DESC:FORM 2

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

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITIONS OF BRIVARACETAM 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

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to a solid pharmaceutical composition comprising brivaracetam 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

Epilepsy is a group of neurological disorders characterized by epileptic seizures. Epileptic seizures are divided fundamentally into two groups: partial and generalised. Partial seizures are those in which the discharge begins locally, and often remains localized. Generalised seizures involve the whole brain, including the reticular system, thus producing abnormal electrical activity throughout both hemispheres and immediate loss of consciousness.

Brivaracetam is an n-propyl derivative of levetiracetam. Brivaracetam is chemically known as (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide and is represented by the following formula:

Brivaracetam is a white to off-white crystalline powder. It is very soluble in water, ethanol, methanol and glacial acetic acid. It is freely soluble in acetonitrile and acetone and soluble in toluene. It is very slightly soluble in n-hexane. As per Biopharmaceutics classification system, brivaracetam is a class I drug and has high solubility and high permeability.
Brivaracetam is commercially available under the brand name BRIVIACT® in 10, 25, 50, 75 and 100 mg film coated tablets, 10 mg/ml Oral Solution and 50 mg/5 ml (10 mg/ml) Intravenous Injection and marketed by UCB Pharma in the United States for the treatment of partial-onset seizures in patients 4 years of age and older. Inactive ingredients of Briviact® tablets are croscarmellose sodium, betadex (ß-cyclodextrin), lactose monohydrate, anhydrous lactose and magnesium stearate.

Following patent publications pertain to various formulations of Brivaracetam:

U.S. Patent Nos. 6,784,197; 6,911,461 & 8,492,416 describes 2-oxo-1-pyrrolidine derivatives and methods for their preparation. Further discloses compound (2S)-2-[(4R)-2-oxo-4-propyl-pyrrolidin-1-yl] butanamide which is known under the international non propriety name as Brivaracetam.

U.S. Patent No. 10,729,653 & U.S. Patent Publication No. 2011/02755693 discloses immediate release oral pharmaceutical formulation of brivaracetam. These patent publications highlight dissolution, sticking problem associated with Brivaracetam, which is a major challenge during the formulation development.

U.S. Patent. Nos. 8,435,564; 8,563,036; 8,460,712; and U.S. Patent Publication No. 2013/0039957 discloses prolonged release matrix formulation of Brivaracetam.

U.S. Patent Publication No. 2019/0125725 discloses a pharmaceutical composition comprising Brivaracetam or its pharmaceutically acceptable salts thereof, wherein the composition is free of cyclodextrin.

Indian Patent Publication No. 201741012882 discloses pharmaceutical composition of Brivaracetam prepared by using wet granulation technique.

Chinese Patent Publication No. CN106692083 discloses composition comprising Brivaracetam, mannitol, lactose with specific ratio.

Chinese Patent Publication No. CN109833300 discloses composition comprising Brivaracetam, calcium hydrogen phosphate, pregelatinized starch, corn starch and microcrystalline cellulose.

Chinese Patent Publication No. CN110638743 discloses pharmaceutical tablet composition containing Brivaracetam and oligosaccharides.

Chinese Patent Publication No. CN104800176 discloses orally-disintegrating tablet composition of Brivaracetam with high amount of disintegrating agent.

Chinese Patent Publication No. CN111407738 discloses Brivaracetam controlled-release preparation and it’s method of preparation.

Published literature suggests that formulating Brivaracetam into suitable solid oral dosage forms like tablet is challenging from the formulation development perspective due to sticky nature of brivaracetam, 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 Brivaracetam or its 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 brivaracetam 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 (BRIVIACT®).

