HK1198287B - Pharmaceutical compositions comprising 2-oxo-1-pyrrolidine derivatives - Google Patents

Description

Pharmaceutical composition comprising 2-oxo-1-pyrrolidine derivative

The application is a divisional application of Chinese patent application with the application date of 27/1/2010, the application number of 201080005399.2 and the invention name of 'pharmaceutical composition containing 2-oxo-1-pyrrolidine derivative'.

Technical Field

The present invention relates to pharmaceutical compositions of 2-oxo-1-pyrrolidine derivatives, processes for their preparation and their therapeutic use.

Background

International patent application publication No. WO01/62726 discloses 2-oxo-1-pyrrolidine derivatives and a process for their preparation. This application discloses inter alia the compound (2S) -2- [ (4R) -2-oxo-4-propyl-pyrrolidin-1-yl ] butanamide, which is known by the international non-proprietary name brivaracetam.

International patent application publication No. WO2005/121082 describes a process for the preparation of 2-oxo-1-pyrrolidine derivatives and in particular (2S) -2- [ (4S) -4- (2, 2-difluorovinyl) -2-oxo-pyrrolidin-1-yl ] butanamide, which is known under the international non-proprietary name sertraline.

The 2-oxo-1-pyrrolidine derivatives are thus particularly useful in the pharmaceutical industry.

Brivaracetam is effective in treating epilepsy. Clinical trials evaluated the efficacy and safety of brivaracetam in adjuvant therapy of adult patients with refractory partial seizure epilepsy, with or without secondary generalized seizures (5, 20 and 50 mg/day). Brivaracetam is also effective in treating patients with post-herpetic neuralgia.

Sertralipine is effective in treating epilepsy. Two studies were conducted in epilepsy using sertraline to evaluate the efficacy and safety of sertraline in the adjuvant treatment of partial seizure epilepsy in highly refractory adult patients who currently receive up to three concurrently administered antiepileptic drugs.

One of the objects of the present invention is a pharmaceutical composition which can be administered orally to obtain immediate release of the pharmaceutically active substance.

Considering that brivaracetam and seletracetam are classified as BCS I, the in vitro Dissolution rate obtained in an in vitro Dissolution test (USP <711> apparatus n ° 2) of the composition according to the immediate release oral dosage form guidelines (Center for Drug Evaluation and Research, 11 months 1995) should meet the test criteria described in example a of the Dissolution document (Dissolution Documentation): 85% was dissolved in 900mL0.1N HCl within 15 minutes. If not, the test described in example B or C should be met.

As a general principle, the term immediate release is not to be understood herein as modified or controlled release and has at least 75% of the in vitro dissolution release within 45min in a suitable buffered aqueous medium (USP <711> apparatus n ° 2).

Disclosure of Invention

The present invention relates to an oral pharmaceutical composition comprising granules comprising an active ingredient and from 0.1% to 60% by weight of at least one cyclodextrin agent, relative to the total weight of the granules,

the active ingredient is a 2-oxo-1-pyrrolidine derivative of formula (I),

wherein

R¹Is C_1-10Alkyl or C_2-6An alkenyl group;

R²is C_1-10Alkyl or C_2-6An alkenyl group;

x is-CONR⁴R⁵、-COOH、-COOR³or-CN;

R³is C_1-10An alkyl group;

R⁴is hydrogen or C_1-10An alkyl group;

R⁵is hydrogen or C_1-10An alkyl group.

Detailed Description

The term "active ingredient" as used herein is defined as a substance or drug having a therapeutic effect. It may also be a mixture of substances with a therapeutic effect.

The amount of active ingredient present in the pharmaceutical compositions of the present invention may vary depending on the patient to whom the compositions are administered and the condition being treated.

The oral compositions of the present invention are in solid form.

The term "alkyl" as used herein is intended to mean a saturated monovalent hydrocarbon radical having straight (unbranched), branched, or cyclic moieties, or a combination thereof. Preferred alkyl groups contain 1-10 carbons. More preferred alkyl groups contain 1-4 carbons. Optionally, the alkyl group may be substituted with 1-5 substituents independently selected from halogen, hydroxy, alkoxy, ester, acyl, cyano, acyloxy, acid, amide, or amino. Preferred alkyl groups are methyl, ethyl, n-propyl, trifluoromethyl and trifluoroethyl.

The term "alkenyl" as used herein denotes an unsubstituted or substituted branched, unbranched or cyclic hydrocarbon group or a combination thereof having at least one double bond. Preferred alkenyl groups contain 2-6 carbons. More preferred alkenyl groups contain 2-4 carbons. The "alkenyl" moiety may be optionally substituted with 1-5 substituents independently selected from halogen, hydroxy, alkoxy, ester, acyl, cyano, acyloxy, carboxylic acid, amide, or amino.

The term "halogen" as used herein denotes a fluorine, chlorine, bromine or iodine atom.

The term "hydroxy" as used herein denotes a group of formula-OH.

The term "alkoxy" as used herein denotes a group of formula-OR^aWherein R is^aIs C as defined above_1-4Alkyl radical。

The term "acyl" as used herein denotes a group of formula R^bGroup of CO-, wherein R^bIs C as defined above_1-4An alkyl group.

The term "ester" as used herein denotes a compound of formula-COOR^cWherein R is^cIs C as defined above_1-4An alkyl group.

The term "cyano" as used herein denotes a group of formula-CN.

The term "acyloxy", as used herein, refers to a radical of formula-O-COR^dWherein R is^dIs C as defined above_1-4Alkyl or aryl.

The term "aryl" as used herein denotes an organic group derived from an aromatic hydrocarbon by removal of one hydrogen, for example phenyl.

The term "carboxylic acid" as used herein denotes a group of formula-COOH.

The term "amino" as used herein denotes the formula-NH₂、NHR^eOr NR^fR^eWherein R is^eAnd R^fIs an alkyl group as defined above in the specification.

The term "amide" as used herein means a compound of the formula-CO-NH₂、-CO-NHR^gor-CO-NR^gR^hWherein R is^gAnd R^hIs an alkyl group as defined above in the specification.

