DESC:FIELD OF THE INVENTION:
The present invention relates to a process of preparing an oral pharmaceutical composition comprising Safinamide or pharmaceutically acceptable salt thereof, having particle size (D90) less than 100µm. The present invention further relates to methods of preparing and administering such pharmaceutical compositions for treating Parkinson's disease.
BACKGROUND OF THE INVENTION:
Safinamide Mesylate is chemically known as (S)-2-[[4-[(3-fluorophenyl) methoxy] phenyl] methyl] amino propanamide methanesulfonate which can be characterized by the following chemical formula:

Safinamide is a highly selective and reversible MAO-B inhibitor that causes an increase in the extracellular levels of dopamine in the striatum. Safinamide is associated with state-dependent inhibition of the voltage dependent sodium channels (Na+) and modulation of the stimulated release of glutamate.

Safinamide Mesylate is the active ingredient of drug (Xadago®) that is administered in the form of oral tablets.

Xadago® is indicated for the treatment of adult patients with idiopathic Parkinson's disease as add-on therapy at a stable dose of levodopa alone or in combination with other drugs for Parkinson's disease in mid- to late-stage fluctuating patients.

Safinamide Mesylate film-coated swallow able oral tablets, at a dosage of 50 and 100 mg, are currently on the market.
The active ingredient of the approved product Xadago® is Safinamide Mesylate. The active ingredient has been explored in various solid state forms such as crystalline or amorphous Safinamide Mesylate.

Patent EP1613296 (Newron Pharmaceuticals S.p.A.) describes novel compositions and methods for treating Parkinson's disease and, specifically, methods for treating Parkinson's disease by administering safinamide in combination with levodopa. This patent describes generic pharmaceutical formulations that comprise the active ingredient, inter alias, formulations for oral administration such as tablets, capsules.

International patent application WO 2011/098456 (Merck Serono SA) relates to the treatment and prophylaxis of dyskinesias, preferably, dyskinesias associated with dopaminergic therapy. It discloses a tablet composition having a core comprising safinamide, a binder and other excipients and a HPMC coating.

Chinese patent application CN 106983730 (Foshan City Hongtai Pharmaceutical R&D CO LTD) discloses a safinamide micro-pellet tablet and a preparation method thereof, wherein safinamide is prepared into a gastric-soluble coated micro-pellets through a fluidized bed coating process; and, then, converted into a film-coated swallow able tablet through a dry tableting technology.
The above attempts only provided compositions of Safinamide, which had shown less bioavailability and less dissolution. Therefore, there exists need to prepare alternate compositions of Safinamide that are stable and shows better dissolution and bioavailability.
Hence, there is an unmet need in the art to develop a simple, reproducible, and cost-effective manufacturing process for pharmaceutical composition of Safinamide Mesylate having particle size (D90) less than 100µm in order to solve the above problem, the present inventors have developed a composition, which provides stable product, as well as improved dissolution and bioavailability.
SUMMARY OF THE INVENTION:
The present invention relates to an oral pharmaceutical composition comprising Safinamide or a pharmaceutical acceptable salt thereof having particle size (D90) less than 100µm and pharmaceutical acceptable excipients.
The present invention relates to an oral stable pharmaceutical composition dosage form composition comprising an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprising Safinamide or a pharmaceutical acceptable salt having D90 less than 100µm and one or more pharmaceutically acceptable excipients and the extra-granular portion comprising one or more pharmaceutically acceptable excipients.

The primary aspect of the present invention relates to oral stable composition of Safinamide, wherein said composition comprises on a total of 100 % by weight:
(a) intra-granular portion comprising from about 30 % to about 70 % of Safinamide or its pharmaceutical salt thereof,
(1) from 0.1 % to about 10 % one or more Glidants;
(2) from 0.1 % to about 10 % one or more Lubricants;
(b) Extra-granular portion comprising;
(1) from about 35 % to about 45 % one or more Diluent;
(2) from about 1 % to about 8 % one or more Disintegrant;
(3) from 0.1 % to about 10 % one or more Lubricants; and
(4) optionally one or more pharmaceutical acceptable excipients;

An another aspect of the present invention relates to the process of preparation of an oral stable composition of Safinamide, wherein the said Safinamide or its pharmaceutical salt thereof, is added to the in intra-granular portion in about 30 % to about 70 % of the total weight of composition.

