quantity of water was added to the above mixer and mixed with a high speed, the above granules were dried and further, the above dried granules were passed through an appropriate mesh and dried starch was added to the above sized granules and blended for 15 min. Stearic acid was added to the above blend for lubrication. The final blend was filled into the capsules.

Example-2

Table-2

S No Components Mg /Cap
1 Fingolimod HC1 0.5
2 Tricalcium phosphate 281.9
3 Sodium lauryl sulphate 3
4 Pregelatinized starch 7.5
5 Dried starch 3
6 Stearic acid 4.5 Total Weight 300
Procedure:

Dispense fingolimod HC1, tricalcium phosphate, sodium lauryl sulphate, pregelatinized starch, dried starch and stearic acid were passed through an appropriate mesh. The fingolimod HC1, tricalcium phosphate, sodium lauryl sulphate and pregelatinized starch were mixed for 15min. The above granules were passed through an appropriate mesh. Dried starch was added to the above dried sized granules and blended for 15min. Stearic acid was added to the above blend for lubrication. The final blend was filled into the capsules.

Example-3:

Table-3

S No Components Mg /Cap
1 Fingolimod HC1 0.56
2 Pregelatinised Starch 44.14
3 Stearic Acid 0.30 Blend filled weight 45
Size '4' Hard Gelatin empty capsules

Manufacturing Process:
Sifting of Ingredients:

Table - 4

S. No Name of the Raw material Mesh Size to be used

i Fingolimod HC1 and Pregelatinized Starch ^Q
2 Stearic Acid #60
a) Fingolimod HC1 & Pregelatinized Starch were sifted and mixed in a blender for 20 min.
b) To the above blend stearic acid was added and mixed for 5 min.
c) Resultant mixture of step (b) was filled into capsules.

ExampIe-4:

Table-5

S. No Name of the ingredient Qty (mg)/capsule

1 Fingolimod HC1 0.56
2 pregelatinized Starch 148.44
3 Stearic Acid 1.00 Blend filled weight 150 mg

Size *3' Hard Gelatin empty capsules
Manufacturing Process:

Manufacturing process is same as Example-3

Dissolution Method:
In vitro dissolution studies on fingolimod HC1 capsules are carried out using USP apparatus 1 (basket) at 100 rpm in 500ml of 0.0IN HC1 + 0.5% Sodium lauryl sulfate as a dissolution medium maintained at a temperature of 37±0.5 C.

Dissolution Profile of Gilenya & Example-3 0.5 mg
% Release in 0.1 N HC1 + 0.5 % SLS, 500 ml, Basket ,100 rpm
Time GILENYA MSN Test
(in min)
5 84.6 82
10 91.3 88.1
15 92.9 89.6
20 95.6 91.2
30 97.3 92.8

Claims:

1. A pharmaceutical composition comprising fingolimod HC1, diluent & lubricant and optionally other pharmaceutical^ acceptable carrier.

2. A pharmaceutical composition comprising fingolimod HC1, pregelatinized starch and stearic acid. Wherein the pharmaceutical composition is a solid oral dosage form.

3. A pharmaceutical composition comprising fingolimod HC1, pregelatinized starch and stearic acid. Wherein the % of the drug content in the composition is about 0.1% to about 2.0%.

4. A solid oral dosage form comprising fingolimod HC1, pregelatinized starch and stearic acid. Wherein the dosage form is in the form of a tablet, capsule, powder, pellets, granules etc.

5. A solid oral dosage form according to the preceding claims, preferably the dosage form is a capsule and more preferably the capsule size is 3 to 4.

6. A solid oral dosage form according to the preceding claims, wherein the weight of the filled blend in the capsule is about 30 mg to about 200 mg.

7. A process for preparing a pharmaceutical composition comprising fingolimod HC1, pregelatinized starch and stearic acid.

8. A process for preparing a pharmaceutical composition comprising (a) co-sifting fingolimod & pregelatinized starch and stearic acid separately; (b) blending fingolimod & pregelatinized starch; (c) blending stearic acid with step (b); (d) filling the blend into hard gelatin capsules.

9. A method of treating multiple sclerosis in a subject in need thereof, said method comprising administration of oral dosage form according to any of the preceding claims.

10. The method according to claim 9, wherein the subject is human.