The term "sulfonate group" as used herein means a group of formula-O-SO₂-RⁱWherein R isⁱIs an alkyl or aryl group as defined above in the specification. Preferred sulfonate groups are mesylate, p-toluenesulfonate or triflate.

In one embodiment of the first aspect of the invention, R¹Is H, C_1-4Alkyl or C_2-4An alkenyl group. In another embodiment of the first aspect of the invention, R¹Is hydrogen, n-propyl or 2, 2-difluorovinyl.

In one embodiment of the first aspect of the invention, R²Is C_1-4An alkyl group. In another embodiment of the first aspect of the invention, R²Is ethyl.

In one embodiment of the first aspect of the invention, X is-CONR⁴R⁵-COOH or-COOR³Wherein R is³Is C_1-4An alkyl group. In another embodiment of the first aspect of the invention, X is-CONR⁴R⁵。

In one embodiment of the first aspect of the invention, X¹is-CONR⁴R⁵or-COOR³Wherein R is³Is C_1-4An alkyl group. In another embodiment of the first aspect of the invention, X¹Is COOR³Wherein R is³Is C_1-4An alkyl group.

In one embodiment of the first aspect of the invention, X²is-CONR⁴R⁵or-COOR³Wherein R is³Is C_1-4An alkyl group. In another embodiment of the first aspect of the invention, X²Is COOR³Wherein R is³Is C_1-4An alkyl group.

In a particular embodiment, R³Is methyl.

In one embodiment of the first aspect of the invention, R⁴Is hydrogen or C_1-4An alkyl group. In another embodiment of the first aspect of the invention, R⁴Is hydrogen.

In one embodiment of the first aspect of the invention, R⁵Is hydrogen or C_1-4An alkyl group. In another embodiment of the first aspect of the invention, R⁵Is hydrogen.

Preferably R¹Is n-propyl or 2, 2-difluorovinyl; r²Is ethyl(ii) a X is-CONH₂。

More preferably the active ingredient is selected from brivaracetam and seletracetam. Best results were obtained with brivaracetam.

The term "particle" includes granules, microgranules, pellets.

Typically, the pharmaceutical composition of the invention comprises particles comprising at least one active ingredient and at least one cyclodextrin agent. There are different types of pharmaceutical compositions comprising granules, such as tablets, powders, granules, capsules. The particles may also be sachets, for example sachets containing a dose of the active ingredient. Thus, the formulations are readily available and can be separated and administered with extreme ease.

The term "cyclodextrin agent" as used herein is defined as a pharmaceutically acceptable excipient which is a cyclic oligosaccharide formed from 6, 7 or 8 α -D-glucopyranose units, referred to as α, β or γ cyclodextrin, respectively. It was added as a compaction reagent. Typically, the cyclodextrin agent is selected from the group consisting of alpha cyclodextrin, beta cyclodextrin, hydroxypropyl beta cyclodextrin, methyl beta cyclodextrin, sulfobutyl beta cyclodextrin, gamma cyclodextrin, and hydroxypropyl gamma cyclodextrin. Generally, the cyclodextrin agent is beta cyclodextrin. Preferably the cyclodextrin agent is a beta cyclodextrin having the opposite crystalline structure to the amorphous cyclodextrin. In a preferred embodiment, the cyclodextrin agent is a beta cyclodextrin having a water content of 4-18%, and preferably 5-16% (w/w), and more preferably 10-16% (w/w). The best results were obtained with beta-cyclodextrin having a water content of 10-14% (w/w).

More preferably the cyclodextrin agent is under the trademark Cyclodextrin @OrOrβ Cyclodextrin sold under W7.

Typically, the pharmaceutical composition of the invention comprises 0.1-50% by weight of the cyclodextrin agent, relative to the total weight of the particles. In particular, the pharmaceutical composition comprises 0.1-45% by weight of the cyclodextrin agent. Preferably the pharmaceutical composition comprises 0.5-40% by weight of the cyclodextrin agent relative to the total weight of the particles; more preferably 1.0-30% by weight of a cyclodextrin agent; and most preferably 1.0-15.0% by weight of the cyclodextrin agent. The best results are obtained with 4.0-11.0% by weight of cyclodextrin agent.

The term "cyclodextrin agent" as used herein is defined as a pharmaceutically acceptable excipient which is a cyclic oligosaccharide formed from 6, 7 or 8 α -D-glucopyranose units, referred to as α, β or γ cyclodextrin, respectively. It was added as a compaction reagent. Typically, the cyclodextrin agent is selected from the group consisting of alpha cyclodextrin, beta cyclodextrin, hydroxypropyl beta cyclodextrin, methyl beta cyclodextrin, sulfobutyl beta cyclodextrin, gamma cyclodextrin, and hydroxypropyl gamma cyclodextrin. Generally, the cyclodextrin agent is beta cyclodextrin. Preferably the cyclodextrin agent is a beta cyclodextrin having the opposite crystalline structure to the amorphous cyclodextrin. In a preferred embodiment, the cyclodextrin agent is a beta cyclodextrin having a water content of 4-18%, and preferably 5-16% (w/w), and more preferably 10-16% (w/w). The best results were obtained with beta-cyclodextrin having a water content of 10-14% (w/w).

More preferably the cyclodextrin agent is under the trademark Cyclodextrin @OrOrβ Cyclodextrin sold under W7.

Typically, the pharmaceutical composition of the invention comprises 0.1-50% by weight of the cyclodextrin agent, relative to the total weight of the particles. In particular, the pharmaceutical composition comprises 0.1-45% by weight of the cyclodextrin agent. Preferably the pharmaceutical composition comprises 0.5-40% by weight of the cyclodextrin agent relative to the total weight of the particles; more preferably 1.0-30% by weight of a cyclodextrin agent; and most preferably 1.0-15.0% by weight of the cyclodextrin agent. The best results are obtained with 4.0-11.0% by weight of cyclodextrin agent.

The granules of the invention may also contain as excipients disintegrants, diluents, processing aids, lubricants, glidants and mixtures thereof.

The granules of the present invention may contain a disintegrant as an excipient.

The term "disintegrant" as used herein is defined as an accelerator for tablet disintegration and dispersion of the active ingredient in water or gastrointestinal fluids. Disintegrants may be present in the pharmaceutical composition as a single compound or as a mixture of compounds.

