Claims: , Description:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

PROVISIONAL SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITIONS OF SAFINAMIDE AND PROCESS FOR PREPARATION THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification describes the invention.
FIELD OF THE INVENTION

The present invention relates to a solid pharmaceutical composition comprising safinamide or its pharmaceutically acceptable salts, esters, solvates, derivatives, amides, polymorphs, enantiomers, prodrugs, analogues, active metabolites or mixtures thereof as an active agent and pharmaceutically acceptable excipients and its preparation process and method of using the same.

BACKGROUND OF THE INVENTION

Parkinson's disease (PD) currently affects about 10 million people worldwide. PD is a highly specific degeneration of dopamine containing cells of the substantia nigra of the midbrain. Degeneration of the substantianigra in Parkinson's disease causes a dopamine deficiency in the striatum. Medications used in the treatment of Parkinson's disease include MAO-B inhibitors.

Safinamide mesylate is a highly selective and reversible MAO-B inhibitor. It is chemically known as (S)-2-[[4-[3-flourophenyl) methoxy] phenyl] methyl] aminopropanamide methane sulfonate and is represented by the following formula:

Safinamide mesylate is a white to off-white crystalline powder. It is freely soluble in water, methanol and dimethyl sulfoxide. It is sparingly soluble in ethanol and practically insoluble in ethyl acetate. As per Biopharmaceutics classification system, safinamide is a class II drug and has low solubility and high permeability.

Safinamide mesylate is commercially available under the brand name XADAGO® in 50mg and 100 mg film coated tablets and marketed by US Worldmeds LLC in the United States indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes. Inactive ingredients of Xadago® tablets are microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate.

Following patent publications pertain to various formulations of Safinamide:
U.S. Patent No 5,236,957 discloses compound (S)-2-[[4-[3-flourophenyl) methoxy] phenyl] methyl] aminopropanamide which is known under the international non propriety name as Safinamide also discloses methane sulfonic acid salt.

US Patent No. 8,283,380 discloses compositions and methods for treating Parkinson’s disease and specifically, methods for treating Parkinson’s disease using safinamide in combination with levodopa.

Chinese Patent No. CN106361711 discloses composition comprising Safinamide mesylate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate with specific percentages.

Chinese Patent Publication No. CN108553440 discloses composition comprising Safinamide, microcrystalline cellulose, crospovidone, hypromellose, silica and magnesium stearate with specific percentages.

Chinese Patent Publication No. CN104546747 discloses composition comprising safinamide mesylate, water soluble diluent, water soluble polymeric binder, disintegrant and lubricant, in which the active ingredient is contained at a percentage of about 20-50 wt%.

US Patent publication No. 2020/0085769 discloses a pharmaceutical composition comprising core comprising safinamide or a pharmaceutically acceptable salt thereof and a binder and a polymer composition which forms a coating on said core.

International patent publication No. 2019/086408 discloses a plurality of particles which including core comprising safinamide or a pharmaceutically acceptable salt thereof and taste masking polymer composition which forms a coating on said core.

Chinese Patent Publication No. CN107281147 discloses tablet composition comprising safinamide and cyclodextrin.

Published literature suggests that formulating Safinamide into suitable solid oral dosage forms like tablet is challenging from the formulation development perspective due to cohesive nature of Safinamide, dissolution issues, compressibility issues, manufacturing process selection, control of process and degradation of product.

Hence, there is an unmet need in the art to develop a simple, reproducible, and cost-effective manufacturing process for pharmaceutical composition of Safinamide or its pharmaceutically acceptable salts, derivatives which also offers desired pharmaceutical technical attributes such as dissolution, stability, bioequivalence and manufactured by simple, reproducible and commercially viable process at industrial scale.

The present inventors have developed solid pharmaceutical composition of safinamide or its pharmaceutically acceptable salts thereof and unexpectedly found that said composition have improved stability and dissolution profile coupled with simple manufacture process at industrial scale and it is bioequivalence to commercially available counterpart tablets (XADAGO®).

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a solid pharmaceutical composition comprising safinamide or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipient.