Yet an another aspect of the present invention relates to the process of preparation of an oral stable composition of Safinamide, wherein the composition is prepared by dry granulation and lubricant is added in intra-granular portion and extra-granular portion

DETAILED DESCRIPTION OF THE INVENTION:
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The term "Safinamide" as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, 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 term, "pharmaceutically acceptable excipients" as used herein refers to diluents, disintegrants, binders, lubricants, glidants, coating agents, solvents, co-solvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavouring agents, antioxidants, solubulizers, plasticizers or dispersing agents and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.

The term "binder" employed in a composition of the present invention is capable for holding the ingredients together and forming the granules with required mechanical strength. The binders of instant invention include, but are not limited to, but are not limited to, polyvinylpyrrolidone (povidone), polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC) and cellulose ethers.

The term "lubricant" employed in a composition of the present invention is capable of preventing the ingredients from clumping together and from sticking to the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a compression machine. Preferred lubricants of instant invention includes, but are not limited to fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid or hydrogenated vegetable oil; polyalkylene glycols such as polyethylene glycol (PEG) or sodium benzoate and the like.

The term " Glidant" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The Glidant of instant invention includes, but are not limited to inorganic phosphates such as dibasic calcium phosphate, Colloidal Silicon dioxide (fumed silica), hydrophilic silica, calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "diluent" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The diluents of instant invention includes, but are not limited to inorganic phosphates such as dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "disintegrant" employed in a composition of the present invention is capable of facilitating the breakup of a pharmaceutical composition prepared from the composition when placed in contact with an aqueous medium. The disintegrants of instant invention includes, but are not limited to alginic acid or sodium alginate; cellulose or cellulose derivatives such as carboxymethylcellulose sodium, microcrystalline cellulose, croscarmellose sodium, powdered cellulose or croscarmellose; iron exchange resin such as amberlite, gums such as agar, locust bean, karaya, pectin and tragacanth, crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, i.e., cross-linked l-ethenyl-2-pyrrolidinone); Pregelatinized starch, sodium starch glycolate or starch.

The term "composition" or "pharmaceutical composition" or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 11 % and about 40 % means 36 % to 44 %.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a tablet, capsule, syrups, suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising Safinamide and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

According to embodiment, the present invention relates to a stable pharmaceutical compositions comprising Safinamide or pharmaceutically acceptable salt thereof having particle size (D90) less than 100µm, and one or more pharmaceutical acceptable excipients.

In one embodiment, the present invention relates to a pharmaceutical tablet dosage form composition comprising an intra-granular portion and an extra-granular portion, the intra-granular portion comprising Safinamide or pharmaceutically acceptable salt thereof having D90 less than 100µm and one or more pharmaceutically acceptable excipients, and the extra-granular portion comprising one or more pharmaceutically acceptable excipients.

In certain exemplary embodiments, the pharmaceutical composition comprises, or is in the form of a pharmaceutically acceptable salt, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids.

In one embodiment, the present invention relates to a stable pharmaceutical compositions comprising Safinamide or pharmaceutically acceptable salt thereof, and one or more pharmaceutical acceptable excipients; wherein Safinamide or pharmaceutically acceptable salt thereof is crystalline form or amorphous form.

In another embodiment, the oral pharmaceutical composition is in the form of tablet or capsule or Syrups or Suspension comprising Safinamide or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In yet another embodiment, the present invention relates to oral pharmaceutical composition comprising
(a) Intra-granular composition comprising safinamide or its pharmaceutical salt thereof, Lubricant, Glidant, and optionally one or more pharmaceutically acceptable excipients;
(b) Extra-granular composition comprising Diluent, Disintegrant, Glidant, Lubricant and optionally one or more pharmaceutically acceptable excipients.