Examples of disintegrants are starch, pregelatinized starch, croscarmellose sodium (also known as cross-linked sodium carboxymethyl cellulose) and cross-linked polyvinylpyrrolidone. Preferred disintegrants of the invention are crospovidone, sodium starch glycolate and croscarmellose sodium. A more preferred disintegrant is croscarmellose sodium (cross-linked sodium carboxymethyl cellulose).

Preferably the granules of the present invention comprise 0.5-25% by weight of disintegrant, more preferably 1.0-15% by weight of disintegrant, most preferably 1.5-8% by weight of disintegrant, relative to the total weight of the granule. The best results are obtained with 2.0-5% by weight of disintegrant.

The granules of the invention may also comprise a diluent as an excipient.

The term "diluent" as used herein is defined as an agent that acts as a filler to give the desired volume or weight of the composition. The diluent may be present in the pharmaceutical composition as a single compound or as a mixture of compounds.

Examples of diluents are, but are not limited to, lactose, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, glucose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose. Preferred diluents are lactose and starch. More preferably, the diluent is lactose monohydrate, lactose anhydrous or a mixture thereof. The best results were obtained with lactose monohydrate.

Typically, the particles of the invention comprise 5 to 95% by weight of diluent relative to the total weight of the particle. Preferably the granules comprise 10-90% by weight of diluent relative to the total weight of the granules. More preferably, the particles comprise 30-90% by weight of diluent relative to the total weight of the particles.

The granules of the invention may also contain a lubricant as an excipient.

Examples of lubricants are, but not limited to, talc, magnesium stearate, calcium stearate, poloxamers, sodium lauryl sulfate, stearic acid, hydrogenated castor oil. A preferred lubricant of the present invention is magnesium stearate.

Generally, the granules of the invention comprise 0 to 5.50% by weight of lubricant, relative to the total weight of the granules. Preferably the particles comprise 0.001-2.50% by weight of lubricant relative to the total weight of the particles. More preferably, the particles comprise 0.01 to 2.0% by weight of lubricant relative to the total weight of the particles.

The present invention preferably comprises the particles as a dispersed phase into a solid continuous phase outside the particles. The solid external phase may be a matrix phase (e.g., in a tablet) or an excipient blend (e.g., in a capsule or sachet).

The granulate of the invention may also be comprised in an external phase which comprises other inactive ingredients, such as disintegrants, diluents, processing aids, lubricants, glidants and mixtures thereof as excipients. The particles are mixed with the external phase.

Examples of lubricants are, but not limited to, talc, magnesium stearate, calcium stearate, poloxamers, sodium lauryl sulfate, stearic acid, hydrogenated castor oil. A preferred lubricant of the present invention is magnesium stearate.

Typically, the pharmaceutical composition of the invention comprises 0-5.50% by weight of lubricant, relative to the total weight of the composition. Preferably, the pharmaceutical composition comprises 0.5-2.50% by weight of the lubricant. More preferably, the pharmaceutical composition comprises 0.5-2.0% by weight of lubricant, relative to the total weight of the particles.

The pharmaceutical composition of the present invention may further comprise a disintegrant as an excipient.

Examples of disintegrants are starch, pregelatinized starch, croscarmellose sodium (also known as cross-linked sodium carboxymethyl cellulose) and polyvinylpyrrolidone. Preferred disintegrants of the invention are crospovidone, sodium starch glycolate and croscarmellose sodium. A more preferred disintegrant is croscarmellose sodium (cross-linked sodium carboxymethyl cellulose).

Preferably, the pharmaceutical composition of the present invention comprises 0-7.0% by weight of disintegrant, more preferably 1.5-6.0% by weight of disintegrant, most preferably 3.0-5.0% by weight of disintegrant, relative to the total weight of the composition.

The pharmaceutical composition of the invention may also comprise an external phase. The outer phase may contain diluents, lubricants and/or glidants as excipients. Preferably the outer phase does not contain an active ingredient.

Examples of diluents are, but are not limited to, lactose, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, glucose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose. Preferred diluents are lactose and starch. More preferably, the diluent is lactose monohydrate, lactose anhydrous or a mixture thereof. The best results were obtained with anhydrous lactose.

Typically, the pharmaceutical composition of the present invention comprises 5 to 90% by weight of diluent, relative to the total weight of the composition. Preferably it comprises 10-90% by weight of diluent. More preferably, it comprises from 15 to 60% by weight of diluent relative to the total weight of the composition.

The external phase of the pharmaceutical composition of the invention may also comprise a lubricant.

Examples of lubricants are, but not limited to, talc, magnesium stearate, calcium stearate, poloxamers, sodium lauryl sulfate, stearic acid, hydrogenated castor oil. A preferred lubricant of the present invention is magnesium stearate.

Typically, the pharmaceutical composition of the invention comprises 0.25 to 5.50% by weight of lubricant, relative to the total weight of the composition. Preferably it contains 0.5 to 2.50% by weight of a lubricant. More preferably, it comprises 0.5 to 2.0% by weight of lubricant, relative to the total weight of the composition.

The external phase of the pharmaceutical composition may also comprise a glidant.

Examples of glidants are, but are not limited to, colloidal silicon dioxide and talc. A preferred glidant of the present invention is colloidal silicon dioxide.

Typically, the pharmaceutical composition of the invention comprises 0-5.00% by weight of glidant, relative to the total weight of the composition. Preferably the composition comprises 0-2.50% by weight of glidant. More preferably, the composition comprises 0-2.0% by weight of glidant, relative to the total weight of the composition.

In one embodiment of the invention, the pharmaceutical composition comprises particles comprising brivaracetam as active ingredient and 0.1-60% by weight of at least one cyclodextrin agent relative to the total weight of the particles. In particular, the pharmaceutical composition comprises particles comprising, relative to the total weight of the particles:

-brivaracetam as active ingredient;

-0.1-60% by weight of at least one cyclodextrin agent;

-0.5-25% by weight of a disintegrant; and

-5-95% by weight of a diluent.