In another aspect, an invention provides a solid pharmaceutical composition comprising:
a) 40-55% w/w of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 30-50% w/w of microcrystalline cellulose;
c) 1.5-2.5% w/w of crospovidone;
d) 1-3% w/w of colloidal silicon dioxide;
e) 1-3% w/w of magnesium stearate;
Wherein at least 95% of safinamide dissolves within 30 minutes in a 900ml of 0.1N HCl at a temperature of 37±0.5°C using a USP apparatus-1 at a basket rotation of about 100 rpm.

In another aspect, an invention provides a solid pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 93-98% w/w of safinamide or its pharmaceutically acceptable salt thereof; 1.3-2.3% w/w of colloidal silicon dioxide; 1.3-2.3% w/w of magnesium stearate; and
b) an extragranular phase comprises 85-95% w/w of microcrystalline cellulose; 4-5% w/w of crospovidone; 1.8-2.5% w/w of colloidal silicon dioxide; 1.8-2.5% w/w of magnesium stearate,
Wherein the weight ratio of intragranular phase to extragranular phase colloidal silicon dioxide is from 1:0.5 to 0.5:1 and composition has a bulk density of ranging from about 0.30 mg/mL to about 0.60 g/mL and tapped density of ranging from about 0.30 mg/mL to about 0.80 g/mL.

In another aspect, an invention provides a solid pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 93-98% w/w of safinamide or its pharmaceutically acceptable salt thereof; 1.3-2.3% w/w of colloidal silicon dioxide; 1.3-2.3% w/w of magnesium stearate; and
b) an extragranular phase comprises 85-95% w/w of microcrystalline cellulose; 4-5% w/w of crospovidone; 1.8-2.5% w/w of colloidal silicon dioxide; 1.8-2.5% w/w of magnesium stearate,
Wherein the weight ratio of intragranular phase to extragranular phase is about 1:0.4 to 1:1 and composition contains not more than 0.3% of any unspecified degradation product and not more than 2.0% of total degradation product by weight relative to safinamide when measured by HPLC method after storage for 3 months at 40oC/75% relative humidity.

In another aspect, an invention provides a solid pharmaceutical composition comprising:
a) 60-140mg of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 40-120mg of microcrystalline cellulose;
c) 1.5-7mg of crospovidone;
d) 1-7mg of colloidal silicon dioxide;
e) 1-7mg of magnesium stearate;
Wherein at least 95% of safinamide dissolves within 30 minutes in a 900ml of 0.1N HCl at a temperature of 37±0.5°C using a USP apparatus-1 at a basket rotation of about 100 rpm and the said composition has a water content of less than 5.0% w/w as measured by Karl Fischer titration method.

In another aspect, an invention provides a solid pharmaceutical composition comprising:
a) 60-140mg of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 40-120mg of microcrystalline cellulose;
c) 1.5-7mg of crospovidone;
d) 1-7mg of colloidal silicon dioxide;
e) 1-7mg of magnesium stearate;
Wherein composition contains not more than 0.3% of any unspecified degradation product and not more than 2.0% of total degradation product by weight relative to safinamide when measured by HPLC method after storage for 3 months at 40oC/75% relative humidity.

In another aspect, there is provided a solid pharmaceutical composition comprising:
a) 60-140mg of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 40-120mg of microcrystalline cellulose;
c) 1.5-7mg of crospovidone;
d) 1-7mg of colloidal silicon dioxide;
e) 1-7mg of magnesium stearate;
Wherein said solid pharmaceutical composition is a tablet or capsule, if the solid pharmaceutical composition is a tablet, then it is coated with film coating material comprising hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide, talc, mica based pearlescent pigment, iron oxide red, the weight ratio of safinamide mesylate to film coating material is 1:0.01 to 1:0.1.

