HK1109071B - Pharmaceutical compositions comprising levetiracetam and process for their preparation - Google Patents

Description

Pharmaceutical composition comprising levetiracetam and process for its preparation

The present invention relates to novel pharmaceutical compositions comprising levetiracetam and processes for their preparation.

In EP 0162036B, levetiracetam or (S) - (-) - [ alpha ] -ethyl-2-oxo-1-pyrrolidineacetamide, a levorotatory compound, is disclosed, which is useful as a protective agent for the treatment and prevention of hypoxia and ischemic attacks (aggregations) in the central nervous system and has the following general formula.

The compounds are also effective in the treatment of epilepsy for which the dextro enantiomer (R) - (-) - α -ethyl-2-oxo-1-pyrrolidineacetamide has been shown to be completely inactive (AJ. Gowe et al, Eur. J. Pharmacol., 222, 1992, 193-203).

Film-coated tablets containing 250mg, 500mg or 1000mg of levetiracetam are described in Rote List Service Gmbh "Rote List 2003, 2002, ECV-edition Cantor, Aulendorf, Germany. The ingredients are corn starch, povidone K30, talc, colloidal anhydrous silicon dioxide, magnesium stearate, and in-coating hypromellose, macrogol 4000, titanium dioxide.

Pharmaceutical compositions comprising levetiracetam may have altered kinetics of active agent release over time. This may result in slower release of the active ingredient and thus reduced stability of the pharmaceutical composition. One of the consequences of this reduced stability is that the pharmaceutical composition fails earlier.

According to one aspect, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of a disintegrant,

0.0 to 3.0% by weight of a glidant,

0.5 to 6.0% by weight of a binder, and

0.0 to 1.0% by weight of a lubricant.

The term "active ingredient" as used herein is defined as a substance having a therapeutic effect.

The amount of active ingredient present in the pharmaceutical composition of the present invention may vary depending on the mammal to which the composition is administered and the condition being treated.

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

Examples of disintegrants are starch, croscarmellose sodium, also known as croscarmellose sodium, and crospovidone. Preferred disintegrants according to the invention are polyvinylpyrrolidone, sodium starch glycolate and croscarmellose sodium. A more preferred disintegrant according to the invention is croscarmellose sodium.

Preferably, the pharmaceutical composition according to the invention comprises 3.0 to 7.0% by weight of disintegrant, more preferably 3.0 to 5.0% by weight of disintegrant, most preferably 3.9% by weight of disintegrant, relative to the total weight of the pharmaceutical composition.

As used herein, the term "flow aid" is defined as a material that improves the flowability of a powder and thus can be filled into the compression chambers of a tablet press. The glidant may be present in the composition as a single compound or as a mixture of compounds.

Examples of glidants are talc, starch, stearic acid and anhydrous colloidal silicon dioxide. A preferred glidant according to the present invention is anhydrous colloidal silicon dioxide.

Preferably, the pharmaceutical composition according to the invention comprises 0.5 to 2.5% by weight of glidant, more preferably 1.0 to 2.0% by weight of glidant, most preferably 1.9% by weight of glidant, relative to the total weight of the pharmaceutical composition.

As used herein, the term "binder" is defined as a material capable of binding particles that cannot be bound solely by compressive forces. The binder may be present in the composition as a single compound or as a mixture of compounds.

Examples of binders are macrogol, microcrystalline cellulose, sucrose, mannitol or sorbitol. The preferred binder according to the invention is macrogol. The most preferred binder according to the present invention is polyethylene glycol 6000, also known as macrogol 6000.

As understood by those skilled in the art, the number "6000" after polyethylene glycol refers to the average molecular weight of the polyethylene glycol.

Typically, the pharmaceutical composition according to the invention comprises 0.5 to 4.0% by weight of binder relative to the total weight of the pharmaceutical composition.

In particular, the pharmaceutical composition according to the invention comprises 0.5 to 2.5% by weight of binder relative to the total weight of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention comprises 0.7 to 1.8% by weight of binder, more preferably 0.8 to 1.6% by weight of binder, most preferably 0.9% by weight of binder, relative to the total weight of the pharmaceutical composition.

As used herein, the term "lubricant" is defined as a material capable of reducing the adhesion of powder to the punch and the friction between particles. The lubricant may be present in the composition as a single compound or as a mixture of compounds.

Examples of lubricants are talc, magnesium stearate or calcium stearate.

A preferred lubricant according to the invention is magnesium stearate.

Typically, the pharmaceutical composition according to the invention comprises 0.0 to 0.75% by weight of lubricant relative to the total weight of the pharmaceutical composition.