In particular, the pharmaceutical composition comprises particles comprising, relative to the total weight of the particles:

-brivaracetam as active ingredient;

-0.1-50% by weight of at least one cyclodextrin agent;

-1.0-15% by weight of a disintegrant; and

-10-90% by weight of a diluent.

In particular, the pharmaceutical composition comprises particles comprising, relative to the total weight of the particles:

-brivaracetam as active ingredient;

-1.0-30% by weight of at least one cyclodextrin agent;

-1.5-8% by weight of a disintegrant; and

-30-90% by weight of a diluent.

In another embodiment of the present invention, the pharmaceutical composition comprises particles comprising brivaracetam as active ingredient; 0.1-60% by weight of at least one cyclodextrin agent relative to the total weight of the granule; croscarmellose sodium; and lactose monohydrate.

In particular, the pharmaceutical composition comprises particles comprising, relative to the total weight of the particles:

-brivaracetam as active ingredient;

-0.1-60% by weight of at least one cyclodextrin agent;

-0.5-25% by weight of croscarmellose sodium; and

5-95% by weight of lactose monohydrate.

In particular, the pharmaceutical composition comprises particles comprising, relative to the total weight of the particles:

-brivaracetam as active ingredient;

-0.1-50% by weight of at least one cyclodextrin agent;

-2.0-15% by weight of croscarmellose sodium; and

10-90% by weight of lactose monohydrate.

In particular, the pharmaceutical composition comprises particles comprising, relative to the total weight of the particles:

-brivaracetam as active ingredient;

-1.0-30% by weight of at least one cyclodextrin agent;

-2.0-8% by weight of croscarmellose sodium; and

-30-90% by weight of lactose monohydrate.

In a preferred embodiment of the invention, the composition comprises granules comprising 10.00mg brivaracetam, 2.70mg beta cyclodextrin, 19.40mg lactose monohydrate and 1.00mg croscarmellose sodium.

In a preferred embodiment of the invention, the composition comprises granules comprising 10.00mg brivaracetam, 2.70mg beta cyclodextrin, 19.30mg lactose anhydrous, 19.40mg lactose monohydrate and 2.00mg croscarmellose sodium.

In a preferred embodiment of the invention, the composition comprises granules comprising 25.00mg brivaracetam, 6.75mg beta cyclodextrin, 48.50mg lactose and 2.50mg croscarmellose sodium.

In a preferred embodiment of the invention, the composition comprises granules comprising 50.00mg brivaracetam, 13.50mg beta cyclodextrin, 97.00mg lactose and 5.00mg croscarmellose sodium.

In a preferred embodiment of the invention, the composition is a tablet comprising granules comprising 10.00mg brivaracetam, 2.70mg beta cyclodextrin, 19.40mg lactose monohydrate and 1.00mg croscarmellose sodium; and the additive comprises 1.00mg croscarmellose sodium, 19.30mg anhydrous lactose and 0.60mg magnesium stearate.

In a preferred embodiment of the invention, the composition is a tablet comprising granules comprising 10.00mg brivaracetam, 2.70mg beta cyclodextrin, 45.00mg lactose monohydrate, and 2.00mg croscarmellose sodium; and in the external phase the additive comprises 2.00mg croscarmellose sodium, 45.10mg anhydrous lactose and 1.20mg magnesium stearate.

In a preferred embodiment of the invention, the composition is a tablet comprising granules comprising 25.00mg brivaracetam, 6.75mg beta cyclodextrin, 48.50mg lactose monohydrate and 2.50mg croscarmellose sodium; and the additive comprises 2.50mg croscarmellose sodium, 48.25mg anhydrous lactose and 1.50mg magnesium stearate.

In a preferred embodiment of the invention, the composition is a tablet comprising granules and a pharmaceutically acceptable additive, the granules comprising 50.00mg brivaracetam, 13.50mg beta cyclodextrin, 97.00mg lactose monohydrate and 5.00mg croscarmellose sodium, and the additive comprising 5.00mg croscarmellose sodium, 96.50mg anhydrous lactose and 3.00mg magnesium stearate.

In a preferred embodiment of the invention, the composition is a tablet comprising granules and a pharmaceutically acceptable additive, the granules comprising 9.2mg brivaracetam, 2.50mg beta cyclodextrin, 41.5mg lactose monohydrate and 1.80mg croscarmellose sodium, and the additive comprising 1.80mg croscarmellose sodium, 41.6mg anhydrous lactose, 0.5mg colloidal silicon dioxide and 1.10mg magnesium stearate.

The pharmaceutical compositions of the present invention are typically prepared by dry granulation.

The preparation method of the particle of the invention comprises the following steps:

-a first step, in which the active ingredient and the cyclodextrin agent and the excipients are mixed;

-a second step in which the resulting blend is compressed and/or compacted; and

-a third step, in which the blend is milled to obtain granules.

The preparation method of the tablet comprises the following steps:

-a fourth step, in which the granules obtained and the excipient are mixed; and

-a fifth step, in which the final blend is compressed and/or compacted to obtain tablets.

The dry granulation process comprises a preliminary mixing step of the active ingredient with a cyclodextrin agent and a diluent and a disintegrant. The resulting blend is compressed using a roller compactor or tablet press and then milled to obtain granules. The resulting granules, diluent and disintegrant were mixed using a blender, then lubricant was added and mixed. The final blend was compressed to give tablets. Possibly, the cores may be coated with a coating suspension or solution.

The granules comprise an active ingredient, a diluent, a cyclodextrin agent and a disintegrant and possibly a lubricant. The granules were prepared as follows: the active ingredient, diluent, cyclodextrin agent and disintegrant were mixed using a planetary mixer. Then possibly adding a lubricant. The blend is mixed. This preblend is then compacted using a roller compactor and the resulting ribbon is sieved, if necessary, to obtain granules. If tablets are desired, the granules are then mixed with a disintegrant and possibly a lubricant. The final blend is then compressed in a tablet press to give tablet cores.

The preparation method of the tablet mainly comprises the following steps:

blending cyclodextrin agent, croscarmellose sodium, lactose monohydrate and active ingredient: the blending operation may be performed using a diffusion mixer, a convection mixer, and/or a pneumatic mixer.

-compacting: compaction may be performed by slugging or rolling using a tablet press and/or dry granulator.