In another aspect, there is provided a solid pharmaceutical composition comprising:
a) 60-140mg of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 40-120mg of microcrystalline cellulose;
c) 1.5-7mg of crospovidone;
d) 1-7mg of colloidal silicon dioxide;
e) 1-7mg of magnesium stearate;
Wherein said composition is compressed to get a tablet and coated with a 3-5% w/w of a film coating material and the weight ratio of microcrystalline cellulose to film coating material is about 1:0.05 to 1:0.15.
In another aspect, an invention provides a solid pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 60-140mg of safinamide or its pharmaceutically acceptable salt thereof; 0.5-3.5mg of colloidal silicon dioxide; 0.5-3.5mg of magnesium stearate; and
b) an extragranular phase comprises 40-120mg of microcrystalline cellulose; 1.5-7mg of crospovidone; 0.5-3.5mg of colloidal silicon dioxide; 0.5-3.5mg of magnesium stearate,
Wherein the colloidal silicon dioxide and magnesium stearate are equally apportioned between the intragranular phase and the extragranular phase.

In another aspect, an invention provides the process for producing a pharmaceutical solid dosage form which comprises steps of:
a) mixing safinamide mesylate with excipients colloidal silicon dioxide and magnesium stearate;
b) compacting the mixture obtained in step “a” using roll compactor;
c) mill the compacts to form a granules;
d) mix the granules obtained in step “c” with excipients microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate; which is further compressed to get tablet dosage form; wherein, the obtained lubricated blend in step “d” has a bulk density of about 0.30 to 0.60 g/ml, tapped density of ranging from about 0.30 mg/mL to about 0.80 g/mL and tablet has a water content of less than 5% w/w as measured by Karl Fischer titration method and the tablet is coated.

Another aspect of an invention provides pharmaceutical composition of the present invention in the manufacture of a medicament for treating parkinson’s disease experiencing “off” episodes.

DETAILED DESCRIPTION OF THE INVENTION

The term “composition”, as in solid pharmaceutical composition, is intended to encompass a drug product comprising safinamide or its pharmaceutically acceptable salts thereof, and other inert ingredient(s). Pharmaceutical composition of the invention include, but is not limited to, granules, tablets, immediate release tablets, caplets, capsules (immediate or modified release) (hard and soft or liquid filled soft gelatin capsules) and the like. Preferably, the pharmaceutical composition refers to tablets and capsules. More preferably, the pharmaceutical composition refers to immediate release oral tablets, which may be uncoated or film coated.

The term “excipient”, means a pharmacologically inactive component such as a diluent, binder, disintegrant, glidant, lubricant, coloring agent or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use.

The term “Safinamide” is used in broad sense to include not only "Safinamide" per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof, and also its various crystalline and amorphous forms. According to the present invention safinamide mesylate is present in an amount from 40 to 55% by weight based on total weight of the composition, preferably, 45 to 55% by weight based on total weight of the composition, more preferably 48% to 53% by weight based on total weight of the composition, most preferably 50% to 52% by weight based on total weight of the composition.

The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions including mesylate, fumarate, maleate, phosphate, L-tartrate, citrate, acetate, oxalate, and sulfate.

The term “bulk density” as used herein according to the present invention is bulk density of a powder or granules and is the ratio of the mass of an untapped powder or granules sample and its volume including the contribution of the interparticulate void volume. The bulk density is expressed in grams per milliliter (g/ml) although the international unit is kilogram per cubic meter (1g/ml=1000kg/m3) because the measurements are made using cylinders. It may also be expressed in grams per cubic centimeter (g/cm3). The bulk density of a powder is determined by measuring the volume of a known mass of powder sample that may have been passed through a sieve, into a graduated cylinder (Method A). Bulk density and Tapped density can be determined using compendial bulk density apparatus, such as the method given in Test 616 “Bulk Density and Tapped Density,” United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Md., 2005 (“USP”). The bulk density of lubricated blend according to the present invention is from 0.30 g/ml to 0.60 g/ml, preferably from 0.35 g/ml to 0.55 g/ml, more preferably 0.40 g/ml to 0.50 g/ml and most preferably the bulk density of lubricated blend is 0.42 g/ml to 0.45 g/ml.

The term “Tapped density” as used herein according to the present invention is an increased bulk density attained after mechanically tapping a container containing the powder sample. Tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing a powder sample. The tapped density is expressed in grams per milliliter (g/ml). The tapped density of lubricated blend according to the present invention is from 0.30 g/ml to 0.80 g/ml, preferably from 0.4 g/ml to 0.7 g/ml, more preferably 0.45 g/ml to 0.60 g/ml and most preferably the tapped density of lubricated blend is 0.52 g/ml to 0.55 g/ml.