According to embodiment, the present invention relates to oral stable composition of Safinamide, wherein said composition comprises on a total of 100 % by weight:
(a) intra-granular portion comprising from about 30 % to about 70 % of Safinamide or its pharmaceutical salt thereof having particle size (D90) less than 100µm;
(1) from 0.1 % to about 10 % one or more Glidants;
(2) from 0.1 % to about 10 % one or more Lubricants;
(b) Extra-granular portion comprising;
(1) from about 35 % to about 45 % one or more Diluent;
(2) from about 1 % to about 8 % one or more Disintegrant;
(3) from 0.1 % to about 10 % one or more Glidants;
(4) from 0.1 % to about 10 % one or more Lubricants; and
(5) optionally one or more pharmaceutical acceptable excipients;

According to embodiment, the present invention relates to oral tablet composition of Safinamide, wherein said composition comprises on a total of 100 % by weight:
(a) intra-granular portion comprising from about 30 % to about 70 % of Safinamide or its pharmaceutical salt thereof having D90 less than 100µm;
(1) from 0.1 % to about 10 % of Colloidal Silicon Dioxide;
(2) from 0.1 % to about 10 % of Magnesium Stearate;
(b) Extra-granular portion comprising;
(1) from about 35 % to about 45 % of Microcrystalline cellulose;
(2) from about 1 % to about 8 % one or more Crospovidone;
(3) from 0.1 % to about 10 % one or more Colloidal Silicon Dioxide;
(4) from 0.1 % to about 10 % one or more Magnesium Stearate; and
(5) optionally one or more pharmaceutical acceptable excipients;

According to embodiment, Safinamide or pharmaceutically acceptable salt thereof has a particle size distribution with the D90 is less than 100 µm, more preferably less than 50 µm.

Particle size analysis can be carried out via different methods. Non-limiting examples of the methods include, but are not limited to, sieve technique, wet dispersion method with laser diffraction analysis, dry dispersion method with laser diffraction analysis, or a combination thereof. Particle size analysis is not limited to the methods described herein and can be carried out using any method known to one skilled in the art. In one embodiment, particle size analysis can be performed via a sieve technique. In another embodiment, particle size analysis can be performed using a wet dispersion method (e.g., water as the dispersing agent, and analysis by laser diffraction using, e.g., Sympatec equipment). In yet another embodiment, particle size analysis can be performed using a dry dispersion method and analyzed by laser diffraction using, e.g., Sympatec equipment.

The pharmaceutical compositions as mentioned above can be prepared by using any suitable method known in the art such as direct compression, dry or wet granulation (aqueous/non-aqueous or combination), extrusion spheronization, melt extrusion, melt granulation, coating over inert spheres, spray coating, spray drying and solvent evaporation.

According to embodiment of the present invention relates to the process of preparation of an oral stable composition of Safinamide, wherein the said Safinamide or its pharmaceutical salt thereof, is added to the in intra-granular portion in about 30 % to about 70 % of the total weight of composition.

According to embodiment of the present invention relates to the process of preparation of an oral stable composition of Safinamide, which is prepared by using dry granulation method.

According to embodiment of the present invention relates to the process of preparation of an oral stable composition of Safinamide, which is prepared by mixing Safinamide Mesylate and Colloidal silicon dioxide, Magnesium stearate is added to the above mixture and lubricate, the lubricated intra-granular mixture is compacted using roller compactor, compact granules were passed through sieve to obtain desired granule size, the granules obtained in the above step are mixed with Microcrystalline cellulose, Crospovidone, Colloidal silicon dioxide are mixed well further to this Magnesium stearate is added and lubricated again. The lubricated granules are then punched in to suitable size tablets and the tablets are coated with a suitable film coating.

According to embodiment, the present invention composition relates to the oral stable pharmaceutical composition comprising Safinamide or its pharmaceutical salt thereof having better stability, good purity profile, dissolution profile and better bioavailability.

The pharmaceutical composition is meant for once daily, twice daily or thrice daily administration.

According to embodiment, the present invention relates to the oral stable composition comprising Safinamide or its pharmaceutical salt thereof, having dissolution more than 90% within 45 minutes.

According to embodiment, the present invention relates to the oral stable composition comprising Safinamide or its pharmaceutical salt thereof, having dissolution more than 98% within 30 minutes.

According to embodiment, the present invention relates to the pharmaceutical composition comprising Safinamide or its pharmaceutical salt thereof for the treatment of Parkinson’s disease.