-grinding: the ribbons obtained by dry granulation may be milled using a screen mill having a screen aperture of 0.22mm to 5mm and more preferably 0.33mm to 4 mm.

-adding anhydrous lactose, croscarmellose sodium and possibly magnesium stearate.

-blending: the blending operation may be performed using a diffusion mixer, a convection mixer, and/or a pneumatic mixer.

Possibly adding a lubricant (magnesium stearate).

-final blending.

-pressing: a tableting operation may be performed using a tableting machine.

-film coating: this may be done using a pan coater or a gas suspension based coater, and more preferably a perforated pan coater.

The cyclodextrin agent surprisingly acts as a binder for dry granulation. No inclusion complex is formed between the active ingredient and the cyclodextrin agent. The inventors have found a surprising binding effect of cyclodextrin agents in the pharmaceutical compositions used in the present invention. The cyclodextrin agent reduces the cohesion of the ribbons obtained after compaction and provides granules which are defined after compaction.

When the pharmaceutical composition of the invention is a tablet, the process may comprise an additional film coating step, wherein water, preferably purified water, is added to the film coating and the resulting suspension and/or solution is sprayed onto the tablet.

Another aspect of the invention relates to a pharmaceutical composition comprising brivaracetam for use in the treatment or prevention of a disease.

By the term "disease" we understand a disease selected from: epileptogenesis (epileptogenesis), seizures, convulsions, parkinson's disease, dopamine replacement therapy-induced dyskinesias, tardive dyskinesias induced by administration of neuroleptics, huntington's chorea and other neuropathies including bipolar disorder, mania, depression, anxiety, Attention Deficit Hyperactivity Disorder (ADHD), migraine, cluster headache, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, arrhythmia, myotonia, cocaine and other substance abuse (e.g. alcohol, benzodiazepines, opioids, cannabis, barbiturates, amphetamines, other stimulants), stroke, myoclonus, tremor, essential tremor, simple or complex tics, tourette's syndrome, restless leg syndrome and other dyskinesias, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, neuroleptic dyskinesia, Spasticity and degenerative diseases.

The term "treatment" as used herein includes both curative and prophylactic treatment.

"curative" refers to efficacy in treating the onset of the current symptoms of a disorder or symptom.

"prophylactic" refers to the prevention of the occurrence or recurrence of a disorder or condition.

The invention also relates to a method of treating a human patient by using said pharmaceutical composition.

The invention also relates to a pharmaceutical composition for use as a medicament for curing said diseases.

The invention also relates to the use of said pharmaceutical composition for the preparation of a medicament for the treatment of said diseases.

Preferably the disease is selected from epilepsy, parkinson's disease, dyskinesias, migraine, tremor, essential tremor, bipolar disorder, chronic pain, neuropathic pain or bronchial, asthma or allergic diseases. More preferably the disorder is epilepsy.

Dry granulation for preparing the pharmaceutical composition of the present invention is convenient, fast, cost effective and can prevent degradation of the active pharmaceutical ingredient form, e.g. by hydrolysis.

The amount of excipients is aimed to be as low as possible to keep the tablet weight low.

Another advantage of the pharmaceutical composition of the invention lies in the fact that: a proportional formulation is possible whereby the same blend can be compressed into tablet cores of increased size and mass depending on the required dosage.

The addition of a cyclodextrin agent to the pharmaceutical composition of the present invention results in good compaction characteristics, compression capacity and/or final in vitro dissolution. The cyclodextrin reagent exhibits high compaction effect and does not require high compaction pressures to produce tablets.

Brivaracetam is a very viscous compound (adhesive capacity). The main advantage of cyclodextrin agents is the reduction of binding during pressing and especially rolling.

Another advantage resides in improved drug dissolution.

The following examples are for illustrative purposes only and are not intended to, nor should they be construed as, limiting the invention in any way. It will be appreciated by those skilled in the art that conventional variations and modifications can be made to the following examples without departing from the spirit or scope of the invention.

Detailed Description

Example 1

Tablets were prepared by dry granulation using the following composition (table 1).

Table 1: composition 100mg

The granules comprise an active ingredient, a diluent, a cyclodextrin agent and part of a disintegrant and part of a lubricant. The outer phase comprises a second portion of disintegrant and a second portion of lubricant.

The granules were prepared as follows. Brivaracetam as active ingredient, lactose monohydrate, cyclodextrin agent and half amount of croscarmellose sodium are mixed using a suitable blender. The blend was mixed until a homogeneous blend was obtained. The blend is then compacted using a compactor or tablet press, and the resulting ribbon or slab core is sieved to obtain granules. The granules were then mixed with half the amount of croscarmellose sodium and magnesium stearate to obtain a homogeneous blend. The final blend is then compressed in a tablet press to give tablet cores.

Table 2: results of 100mg brivaracetam immediate-release tablet in% (Paddle method, 900mL aqueous buffer, 50rpm)

Tablet 2 shows immediate release brivaracetam meeting in vitro dissolution requirements.

The in vitro dissolution profile of the tablets in water was determined according to USP <711> (apparatus n.cndot.2, 50rpm, 900mL of aqueous medium, phosphate buffer pH 6). The dissolution was carried out at 37 ℃.

The cyclodextrin reagent is added into the pharmaceutical composition of the invention to obtain good compaction property and good compression capacity. The cyclodextrin reagent showed good compaction and did not require high compaction pressures to obtain tablets.

The cyclodextrin agent can reduce binding during rolling.

Example 2

Tablets were prepared by dry granulation using the following composition (table 3).

Table 3: composition 5mg

The granules were prepared as follows. Brivaracetam as active ingredient, lactose monohydrate, cyclodextrin agent and half amount of croscarmellose sodium are mixed using a suitable blender. The blend was mixed until a homogeneous blend was obtained. The blend is then compacted using a compactor or tablet press, and the resulting ribbon or slab core is sieved to obtain granules. The granules were then mixed with half the amount of croscarmellose sodium, anhydrous lactose and magnesium stearate to obtain a homogeneous blend. The final blend is then compressed in a tablet press to give tablet cores.