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a solid oral pharmaceutical composition comprising brivaracetam 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 oral pharmaceutical composition comprising:
a) 15-25% w/w of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 60-80% w/w of diluent selected from anhydrous lactose, lactose monohydrate or a combination thereof;
c) 3-10% w/w of croscarmellose sodium;
d) 0.5-2% w/w of magnesium stearate;
Wherein at least 95% of brivaracetam dissolves within 30 minutes in a 900ml of pH 6.4 phosphate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 50 rpm.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 15-25% w/w of brivaracetam; 50-60% w/w of anhydrous lactose; 0.5-2.5% w/w of croscarmellose sodium; 0.1-1% w/w of magnesium stearate; and
b) an extragranular phase comprises 10-25% w/w of lactose monohydrate; 1-6% w/w of croscarmellose sodium and 0.1-1% w/w of magnesium stearate;
Wherein the weight ratio of intragranular to extragranular croscarmellose sodium is from 1:1.5 to 1:2.5 and composition has a bulk density of ranging from about 0.40 mg/mL to about 0.70 mg/mL and tapped density of ranging from about 0.60 mg/mL to about 0.90 mg/mL.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising:
a) 15-25% w/w of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 60-80% w/w of diluent selected from anhydrous lactose, lactose monohydrate or a combination thereof;
c) 3-10% w/w of croscarmellose sodium;
d) 0.5-2% w/w of magnesium stearate;
Wherein the composition has a water content of less than 8.0 % w/w as measured by Karl Fischer titration method.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 15-25% w/w of brivaracetam; 50-60% w/w of anhydrous lactose; 0.5-2.5% w/w of croscarmellose sodium; 0.1-1% w/w of magnesium stearate; and
b) an extragranular phase comprises 10-25% w/w of lactose monohydrate; 1-6% w/w of croscarmellose sodium and 0.1-1% w/w of magnesium stearate,
Wherein the weight ratio of intragranular phase to extragranular phase is about 1:0.1 to 1:0.4 and composition contains not more than 0.20% of any unspecified degradation product and not more than 0.80% of total degradation product by weight relative to brivaracetam when measured by HPLC method after storage for 3 months at 40oC/75% relative humidity.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising:
a) 50-100mg of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 180-420mg of diluent selected from anhydrous lactose, lactose monohydrate or a combination thereof;
c) 10-40mg of croscarmellose sodium;
d) 1.5-8mg of magnesium stearate;
Wherein the weight ratio of anhydrous lactose to croscarmellose sodium is from 1:0.05 to 1:0.5 and at least 95% of brivaracetam dissolves within 30 minutes in a 900ml of pH 6.4 phosphate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 50 rpm.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising:
a) 50-100mg of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 180-420mg of diluent selected from a combination of anhydrous lactose and lactose monohydrate, wherein the weight ratio of anhydrous lactose to lactose monohydrate is from 1:0.20 to 1:0.45;
c) 10-40mg of croscarmellose sodium;
d) 1.5-8mg of magnesium stearate;
Wherein composition contains not more than 0.20% of any unspecified degradation product and not more than 0.80% of total degradation product by weight relative to brivaracetam when measured by HPLC after storage for 3 months at 40oC/75% relative humidity.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 50-100mg of brivaracetam; 140-330mg of anhydrous lactose; 4-12mg of croscarmellose sodium; 1.2-4mg of magnesium stearate; and
b) an extragranular phase comprises 35-100mg of lactose monohydrate; 8-25mg of croscarmellose sodium and 1.2-4mg of magnesium stearate,
Wherein the weight ratio of intragranular to extragranular croscarmellose sodium is from 1:1.5 to 1:2.5 and the weight ratio of intragranular to extragranular phase is about 1:0.1 to 1:0.4.

In another aspect, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 50-100mg of brivaracetam; 140-330mg of anhydrous lactose; 4-12mg of croscarmellose sodium; 1.2-4mg of magnesium stearate; and
b) an extragranular phase comprises 35-100mg of lactose monohydrate; 8-25mg of croscarmellose sodium and 1.2-4mg of magnesium stearate,
Wherein the composition has a bulk density of ranging from about 0.40 mg/mL to about 0.70 mg/mL, tapped density of ranging from about 0.60 mg/mL to about 0.90 mg/mL and hausner ratio of less than 1.30 and tablet has a water content of less than 8% w/w as measured by Karl Fischer titration method.

In another aspect, an invention provides the process for producing a pharmaceutical solid oral dosage form which comprises steps of:
a) mixing brivaracetam with excipients selected from anhydrous lactose, croscarmellose sodium, 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 lactose monohydrate, croscarmellose sodium 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 0.55 to 0.65 g/ml, tapped density from about 0.70 to 0.80 g/ml and hausner ratio of less than 1.30 and tablet has a water content of less than 8% w/w as measured by Karl Fischer titration method and the tablet is optionally coated.