The term “Hausner ratio (HR)” is a number that is correlated to the flowability of a powder or granular material. The Hausner ratio is determined by measurement of the tapped and untapped (or aerated) bulk density. The hausner ratio of lubricated blend according to the present invention is 1.233.

The term “% by weight of the tablet” refers to the percentage by weight of each ingredient in the uncoated / coated tablet, including / excluding any exterior coatings.

The term “loss on drying” is a widely used test method to determine the water content of a sample, although occasionally it may refer to the loss of any volatile matter from the sample. The step of drying is obtained by heating the granules to a temperature above room temperature and maintaining the elevated temperature, until the LOD of the granules reaches a desired value. The granules are typically characterized by having a solvent loss on drying at 105°C of less than 5% w/w, preferably less than 4% w/w, 3.5% w/w, 3.4% w/w, 3.3% w/w, 3.2% w/w, 3.1% w/w, 3.0% w/w, 2.9% w/w, 2.8% w/w or 2.7% w/w, 2.6% w/w and 2.5% w/w.

Methods have been described, for example Karl Fischer (KF) or loss on drying (LOD), to determine liquid, e.g., water, content of solids, such as tablets, powders and granules. LOD measures all volatiles in a sample, while KF is typically used to measure all water. Thus, for a sample containing only water, LOD values are usually less than or equal to KF values for a given sample. Granules containing excipients are conveniently tested for water content by Karl Fischer titration using a Metrohm 684 KF Coulometer according to a published procedure (U.S. Pharmacopoeia, vol. 23, 1995, chapter <921>, U.S. Pharmacopeial Convention, Inc., Rockville, Md.) and manufacturer's Coulometer instructions. According to the present invention the water content in the tablet was measured using the Karl Fischer method. The tablet having a water content of less than 5% w/w, preferably tablet having a water content between 2 – 4% w/w and more preferably tablet having a water content less than 3.5% w/w, 3.4% w/w, 3.3% w/w, 3.2% w/w, 3.1% w/w, 3.0% w/w and 2.9% w/w.

The term “degradation product” are unwanted chemicals that can develop during the manufacturing, transportation, and storage of drug products and can affect the efficacy of pharmaceutical products.

The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.

The dissolution is performed as per conditions mentioned or provided in office of generic drugs dissolution database and as determined by the USP. The dissolution profile of tablets dosage form was measured in 900ml of 0.1N HCl using a USP I apparatus (Basket) at a temperature of 37±0.5°C and a rotation speed of 100 revolutions per minute.

The term "treating" or "treatment" refers to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

The term “about” is used herein to mean approximately, roughly, around, or in the regions of. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent.

The term “intra-granular / intragranular” (part/ phase/ portion) refers to the components of formulation of the present invention that are within granules.

The term “extra-granular / extragranular” (part/ phase/ portion) refers to those components of formulation of the present invention that are outside the granules.

The weight ratio of intragranular phase to extragranular phase is about 1:0.4 to 1:1, preferably the weight ratio of intra-granular phase to extra-granular phase is about 1:0.5 to 1:1, more preferably the weight ratio of intra-granular phase to extra-granular phase is about 1:0.7 to 1:0.99.

The weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:0.5 to 0.5:1, preferably the weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:0.8 to 0.8:2.2, more preferably the weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:1.

The term "particle(s)" as used herein refers to individual particles of safinamide or pharmaceutically acceptable salt thereof. The term “particle size” having a particle size distribution such that more than 90% of the particles are between 40µm to 100µm, preferably particles are between 40µm to 90µm, more preferably particles are between 40µm to 70µm and most preferably particles are less than 60µm, 55µm or 50µm. The particle size of safinamide was measured using a Malvern light scattering technique.

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 the acceptable limit.