Table 4: results of 5mg brivaracetam immediate-release tablet in% (Paddle method, 500mL, phosphate buffer pH6.4, 50rpm)

Time (hours)	Dissolved% brivaracetam
		0	0
0:15:00	101
		0:30:00	101
0:45:00	102
		1:00:00	102

Tablet 4 showed immediate release brivaracetam meeting in vitro dissolution requirements.

Example 3

Tablets C, D, E, F and G (table 5) were prepared by dry granulation using the following core composition.

The procedure was the same as described in example 2. After preparation of the tablet cores, the cores were film coated using an aqueous suspension of Opadry TM white using appropriate equipment to obtain film coated tablets.

TABLE 5 core composition of tablets C, D, E, F and G

Granules

Amount (mg)	C	D	E	F	G
						Brivaracetam	5.00	10.00	10.00	25.00	50.00
β Cyclodextrin	1.35	2.70	2.70	6.75	13.50
						Lactose monohydrate	22.5	19.40	45.00	48.50	97.00
Croscarmellose sodium	1.00	1.00	2.00	2.50	5.00

Blend (exterior phase)

	C	D	E	F	G
						Croscarmellose sodium	1.00	1.00	2.00	2.50	5.00
Anhydrous lactose	22.55	19.30	45.10	48.25	96.50
						Magnesium stearate	0.6	0.60	1.20	1.50	3.00

Coating film

	C	D	E	F	G
						Opadry TM white	2.70	2.70	5.40	6.75	13.50

Tablet core quality (mg)

54mg

54mg

108mg

135mg

270mg

TM-white is used for masking main active ingredientA bitter film coating. The amount of film coating on the core tablet was about 5% (w/w). The film coating consists of a mixture of hydroxypropyl methylcellulose, polyethylene glycol 4000 (also known as PEG3350), sodium saccharin, and titanium dioxide.

Table 6: coating tablets C; results of 5mg brivaracetam immediate-release tablet in% (Paddle method, 900mL phosphate buffer pH6.4, 50rpm, using 6 tablets)

Time (min)	0	5	30	45
					Average (%)	0	88.1	100.6	101.6

Table 7: coating a tablet D; results of 10mg brivaracetam immediate-release tablet in% (Paddle method, 900mL phosphate buffer pH6.4, 50rpm, using 6 tablets)

Time (min)	0	5	30	45
					Average (%)	0	78.0	96.9	97.0

Table 8: coating a tablet E; results of 10mg brivaracetam immediate-release tablet in% (Paddle method, 900mL phosphate buffer pH6.4, 50rpm, using 6 tablets)

Time (min)	0	10	30	45
					Average (%)	0	100.1	99.8	101.0

Table 9: coating tablets F; results of 25mg brivaracetam immediate-release tablet in% (Paddle method, 900mL phosphate buffer pH6.4, 50rpm, using 6 tablets)

Time (min)	0	10	30	45
					Average (%)	0	86.6	99.3	100.4

Table 10: tablet G: results of 50mg brivaracetam immediate-release tablet in% (Paddle method, 900mL phosphate buffer pH6.4, 50rpm, using 6 tablets)

Time (min)	0	15	30	45
					Average (%)	0	100.0	100.7	99.8

Tablets C, D, E, F and G showed that immediate release brivaracetam meets the in vitro dissolution requirements.

Example 4

Tablets H and I (table 13) were prepared by direct compression using the following core composition.

TABLE 13 tablets H and I

Amount (mg)	H	I
			Brivaracetam	10.00	25.00
β RingDextrin	2.70	6.75
			Lactose monohydrate	45.00	48.50
Croscarmellose sodium	2.00	2.50
			Croscarmellose sodium	2.00	2.50
Anhydrous lactose	45.10	48.25
			Magnesium stearate	1.20	1.50

The preparation method of the tablet mainly comprises the following steps:

-blending the cyclodextrin agent, all excipients and brivaracetam: the blending operation is carried out using a suitable mixer to obtain a homogeneous blend.

-compacting: compaction may be performed using a dry granulator or a tablet press.

-grinding: the resulting ribbon is then ground.

-pressing: a tableting operation may be performed using a tableting machine.

The tablets showed immediate release brivaracetam meeting in vitro dissolution requirements.

Table 14: tablet H: results of 10mg brivaracetam immediate-release tablets in% (paddle method, 900mL phosphate buffer ph6.4, 50rpm, using 6 tablets).

Time (min)	0	15	30	45
					Average (%)	0	101	101	101

Table 15: tablet I: results of 25mg brivaracetam immediate-release tablet in% (Paddle method, 900mL phosphate buffer pH6.4, 50rpm, using 6 tablets)

Time (min)	0	15	30	45
					Average (%)	0	100.0	100.0	100.0

Example 5

Tablets were prepared by dry granulation using the following composition (table 16).

TABLE 16

The granules comprise an active ingredient, an excipient, and a cyclodextrin agent.

The granules were prepared as follows. The active ingredient, excipients and cyclodextrin agent are mixed using a planetary mixer. The blend is mixed. This preblend was then compacted using a roller compactor and the resulting ribbon was sieved to obtain granules.

The granules are placed into capsules.

The capsule shows that the quick release brivaracetam meets the in vitro dissolution requirement.

Example 6

Tablets were prepared by dry granulation using the following composition (table 17).

TABLE 17

Particles were prepared as described in example 5.

The capsule shows that the quick release sertraline meets the in vitro dissolution requirement.

Example 7

Tablets were prepared by dry granulation using the following composition (table 18).

Table 18: composition 50mg

The test result shows that the quick-release tablet meets the in vitro dissolution requirement.

Example 8

The granules comprise an active ingredient, a diluent, a cyclodextrin agent, and a portion of a disintegrant. The outer phase comprises a second portion of disintegrant and lubricant and glidant.

The granules were prepared as follows. Brivaracetam as an active ingredient, a cyclodextrin reagent and half the amount of croscarmellose sodium were mixed using a planetary mixer. The blend is mixed. The blend was then compacted using a roller compactor and the resulting ribbon was sieved to obtain granules. The granules were then mixed with half the amount of croscarmellose sodium and magnesium stearate and colloidal silicon dioxide. The final blend is then compressed in a tablet press to give tablet cores.