In yet another embodiment, pharmaceutical compositions disclosed herein are contemplated to be administered in combination with other the agent(s) such as carbidopa, levodopa or combinations thereof for treatment of Parkinson’s disease. The present invention relates to a pharmaceutical stable dosage form composition comprising immediate release tablet.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Examples:
S. No. Ingredients Quantity/ Tablet (mg)
Example-1
50 mg Example-2
100 mg
Intra granular Part
1. Safinamide Mesylate (D (90) < 50µm) 65.88 131.76
2. Colloidal silicon dioxide 1.25 2.50
3. Magnesium stearate 1.25 2.50
Extra granular Part
4. Microcrystalline cellulose 49.12 98.24
5. Crospovidone type A 5.00 10.00
6. Colloidal silicon dioxide 1.25 2.50
7. Magnesium stearate 1.25 2.50
Uncoated tablet Weight(mg) 125.00 250.00
Coating materials
8. Opadry FX orange 6.25 12.5
9. Purified Water QS QS
Coated tablet weight(mg) 131.25 262.50
MANUFACTURING PROCESS:
1. Sifting and Pre Mixing:
I. Safinamide Mesylate and Colloidal silicon dioxide were blender for 20 minutes.
II. Added Magnesium stearate to step I and lubricated for 5 minutes.
2. Dry granulation:
III. Blended materials of Step II was compacted using roller compactor.
IV. Compact granules are milled to obtain suitable size of granules
3. Blending and Lubrication:
V. Microcrystalline cellulose, Crospovidone, Colloidal silicon dioxide are added to step IV and blended for 20 minutes at slow speed in octagonal blender.
VI. To the above blend Magnesium stearate was added and lubricated for 5 minutes.
4. Compression:
VII. Compress the above blend by using suitable punches.
5. Film Coating:
VIII. Prepare the coating dispersion by dispersing Opadry FX Orange in purified water under stirring and coat the compressed tablets with coating dispersion.

Dissolution performance for the composition of Example 2:

Medium Time (Min) % drug release

0.1 N Hcl with 2 % NaCl with 100 rpm and paddle volume 900 mL 5 34
10 68
15 99
30 102
45 103

,CLAIMS:1. Oral pharmaceutical composition comprising:
(a) Intra granular portion comprising Safinamide or pharmaceutically acceptable salt thereof having particle size (D90) less than 100 µm, glidant, lubricant and optionally one or more excipients;
(b) Extra granular portion comprising glidant, diluent, disintegrant, lubricant and optionally one or more excipients.

2. The Oral pharmaceutical composition as claimed in claim 1, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, talc, starch, magnesium stearate and the like or a mixture thereof.

3. The Oral pharmaceutical composition as claimed in claim 1, wherein the lubricant is selected from the group consisting of sodium lauryl sulphate, metallic stearates such as magnesium stearate, talc, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glycerylpalmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearylfumarate, sodium benzoate, mineral oil, glycerine fumarate and mixtures thereof.

4. The Oral pharmaceutical composition as claimed in claim 1, wherein the disintegrant is selected from the group consisting of starches, croscarmellose sodium, carmellose, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, low-substituted hydroxypropylcellulose, crospovidone and mixtures thereof.

5. The Oral pharmaceutical composition as claimed in claim 1, wherein composition is in the form of tablet, capsule, sachet, granules, beads, pellets or powder.

6. Oral tablet composition of Safinamide, wherein said composition comprises on a total of 100 % by weight:
(a) intra-granular portion comprising from about 30 % to about 70 % of Safinamide or its pharmaceutical salt thereof having particle size (D90) less than 100µm;
(1) from 0.1 % to about 10 % of Colloidal Silicon Dioxide;
(2) from 0.1 % to about 10 % of Magnesium Stearate;
(3) optionally one or more pharmaceutical acceptable excipients;
(b) Extra granular portion comprising; (1) from about 35 % to about 45 % of Microcrystalline cellulose;
(2) from about 1 % to about 8 % one or more Crospovidone;
(3) from 0.1 % to about 10 % one or more Colloidal Silicon Dioxide;
(4) from 0.1 % to about 10 % one or more Magnesium Stearate; and
(5) optionally one or more pharmaceutical acceptable excipients;

7. The oral tablet composition as claimed in claim 6, wherein the dissolution is more than 98% within 30 minutes.

8. The oral tablet composition as claimed in claim 6, wherein manufacturing process of composition involves dry granulation method or wet granulation method or extrusion-spheronization method.

9. The dry granulation method for preparing the tablet as claimed in claim 6, wherein the method involves following steps:
(a) Sifting and Pre Mixing:
(b) Dry granulation:
(c) Blending and Lubrication:
(d) Compression:
(e) Film Coating:

10. The method of preparation as claimed in claim 9, wherein the composition is prepared by dry granulation and lubricant is added in intra-granular portion and extra-granular portion.