In another aspect, an invention provides the process for producing a pharmaceutical solid oral dosage form which comprises steps of:
a) mixing brivaracetam with excipients selected from anhydrous lactose, croscarmellose sodium, 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 lactose monohydrate, croscarmellose sodium and magnesium stearate; which is further filled to get capsule dosage form; wherein, the obtained lubricated blend in step “d” has a bulk density of 0.55 to 0.65 g/ml, tapped density from about 0.70 to 0.80 g/ml and hausner ratio of less than 1.30.

Another aspect of an invention provides pharmaceutical composition of the present invention in the manufacture of a medicament for treating partial-onset seizures in patients 4 years of age and older.

DETAILED DESCRIPTION OF THE INVENTION

The term “composition”, as in solid oral pharmaceutical composition, is intended to encompass a drug product comprising Brivaracetam 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 “Brivaracetam” is used in broad sense to include not only "Brivaracetam" 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 brivaracetam is present in an amount from 15 to 25% 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 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 0.40 g/ml to 0.70 g/ml, preferably from 0.45 g/ml to 0.70 g/ml, more preferably 0.50 g/ml to 0.70 g/ml and most preferably the bulk density of lubricated blend is 0.55 g/ml to 0.65 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 is from 0.60 g/ml to 0.90 g/ml, preferably from 0.65 g/ml to 0.85 g/ml, more preferably 0.70 g/ml to 0.80 g/ml and most preferably the tapped density of lubricated blend is 0.70 g/ml to 0.77 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 granules according to the present invention is having a hausner ratio of less than 1.30, preferably less than 1.28 and more preferably less than 1.26.
Hausner ratio is calculated by formula: V0 / Vf.
V0 – Bulk density of the powder
Vf – Tapped density of the powder.

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.

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 8% w/w, preferably tablet having a water content between 2 – 7% w/w and more preferably tablet having a water content between 4 – 7% 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 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 phosphate buffer, pH 6.4 using a USP II apparatus (Paddle) at a temperature of 37±0.5°C and a rotation speed of 50 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. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. 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 1:0.1 to 1:0.4, preferably the weight ratio of intra-granular phase to extra-granular phase is about 1:0.19 to 1:0.3, more preferably the weight ratio of intra-granular phase to extra-granular phase is about 1:0.24 to 1:0.28.

The weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:1.5 to 1:2.5, preferably the weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:1.9 to 1:2.2, more preferably the weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:2.

The brivaracetam having a particle size distribution such that more than 90% of the particles are between 350µm to 600µm. Preferably more than 90% of the particles are between 350µm to 550µm, more preferably more than 90% of the particles are between 350µm to 500µm and most preferably 370µm to 460µm. The particle size of brivaracetam was measured using a Malvern light scattering technique.