The term "diluent" or "filler" as used herein is defined as an inert agent designed to increase the weight and/or the size of the pharmaceutical composition, for example in the case of a tablet. Examples of diluents according to present invention include, but not limited to microcrystalline cellulose, silicified MCC, microfine cellulose, anhydrous lactose, lactose monohydrate, mannitol and mixtures thereof. Diluent is present in an amount from 30 to 50%. Preferably, the amount of diluent is from 35% to 45% w/w, more preferably, the amount of diluent is from 38% to 43% w/w, most preferably the amount of diluent is 39% or 40% or 41% or 42%w/w, and preferred diluent according to the present invention is microcrystalline cellulose.

The weight ratio of microcrystalline cellulose to film coating material is about 1:0.05 to 1:0.15, preferably the weight ratio of microcrystalline cellulose to film coating material is about 1:0.07 to 1:0.1, more preferably the weight ratio of microcrystalline cellulose to film coating material is about 1:0.08 to 1:0.09.

The term "binder" as used herein is defined as an agent able to bind particles which cannot be bound only by a compression force.

Examples of binders include, but are not limited to acacia, dextrin, ethyl cellulose hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose sodium, povidone and / or mixtures thereof.

The term "disintegrant" as used herein is defined as an accelerating agent of the disintegration of the tablet and the dispersion of the active ingredient in water or gastrointestinal fluids. Examples of disintegrants according to present invention include, but not limited to croscarmellose sodium, carboxymethyl cellulose calcium, crospovidone, polacrilin potassium, sodium starch glycolate and/or combinations thereof. Disintegrant is present in an amount from 1 to 2.5% w/w, preferably, the amount of disintegrant is from 1.5% to 2.2% w/w, more preferably, the amount of disintegrant is from 1.7% to 2.1% w/w, most preferably, the amount of disintegrant is 1.8% or 1.9% or 2%, preferred disintegrant according to the present invention is crospovidone.

The total amount of disintegrant is present in extra granular phases. The weight ratio of microcrystalline cellulose to crospovidone is about 1:0.01 to 1:0.1, preferably the weight ratio of microcrystalline cellulose to crospovidone is about 1:0.02 to 1:0.06, more preferably the weight ratio of microcrystalline cellulose to crospovidone is 1:0.03 to 1: 0.05.

The term “glidant” as used herein is defined as an agent improving the fluidity of the powder and thus the filling of the compression chamber of the tablet press. The gliding agent may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. Examples of glidants according to present invention include, but not limited to calcium silicate, magnesium silicate, magnesium trisilicate, talc and colloidal silicon dioxide or mixtures thereof. Glidant is present in an amount from 1 to 3%, preferably, the amount of glidant is from 1.5% to 2.5% w/w, more preferably, the amount of glidant is from 1.7 to 2.2% w/w, most preferably, the amount of glidant is 1.8% or 1.9% or 2%, or 2.1% w/w, preferred glidant according to the present invention is colloidal silicon dioxide.

The glidant is present in both intragranular and extragranular phases. The weight ratio of intra-granular colloidal silicon dioxide to extra-granular colloidal silicon dioxide is about 1:0.5 to 0.5:1, preferably the weight ratio of intra-granular colloidal silicon dioxide to extra-granular colloidal silicon dioxide is about 1:0.7 to 0.5:0.6, more preferably the weight ratio of intra-granular colloidal silicon dioxide to extra-granular colloidal silicon dioxide is 1:1.

The weight ration of colloidal silicon dioxide to magnesium stearate is about 1:0.5 to 0.5:1, preferably the weight ratio of colloidal silicon dioxide to magnesium stearate is about 1:0.7 to 0.5:0.6, more preferably the weight ratio of colloidal silicon dioxide to magnesium stearate is 1:1.

The term "lubricant" as used herein is defined as an agent able to decrease adhesion of a powder to punches and friction between particles. Examples of lubricants according to present invention include, but not limited to stearic acid, Zinc stearate, sodium stearyl Fumarate, magnesium stearate. Lubricant is present in an amount from 1 to 3%, preferably, the amount of lubricant is from 1.5% to 2.5% w/w, more preferably, the amount of lubricant is from 1.7 to 2.2% w/w, most preferably, the amount of lubricant is 1.8% or 1.9% or 2%, or 2.1% w/w, preferred lubricant according to the present invention is magnesium stearate.