The preparation method of the tablet mainly comprises the following steps:

blending cyclodextrin reagent, croscarmellose sodium, lactose monohydrate and brivaracetam: the blending operation may be performed using a diffusion mixer, a convection mixer, and/or a pneumatic mixer to perform the blending operation to obtain a homogeneous blend.

-compacting: compaction may be performed by slugging or rolling using a tablet press and/or dry granulator.

-grinding: the ribbons obtained by dry granulation may be ground using a screen mill having a screen size of 0.33mm to 4 mm.

-adding anhydrous lactose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

-blending: the blending operation may be performed using a diffusion mixer, a convection mixer, and/or a pneumatic mixer.

-pressing: a tableting operation may be performed using a tableting machine.

-film coating: this may be done using a pan coater or a gas suspension based coater and more preferably a perforated coater.

The disintegration time of the above tablets was 1 min 53 s when determined according to eur.ph.2.9.1.. So, and the test results showed that the immediate release tablets met the in vitro dissolution requirements.

Example 9:

all experiments were performed according to the guidelines of the local ethical committee on animal experiments.

Epileptiform response in hippocampal slices: levetiracetam reduced the epileptiform response induced by high-K +/low-Ca 2+ concentrations in the perfusate and by bicuculline in rat hippocampal slices. The effect of brivaracetam on high-K +/low-Ca 2+ concentration or bicuculline-induced epileptiform responses was examined in hippocampal cross-sections prepared from Sprague-Dawley rats according to standard methods reported previously. Epileptiform responses were induced by changing the normal perfusion (K +3 mM; Ca2+2.4mM) of artificial cerebrospinal fluid (ACSF) to high-K +/low-Ca 2+ fluid (HKLCF) (K +7.5 mM; Ca2+0.5mM) or to ACSF containing 5M meiododicentrine (BMI).

Extracellular Field Potentials (FPs) in the area of section CA3 were recorded using 2M NaCl-perfused glass microelectrodes. The resulting FPs were recorded at 10-min intervals as a response to the cymba stimulation using constant current rectangular pulses that resulted in a single burst of peak Potentials (PS) of 50-75% of the maximum amplitude when sliced in ACSF. In the HKLCF model, 2min of spontaneous activity was also recorded in the middle of each 10-min interval between the recordings of the evoked responses.

Brivaracetam or levetiracetam was added to the bath fluid of the slices 20min before changing from ACSF to HKLCF or ACSF containing 5M BMI, which was kept in the perfusate throughout the experiment.

Audiogenic seizures in mice: genetically sound-sensitive male mice (16-28 g; n-10/group) with field-continuous, clonic and tonic convulsive responses to auditory stimuli were used. The application of 30s auditory stimuli (90dB,10-20kHz) induced an audiogenic seizure. Mice were pretreated with saline, brivaracetam (i.p.,30min), or levetiracetam (i.p.,60min), and the proportion of anti-clonic convulsions mice was used as an endpoint for evaluation of anticonvulsant activity.

Chemically induced seizures in mice: penetranitramine 83mg kg^-1s.c. for the evaluation of the anticonvulsant properties of brivaracetam. The dose was selected as the convulsive dose that induced clonic convulsions of all limbs in 97% of the animals based on the dose-response curve in saline treated animals. After administration of a chemoconvulsantImmediately, the mice were each placed in a small plastic cage (25138cm), and the presence of clonic convulsions in all limbs was observed for 60 min. The incidence of clonic convulsions (hindlimb elongation) and mortality were also recorded during this interval. The proportion of mice with anti-clonic convulsions was calculated and used as the end point for the anticonvulsant activity.

Results

Epileptiform response in hippocampal slices: changing the perfusion of rat hippocampal slices from normal ACSF to HKLCF gradually produced epileptiform FPs in the CA3 region as a response to constant current cymbal stimulation. In the control group, which exposed the slices to HKLCF alone, PS1 increased in amplitude, reaching a plateau (4.250.77mV) within 20min, close to 2 times higher than the value recorded at ACSF perfusion (2.180.15 mV; mean. d., n ═ 10 slices). Furthermore, the burst of repetitive PSs (i.e., PS2, PS3, etc.) resulting from constant current single stimulation increased significantly in value within the first 30min of HKLCF perfusion, increased from a single PS1 to an average of 7.62.3 PS/evoked bursts, and continued to increase moderately to the end of the recording, reaching an average of 8.81.6 PS/evoked bursts after 80min of HKLCF perfusion. Brivaracetam and levetiracetam reduce these epileptiform responses. At 15min HKLCF perfusion, spontaneous field bursts occurred in 4 of the 10 control slices exposed to HKLCF alone, while all control slices exhibited regular field bursts from 25min in HKLCF to the end of the recording. Brivaracetam (3.2M), but not levetiracetam (32M), reduced the proportion of this spontaneous burst.

In vivo studies: in rats with complete tonsillar inflammation, brivaracetam was from 21.2mg kg^-1The start of the dose induced significant inhibition of the severity of moto-epilepsy, whereas levetiracetam was from 170mgkg^-1The dose started to induce similar effects. Brivaracetam was also at the highest dose tested (212.3mg kg)^-1) Significantly reduces the post-shelf life, while levetiracetam is at most 1700mgkg^-1The following are inactive to this parameter.

Clonic convulsions in audiogenic seizure-prone mice were prevented with brivaracetam and levetiracetam. Administration of brivaracetam 30min i.p. prior to induction of seizures in mice also prevented clonic convulsions induced by pentaerythrine and maximal electroshock-induced tonic hindlimb elongation in mice, although the ED50 value was higher.

From 2.1mg kg of brivaracetam^-1Dose initiation significantly inhibited spontaneous SWDs in GAERS rats, with the highest dose tested (67.9mg kg)^-1) Showing complete inhibition.

Pretreatment with brivaracetam during corneal inflammation in mice resulted in a significant decrease in the incidence of generalized motor seizures, and a similar decrease in incidence was observed with levetiracetam at higher doses. Continued corneal stimulation after termination of treatment showed a continued decrease in the incidence of generalized motor seizures in the group previously treated with the highest dose of brivaracetam.