In one embodiment, the invention relates to a solid oral pharmaceutical composition comprising Brivaracetam 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 oral pharmaceutical composition comprising:
a) 15-25% w/w of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 60-80% w/w of diluent selected from anhydrous lactose, lactose monohydrate or a combination thereof;
c) 3-10% w/w of croscarmellose sodium;
d) 0.5-2% w/w of magnesium stearate;
Wherein at least 95% of brivaracetam dissolves within 30 minutes in a 900ml of pH 6.4 phosphate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 50 rpm.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 15-25% w/w of brivaracetam; 50-60% w/w of anhydrous lactose; 0.5-2.5% w/w of croscarmellose sodium; 0.1-1% w/w of magnesium stearate; and
b) an extragranular phase comprises 10-25% w/w of lactose monohydrate; 1-6% w/w of croscarmellose sodium and 0.1-1% w/w of magnesium stearate;
Wherein the weight ratio of intragranular to extragranular croscarmellose sodium is from 1:1.5 to 1:2.5 and the composition has a bulk density of ranging from about 0.40 mg/mL to about 0.70 mg/mL and tapped density of ranging from about 0.60 mg/mL to about 0.90 mg/mL.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising:
a) 15-25% w/w of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 60-80% w/w of diluent selected from anhydrous lactose, lactose monohydrate or a combination thereof;
c) 3-10% w/w of croscarmellose sodium;
d) 0.5-2% w/w of magnesium stearate;
Wherein the composition has a water content of less than 8% w/w as measured by Karl Fischer titration method.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 15-25% w/w of brivaracetam; 50-60% w/w of anhydrous lactose; 0.5-2.5% w/w of croscarmellose sodium; 0.1-1% w/w of magnesium stearate; and
b) an extragranular phase comprises 10-25% w/w of lactose monohydrate; 1-6% w/w of croscarmellose sodium and 0.1-1% w/w of magnesium stearate,
Wherein the weight ratio of intragranular phase to extragranular phase is about 1:0.1 to 1:0.4.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising:
a) 10-100mg of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 180-420mg of diluent selected from anhydrous lactose, lactose monohydrate or a combination thereof;
c) 10-40mg of croscarmellose sodium;
d) 1.5-8mg of magnesium stearate;
Wherein atleast 95% of brivaracetam dissolves within 30 minutes in a 900ml of pH 6.4 phosphate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 50 rpm.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising:
a) 50-100mg of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 180-420mg of diluent selected from a combination of anhydrous lactose and lactose monohydrate, wherein the weight ratio of anhydrous lactose to lactose monohydrate is from 1:0.20 to 1:0.45;
c) 10-40mg of croscarmellose sodium;
d) 1.5-8mg of magnesium stearate;
Wherein the weight ratio of anhydrous lactose to croscarmellose sodium is from 1:0.05 to 1:0.5 and composition contains not more than 0.20% of any unspecified degradation product and not more than 0.80% of total degradation product by weight relative to brivaracetam when measured by HPLC after storage for 3 months at 40oC/75% relative humidity.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 50-100mg of brivaracetam; 140-330mg of anhydrous lactose; 4-12mg of croscarmellose sodium; 1.2-4mg of magnesium stearate; and
b) an extragranular phase comprises 35-100mg of lactose monohydrate; 8-25mg of croscarmellose sodium and 1.2-4mg of magnesium stearate,
Wherein at least 95% of brivaracetam dissolves within 30 minutes in a 900ml of pH 6.4 phosphate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 50 rpm.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 50-100mg of brivaracetam; 140-330mg of anhydrous lactose; 4-12mg of croscarmellose sodium; 1.2-4mg of magnesium stearate; and
b) an extragranular phase comprises 35-100mg of lactose monohydrate; 8-25mg of croscarmellose sodium and 1.2-4mg of magnesium stearate,
Wherein the weight ratio of intragranular phase to extragranular phase is about 1:0.1 to 1:0.4.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 15-25% w/w of brivaracetam; 50-60% w/w of anhydrous lactose; 0.5-2.5% w/w of croscarmellose sodium; 0.1-1% w/w of magnesium stearate; and
b) an extragranular phase comprises 10-25% w/w of lactose monohydrate; 1-6% w/w of croscarmellose sodium and 0.1-1% w/w of magnesium stearate,
Wherein the total amount of API is present in intragranular phase with a particle size distribution such that more than 90% of the particles are between 350µm to 600µm.

In another embodiment, an invention provides a solid oral pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 50-100mg of brivaracetam; 140-330mg of anhydrous lactose; 4-12mg of croscarmellose sodium; 1.2-4mg of magnesium stearate; and
b) an extragranular phase comprises 35-100mg of lactose monohydrate; 8-25mg of croscarmellose sodium and 1.2-4mg of magnesium stearate,
Wherein the composition has a bulk density of ranging from about 0.40 mg/mL to about 0.70 mg/mL, tapped density of ranging from about 0.60 mg/mL to about 0.90 mg/mL and hausner ratio of less than 1.30 and tablet has a water content of less than 8% w/w as measured by Karl Fischer titration method.

In another embodiment, an invention provides the process for producing a pharmaceutical solid oral dosage form which comprises steps of:
a) mixing brivaracetam with excipients selected from anhydrous lactose, croscarmellose sodium, 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 lactose monohydrate, croscarmellose sodium 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 0.55 to 0.65 g/ml, tapped density from about 0.70 to 0.80 g/ml and hausner ratio of less than 1.30 and tablet has a water content of less than 8% w/w as measured by Karl Fischer titration method and the tablet is optionally coated.