The lubricant is present in both intragranular and extragranular phases. The weight ratio of intra-granular magnesium stearate to extra-granular magnesium stearate is about 1:0.5 to 0.5:1, preferably the weight ratio of intra-granular magnesium stearate to extra-granular magnesium stearate is about 1:0.7 to 0.5:0.6, more preferably the weight ratio of intra-granular magnesium stearate to extra-granular magnesium stearate is 1:1.

The term "coated tablet" as used herein is defined as tablet provided with a coating layer is preferable to achieve long-term storage stability and prevent degradation due to light and the like. The coating layer comprise pharmaceutical additives, such as a coating agent, plasticizer, dispersant, defoaming agent, and the like, usually used for coating (for providing a coat to) orally administrable pharmaceutical preparations. Colorants are added to the coating agent for coating the tablet. Examples of colorants include but are not limited to iron oxides such as red iron oxide, yellow iron oxide, and black iron oxide; titanium oxide; beta-carotene; food blue No. 2; food blue No. 2 Aluminium Lake; and riboflavin and the like. Among these, red iron oxide is more preferable. Examples of film coating material includes Opadry which is Colorcon’s customized, one-step film coating system which combines polymer, plasticizer, opacifier and pigment, as required, in a dry concentrate. Examples of Opadry coating material according to present invention include, but not limited to Opadry orange, Opadry pink, Opadry red, Opadry blue, Opadry tan and the like, preferably Opadry coating material used according to the present invention is Opadry orange.

Opadry orange contains 75% of hydroxypropyl methyl cellulose, 12% of mica based pearlescent pigment, 10% polyethylene glycol, 2% of iron oxide red and 0.9% of titanium dioxide.

The weight ratio of safinamide mesylate to film coating material is 1:0.01 to 1:0.1, preferably 1:0.03 to 1:0.09, more preferably the weight ratio of film coating material to safinamide mesylate is about 1:0.05 to 1:0.09 or 1:0.06 or 1:0.07 or 1:0.08% w/w.

The weight ratio of film coating material to microcrystalline cellulose is 1:0.05 to 1:0.2, preferably 1:0.07 to 1:0.1 or 1:0.08 or 1:0.09 or 1:0.95% w/w.

In one embodiment, the invention relates to a solid pharmaceutical composition comprising safinamide or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipient.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 40-55% w/w of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 30-50% w/w of microcrystalline cellulose;
c) 1.5-2.5% w/w of crospovidone;
d) 1-3% w/w of colloidal silicon dioxide;
e) 1-3% w/w of magnesium stearate;
Wherein at least 95% of safinamide dissolves within 30 minutes in a 900ml of 0.1N HCl at a temperature of 37±0.5°C using a USP apparatus-1 at a basket rotation of about 100 rpm.

In another embodiment, an invention provides a solid pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 93-98% w/w of safinamide or its pharmaceutically acceptable salt thereof; 1.3-2.3% w/w of colloidal silicon dioxide; 1.3-2.3% w/w of magnesium stearate; and
b) an extragranular phase comprises 85-95% w/w of microcrystalline cellulose; 4-5% w/w of crospovidone; 1.8-2.5% w/w of colloidal silicon dioxide; 1.8-2.5% w/w of magnesium stearate,
Wherein the weight ratio of intragranular to extragranular colloidal silicon dioxide is from 1:0.5 to 0.5:1 and composition has a bulk density of ranging from about 0.30 mg/mL to about 0.60 mg/mL and tapped density of ranging from about 0.30 mg/mL to about 0.80 g/mL.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 60-140mg of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 40-120mg of microcrystalline cellulose;
c) 1.5-7mg of crospovidone;
d) 1-7mg of colloidal silicon dioxide;
e) 1-7mg of magnesium stearate;
Wherein at least 95% of safinamide dissolves within 30 minutes in a 900ml of 0.1N HCl at a temperature of 37±0.5°C using a USP apparatus-1 at a basket rotation of about 100 rpm and the said composition has a water content of less than 5.0% w/w as measured by Karl Fischer titration method.