Claims (27)

1. An oral pharmaceutical composition comprising granules, wherein the pharmaceutical composition is an immediate release film coated tablet, said granules comprising brivaracetam as active ingredient and at least one cyclodextrin agent as excipient in an amount of 0.1-60% by weight of the total weight of the granules.

2. The oral pharmaceutical composition of claim 1, wherein the cyclodextrin agent is selected from the group consisting of alpha cyclodextrin, beta cyclodextrin, hydroxypropyl beta cyclodextrin, methyl beta cyclodextrin, sulfobutyl beta cyclodextrin, gamma cyclodextrin, and hydroxypropyl gamma cyclodextrin.

3. The oral pharmaceutical composition of claim 2, wherein the cyclodextrin agent is beta cyclodextrin.

4. An oral pharmaceutical composition according to any one of claims 1 to 3 wherein the granules comprise from 1.0 to 30% by weight of the cyclodextrin agent, based on the total weight of the granules.

5. The oral pharmaceutical composition of any one of claims 1-3, wherein the granules comprise a disintegrant as an excipient.

6. The oral pharmaceutical composition of claim 5, wherein the disintegrant is croscarmellose sodium.

7. An oral pharmaceutical composition according to claim 5, wherein the granules comprise 0.5 to 25% by weight of disintegrant based on the total weight of the granules.

8. An oral pharmaceutical composition according to claim 6, wherein the granules comprise 0.5 to 25% by weight of disintegrant based on the total weight of the granules.

9. The oral pharmaceutical composition of claim 1, wherein the granules comprise a diluent as an excipient.

10. The oral pharmaceutical composition of claim 9, wherein the diluent is lactose monohydrate.

11. An oral pharmaceutical composition according to claim 9 or 10, wherein the granules comprise from 5 to 95% by weight of diluent based on the total weight of the granules.

12. An oral pharmaceutical composition according to claim 1, comprising granules comprising, relative to the total weight of the granules:

-brivaracetam as active ingredient;

-0.1-60% by weight of at least one cyclodextrin agent;

-0.5-25% by weight of a disintegrant; and

-5-95% by weight of a diluent.

13. An oral pharmaceutical composition according to claim 1, comprising granules comprising, relative to the total weight of the granules:

-brivaracetam as active ingredient;

-0.1-60% by weight of at least one cyclodextrin agent;

-0.5-25% by weight of croscarmellose sodium; and

5-95% by weight of lactose monohydrate.

14. The oral pharmaceutical composition of claim 1, wherein the granules comprise 10.00mg brivaracetam, 2.70mg beta cyclodextrin, 19.40mg lactose monohydrate, and 1.00mg croscarmellose sodium.

15. The oral pharmaceutical composition of claim 1, wherein the granules comprise 10.00mg brivaracetam, 2.70mg beta cyclodextrin, 19.30mg lactose anhydrous, 19.40mg lactose monohydrate, and 2.00mg croscarmellose sodium.

16. The oral pharmaceutical composition of claim 1, wherein the granules comprise 25.00mg brivaracetam, 6.75mg beta cyclodextrin, 48.50mg lactose, and 2.50mg croscarmellose sodium.

17. The oral pharmaceutical composition of claim 1, wherein the granules comprise 50.00mg brivaracetam, 13.50mg beta cyclodextrin, 97.00mg lactose, and 5.00mg croscarmellose sodium.

18. The oral pharmaceutical composition of claim 1, wherein the composition comprises granules comprising 10.00mg brivaracetam, 2.70mg beta cyclodextrin, 19.40mg lactose monohydrate, and 1.00mg croscarmellose sodium; and the additive comprises 1.00mg croscarmellose sodium, 19.30mg anhydrous lactose and 0.60mg magnesium stearate.

19. The oral pharmaceutical composition of claim 1, wherein the composition comprises granules comprising 10.00mg brivaracetam, 2.70mg beta cyclodextrin, 45.00mg lactose monohydrate, and 2.00mg croscarmellose sodium; and in the external phase the additive comprises 2.00mg croscarmellose sodium, 45.10mg anhydrous lactose and 1.20mg magnesium stearate.

20. The oral pharmaceutical composition of claim 1, wherein the composition comprises granules comprising 25.00mg brivaracetam, 6.75mg beta cyclodextrin, 48.50mg lactose monohydrate, and 2.50mg croscarmellose sodium; and the additive comprises 2.50mg croscarmellose sodium, 48.25mg anhydrous lactose and 1.50mg magnesium stearate.

21. The oral pharmaceutical composition of claim 1, wherein the composition comprises granules and a pharmaceutically acceptable additive, the granules comprising 50.00mg brivaracetam, 13.50mg beta cyclodextrin, 97.00mg lactose monohydrate, and 5.00mg croscarmellose sodium, and the additive comprising 5.00mg croscarmellose sodium, 96.50mg anhydrous lactose, and 3.00mg magnesium stearate.

22. The oral pharmaceutical composition of claim 1, wherein the composition comprises granules and a pharmaceutically acceptable additive, the granules comprising 9.2mg brivaracetam, 2.50mg beta cyclodextrin, 41.5mg lactose monohydrate, and 1.80mg croscarmellose sodium, and the additive comprising 1.80mg croscarmellose sodium, 41.6mg anhydrous lactose, 0.5mg colloidal silicon dioxide, and 1.10mg magnesium stearate.

23. The oral pharmaceutical composition of claim 1, wherein the granules comprise 1.0-15% by weight of the cyclodextrin agent, based on the total weight of the granules.

24. The oral pharmaceutical composition of claim 1, wherein the granules comprise 4.0 to 11% by weight of the cyclodextrin agent, based on the total weight of the granules.

25. A process for the preparation of an oral pharmaceutical composition according to any one of claims 1 to 24, wherein it comprises at least one dry granulation step.

26. The method of claim 25, wherein it comprises:

-a first step, in which the active ingredient and the cyclodextrin agent and the excipients are mixed;

-a second step in which the resulting blend is compressed and/or compacted; and

-a third step, in which the blend is milled to obtain granules.

27. The method of claim 26, wherein it comprises:

-a fourth step, in which the granules obtained and the excipient are mixed; and

-a fifth step, in which the final blend is compressed and/or compacted to obtain tablets.