In another embodiment, an invention provides the process for producing a pharmaceutical solid oral dosage form which comprises steps of:
a) mixing brivaracetam with excipients selected from anhydrous lactose, croscarmellose sodium, 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 lactose monohydrate, croscarmellose sodium and magnesium stearate; which is further filled to get capsule dosage form; wherein, the obtained lubricated blend in step “d” has a bulk density of 0.55 to 0.65 g/ml, tapped density from about 0.70 to 0.80 g/ml and hausner ratio of less than 1.30.

In another embodiment of the present invention there is provided a pharmaceutical composition comprising brivaracetam or its pharmaceutically acceptable salts, wherein the composition comprises at least one or more pharmaceutically acceptable excipient like diluent, binder, disintegrant, glidant, lubricant and coloring agent.

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 include, but are not limited to microcrystalline cellulose, sodium alginate, silicified MCC, microfine cellulose, anhydrous lactose, lactose monohydrate, mannitol and mixtures thereof. Diluent is present in an amount from 60 to 80%. Preferably, the amount of diluent is from 65% to 80% w/w, more preferably, the amount of diluent is from 70% to 75% w/w. Preferred diluent according to the present invention is combination of anhydrous lactose and lactose monohydrate.

The weight ratio of anhydrous lactose to lactose monohydrate is about 1:0.20 to 1:0.45. Preferably, the weight ratio of anhydrous lactose to lactose monohydrate is about 1:0.20 to 1:0.40 and more preferably, the weight ratio of anhydrous lactose to lactose monohydrate is about 1:0.25 to 1:0.35, most preferably the weight ratio of anhydrous lactose to lactose monohydrate is about 1:0.26 to 1:0.30.

The weight ratio of anhydrous lactose to croscarmellose sodium is about 1:0.05 to 1:0.5, preferably the weight ratio of anhydrous lactose to croscarmellose sodium is about 1:0.05 to 1:0.2, more preferably the weight ratio of anhydrous lactose to croscarmellose sodium is about 1:0.07 to 1:0.15.

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 include, but are not limited to croscarmellose sodium, carboxymethyl cellulose calcium, crospovidone, polacrilin potassium, sodium starch glycolate and/or combinations thereof. Disintegrants are present in an amount from 3 to 10% w/w, preferably, the amount of disintegrant is from 4% to 9% w/w, more preferably, the amount of disintegrant is from 4% to 7% w/w, most preferably, the amount of disintegrant is from 4% to 6% w/w. Preferred disintegrant according to the present invention is croscarmellose sodium.

The disintegrant is present in both intra and extra granular phases. The weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:1.5 to 1:2.5, preferably the weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:1.9 to 1:2.2, more preferably the weight ratio of intra-granular phase croscarmellose sodium to extra-granular phase croscarmellose sodium is about 1:2.

The term "lubricant" as used herein is defined as an agent able to decrease adhesion of a powder to punches and friction between particles. The lubricant 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 lubricants include, but are not limited to stearic acid, Zinc stearate, sodium stearyl Fumarate, magnesium stearate. Lubricant is present in an amount from 0.5% to 2% w/w, preferably, the amount of Lubricant is from 0.5% to 1.5% w/w, more preferably, the amount of Lubricant is from 1% to 1.5% w/w. Preferred lubricant according to the present invention is magnesium stearate.

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 BRIVIACT®.

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: Brivaracetam tablets were prepared by using quantitative formulas as given in Table 1:

Table – 1:

No Ingredients Quantity per unit (mg)
Example 1 Example 2 Example 3 (% w/w)
Intra-granular
1 Brivaracetam 50.00 100.00 50.00 100.00 50.00 100.00 15 – 25
2 Anhydrous lactose 141.75 283.50 173.25 346.50 157.50 315.00 50 – 60
3 Croscarmellose sodium 4.50 9.00 5.50 11.00 5.00 10.00 1 – 3
4 Magnesium stearate 1.35 2.70 1.65 3.30 1.50 3.00 0.25 - 1
Extra-granular
5 Lactose monohydrate 40.05 80.10 48.95 97.90 44.50 89.00 10 – 20
6 Croscarmellose sodium 9.00 18.00 11.00 22.00 10.00 20.00 2 - 5
7 Magnesium stearate 1.35 2.70 1.65 3.30 1.50 3.00 0.25 - 1
Core tablet weight 248.00 496.00 292.00 584.00 270.00 540.00 -
8 Film coating 9.47 18.95 11.58 23.16 10.53 21.06 2.5 – 4
Coated tablet weight 257.47 514.95 303.58 607.16 280.53 561.06 -