In another embodiment, an invention provides a solid pharmaceutical composition comprising:
a) 60-140mg of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 40-120mg of microcrystalline cellulose;
c) 1.5-7mg of crospovidone;
d) 1-7mg of colloidal silicon dioxide;
e) 1-7mg of magnesium stearate;
Wherein the colloidal silicon dioxide magnesium stearate is equally apportioned between the intragranular phase and the extragranular phase and composition contains not more than 0.3% of any unspecified degradation product and not more than 2.0% of total degradation product by weight relative to safinamide when measured by HPLC method after storage for 3 months at 40oC/75% relative humidity.

In another embodiment, there is provided a solid pharmaceutical composition comprising:
a) 60-140mg of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 40-120mg of microcrystalline cellulose;
c) 1.5-7mg of crospovidone;
d) 1-7mg of colloidal silicon dioxide;
e) 1-7mg of magnesium stearate;
Wherein said solid pharmaceutical composition is a tablet or capsule, if the solid pharmaceutical composition is a tablet, then it is coated with film coating material, the weight ratio of film coating material to safinamide mesylate is 1:0.01 to 1:2.

In another embodiment, there is provided a solid pharmaceutical composition comprising:
a) 60-140mg of safinamide or its pharmaceutically acceptable salt thereof, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm;
b) 40-120mg of microcrystalline cellulose;
c) 1.5-7mg of crospovidone;
d) 1-7mg of colloidal silicon dioxide;
e) 1-7mg of magnesium stearate;
Wherein said composition is compressed to get a tablet and coated with a 3-5% w/w of a film coating material comprising hydroxypropyl methyl cellulose, polyethylene glycol, titanium dioxide, talc, mica based pearlescent pigment, iron oxide red and the weight ratio of microcrystalline cellulose to film coating material is about 1:0.05 to 1:0.15.

In another embodiment, an invention provides a solid pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 60-140mg of safinamide or its pharmaceutically acceptable salt thereof; 0.5-3.5mg of colloidal silicon dioxide; 0.5-3.5mg of magnesium stearate; and
b) an extragranular phase comprises 40-120mg of microcrystalline cellulose; 1.5-7mg of crospovidone; 0.5-3.5mg of colloidal silicon dioxide; 0.5-3.5mg of magnesium stearate,
Wherein the colloidal silicon dioxide and magnesium stearate are equally apportioned between the intragranular phase and the extragranular phase and at least 95% of safinamide dissolves within 30 minutes in a 900ml of 0.1N HCl at a temperature of 37±0.5°C using a USP apparatus-1 at a basket rotation of about 100 rpm.

In another embodiment, an invention provides a solid pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 93-98% w/w of safinamide or its pharmaceutically acceptable salt thereof; 1.3-2.3% w/w of colloidal silicon dioxide; 1.3-2.3% w/w of magnesium stearate; and
b) an extragranular phase comprises 85-95% w/w of microcrystalline cellulose; 4-5% w/w of crospovidone; 1.8-2.5% w/w of colloidal silicon dioxide; 1.8-2.5% w/w of magnesium stearate,
Wherein the total amount of API is present in intragranular phase, wherein safinamide or a salt thereof has a particle size distribution such that more than 90% of the particles are between 40µm to 90µm.

In another embodiment, an invention provides the process for producing a pharmaceutical solid dosage form which comprises steps of:
a) mixing safinamide mesylate with excipients selected from colloidal silicon dioxide and magnesium stearate;
b) compacting the mixture obtained in step “a” using roll compactor;
c) mill the compacts to form a granules;
d) mix the granules obtained in step “c” with excipients selected from microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate; which is further compressed to get tablet dosage form; wherein, the obtained lubricated blend in step “d” has a bulk density of 0.30 to 0.60 g/ml, tapped density of ranging from about 0.30 mg/mL to about 0.80 g/mL and tablet has a water content of less than 5% w/w as measured by Karl Fischer titration method and the tablet is optionally coated.