Manufacturing process:
1. Sifting and Blending: Sift Brivaracetam, anhydrous lactose and croscarmellose sodium 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 lactose monohydrate and croscarmellose sodium 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 15 minutes;
5. Compression: Compress the above blend with suitable punches;
6. Coating: Coat the tablets obtained in Step 5.

Brivaracetam 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 0.60±0.05 g/ml
Tapped Density 0.75±0.05 g/ml
Hausner Ratio 1.25
Water content 5 % 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 (BRIVIACT®) and Examples 1 to 3 at particular time intervals:
Time point (Minutes) % brivaracetam released (±5%)
BRIVIACT® Example 1 Example 2 Example 3
15 102 99 99 99
30 102 99 99 99
Two dissolution profiles (BRIVIACT® 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 0.80% NMT 0.80% NMT 0.80% NMT 0.80%
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.
,CLAIMS:WE CLAIM:

1. A solid pharmaceutical composition comprising:
a) 15-25% w/w of brivaracetam or its pharmaceutically acceptable salt thereof, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 60-80% w/w of diluent selected from anhydrous lactose, lactose monohydrate or a combination thereof;
c) 3-10% w/w of croscarmellose sodium;
d) 0.5-2% w/w of magnesium stearate;
Wherein at least 95% of brivaracetam dissolves within 30 minutes in a 900ml of pH 6.4 phosphate buffer at a temperature of 37±0.5°C using a USP apparatus-2 at a paddle rotation of about 50 rpm.

2. A solid pharmaceutical composition comprising an intragranular phase and an extragranular phase, wherein
a) intragranular phase comprises 15-25% w/w of brivaracetam; 50-60% w/w of anhydrous lactose; 0.5-2.5% w/w of croscarmellose sodium; 0.1-1% w/w of magnesium stearate; and
b) an extragranular phase comprises 10-25% w/w of lactose monohydrate; 1-6% w/w of croscarmellose sodium and 0.1-1% w/w of magnesium stearate,
Wherein the weight ratio of intragranular to extragranular croscarmellose sodium is from 1:1.5 to 1:2.5 and composition contains not more than 0.20% of any unspecified degradation product and not more than 0.80% of total degradation product by weight relative to brivaracetam when measured by HPLC method after storage for 3 months at 40oC/75% relative humidity.

3. A solid pharmaceutical composition comprising:
a) 50-100mg of brivaracetam, wherein brivaracetam has a particle size distribution such that more than 90% of the particles are between 350µm to 600µm;
b) 180-420mg of diluent selected from a combination of anhydrous lactose and lactose monohydrate, wherein the weight ratio of anhydrous lactose to lactose monohydrate is from 1:0.20 to 1:0.45;
c) 10-40mg of croscarmellose sodium;
d) 1.5-8mg of magnesium stearate;
Wherein composition contains not more than 0.20% of any unspecified degradation product and not more than 0.80% of total degradation product by weight relative to brivaracetam when measured by HPLC after storage for 3 months at 40oC/75% relative humidity.

4. The solid pharmaceutical composition according to claim 1 and claim 3, wherein the particles of brivaracetam has a particle size distribution such that more than 90% of the particles are between 370µm to 460µm.

5. The solid pharmaceutical composition according to claim 2, wherein the weight ratio of intragranular to extragranular croscarmellose sodium is 1:2.

6. The solid pharmaceutical composition according to claim 2, wherein the weight ratio of anhydrous lactose to croscarmellose sodium is from 1:0.07 to 1:0.15.

7. The solid pharmaceutical composition according to claim 3, wherein the weight ratio of anhydrous lactose to lactose monohydrate is from 1:0.27 to 1:0.30.

8. The solid pharmaceutical composition according to claim 1, wherein the solid pharmaceutical composition is a tablet dosage form.