Surprisingly, it has been found that the pharmaceutical composition of the present invention has been found to have improved stability and dissolution profile coupled with simple manufacturing process at industrial scale and it is bioequivalence to commercially available counterpart tablets XADAGO®.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Examples: The following examples further illustrate the invention and do not limit the scope of the invention.

Example 1 - 3: Safinamide mesylate tablets were prepared by using quantitative formulas as given in Table 1:

Table – 1:

No Ingredients Quantity per unit (mg)
Intra-granular Example 1 Example 2 Example 3 (% w/w)
1 Safinamide Mesylate 65.90 131.80 65.90 131.80 65.90 131.80 40 – 55
2 Colloidal silicon dioxide 1.125 2.25 1.375 2.75 1.25 2.50 0.5 – 1.5
3 Magnesium stearate 1.125 2.25 1.375 2.75 1.25 2.50 0.5 – 1.5
Extra-granular
4 Microcrystalline cellulose 46.44 92.88 56.76 113.52 51.60 103.20 30 – 50
5 Crospovidone 2.25 4.50 2.75 5.50 2.50 5.00 1.5 – 2.5
6 Colloidal silicon dioxide 1.125 2.25 1.375 2.75 1.25 2.50 0.5 – 1.5
7 Magnesium stearate 1.125 2.25 1.375 2.75 1.25 2.50 0.5 – 1.5
Core tablet weight 119.09 238.18 130.91 261.82 125.00 250.00 -
8 Film coating 4.3875 8.775 5.3625 10.725 4.875 9.750 3.2 – 4.2
Coated tablet weight 123.47 246.95 136.27 272.54 128.75 257.50 -
Manufacturing process:
1. Sifting and Blending: Sift Safinamide mesylate, colloidal silicon dioxide & magnesium stearate through sieve and load the materials in low shear blender and blend for 15 minutes;
2. Compacting and Milling: Compact the material of Step 1 using roll compactor and mill the compacted granules;
3. Sifting and Blending: Co-sift crospovidone, microcrystalline cellulose and colloidal silicon dioxide with sifted and milled granules of Step 2 through sieve;
4. Sift extra granular magnesium stearate through sieve and add to the materials of Step 3 and blend for 20 minutes;
5. Compression: Compress the above blend with suitable punches;
6. Coating: Coat the tablets obtained in Step 5.

Safinamide granules prepared as per Example 1 to 3 has the following properties which is represented in Table 2:

Table – 2: Properties of obtained granules:
Elements Results
Bulk Density 0.434±0.05 g/ml
Tapped Density 0.535±0.05 g/ml
Hausner Ratio 1.233
Compressibility index 18.878
Water content 2.67 % w/w

Dissolution study: The dissolution profile of the tablets (100mg) prepared using quantitative composition as mentioned in example 1 to 3 is shown in Table 3 below:

Table 3: Dissolution profile of commercially marketed tablets (XADAGO®) and Examples 1 to 3 at particular time intervals:

Time point (Minutes) % Safinamide released (±5%)
XADAGO® Example 1 Example 2 Example 3
10 51 68 67 66
20 101 98 99 99
Two dissolution profiles (XADAGO® and Example 1 to 3) are considered similar based on f1 and f2 results of above table.

Stability studies:

Tablet dosage form prepared in Example 1 to 3 was subjected to Accelerated stability testing as per the ICH guidelines at temperature 40°±2°C and relative humidity of 75%±5% for 3 months. The tablet dosage form was placed in a high density polyethylene (HDPE) bottles exposed to above mentioned condition and then evaluated for degradation of product which is shown in Table 4:

Table 4: Results of stability tests by high performance liquid chromatography method:

Degradation of product Examples 1 – 3
0 Months 1 Month 2 Months 3 Months
Any unspecified degradation product NMT 0.20% NMT 0.20% NMT 0.20% NMT 0.20%
Total degradation product NMT 1.0% NMT 1.0% NMT 1.0% NMT 1.0%
NMT – Not more than

The present formulation clearly indicates excellent chemical stability upon storage at accerlerated stability conditions at 40°±2°C and 75%±5% relative humidity for three months showed no evidence of any degradation of product and no reduction in the content of active substance.