In particular, the pharmaceutical composition according to the invention comprises 0.0 to 0.50% by weight of lubricant with respect to the total weight of the pharmaceutical composition.

Preferably, the pharmaceutical composition according to the invention comprises 0.05 to 0.25% by weight of lubricant, more preferably 0.08 to 0.15% by weight of lubricant, most preferably 0.11% by weight of lubricant, relative to the total weight of the pharmaceutical composition.

The pharmaceutical composition according to the present invention shows increased stability upon release of levetiracetam as active ingredient compared to known pharmaceutical compositions comprising levetiracetam. In particular, the pharmaceutical composition according to the present invention shows increased stability in releasing levetiracetam as an active ingredient, compared to pharmaceutical compositions comprising levetiracetam prepared using conventional methods, such as wet granulation.

Preferably, the pharmaceutical composition according to the invention is capable of ensuring a substantially stable release of the active ingredient over time.

In one embodiment, the pharmaceutical composition according to the invention comprises at least 2.0 to 9.0% by weight of croscarmellose sodium relative to the total weight of the pharmaceutical composition.

In another embodiment, the pharmaceutical composition according to the invention comprises at least 0.0 to 3.0% by weight of anhydrous colloidal silicon dioxide relative to the total weight of the pharmaceutical composition.

In yet another embodiment, the pharmaceutical composition according to the invention comprises at least 0.5 to 6.0% by weight of polyethylene glycol 6000 relative to the total weight of the pharmaceutical composition.

In a further embodiment, the pharmaceutical composition according to the invention comprises at least 0.0 to 1.0% by weight of magnesium stearate relative to the total weight of the pharmaceutical composition.

In general, the present invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and the amount thereof relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of a disintegrant,

0.0 to 3.0% by weight of a glidant,

0.5 to 4.0% by weight of a binder, and

0.0 to 0.75% by weight of a lubricant.

In particular, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and the amount thereof relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of a disintegrant,

0.0 to 3.0% by weight of a glidant,

0.5 to 2.5% by weight of a binder, and

0.0 to 0.50% by weight of a lubricant,

preferably, the present invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and relative to the total weight of the pharmaceutical composition

3.0 to 7.0% by weight of a disintegrant,

0.5 to 2.5% by weight of a glidant,

0.7 to 1.8% by weight of a binder, and

0.05 to 0.25% by weight of a lubricant,

more preferably, the present invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and the amount thereof relative to the total weight of the pharmaceutical composition

3.0 to 5.0% by weight of a disintegrant,

1.0 to 2.0% by weight of a glidant,

0.8 to 1.6% by weight of a binder, and

0.08 to 0.15% by weight of a lubricant,

typically, the pharmaceutical composition according to the invention comprises 80 to 95% by weight of levetiracetam, preferably 80 to 93% by weight of levetiracetam, more preferably 90 to 92% by weight of levetiracetam, relative to the total weight of the pharmaceutical composition.

In a particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 6.0% by weight of polyethylene glycol 6000, and

0.0 to 1.0% by weight of magnesium stearate.

In general, in this particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 4.0% by weight of polyethylene glycol 6000, and

0.0 to 0.75% by weight of magnesium stearate.

In particular, in this particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 2.5% by weight of polyethylene glycol 6000, and

0.0 to 0.50% by weight of magnesium stearate.

Preferably, in this particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

3.0 to 7.0% by weight of croscarmellose sodium,

0.5 to 2.5% by weight of anhydrous colloidal silica,

0.7 to 1.8% by weight of polyethylene glycol 6000, and

0.05 to 0.25% by weight of magnesium stearate.

More preferably, in this particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and relative to the total weight of the pharmaceutical composition

3.0 to 5.0% by weight of croscarmellose sodium,

1.0 to 2.0% by weight of anhydrous colloidal silica,

0.8 to 1.6% by weight of polyethylene glycol 6000, and

0.08 to 0.15% by weight of magnesium stearate.

In a further particular embodiment, the present invention relates to a pharmaceutical composition comprising, relative to the total weight of the pharmaceutical composition

80 to 95% by weight of levetiracetam,

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 6.0% by weight of polyethylene glycol 6000, and

0.0 to 1.0% by weight of magnesium stearate,

in general, in this further particular embodiment, the invention relates to a pharmaceutical composition comprising, relative to the total weight of the pharmaceutical composition

80 to 95% by weight of levetiracetam,

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 4.0% by weight of polyethylene glycol 6000, and

0.0 to 0.75% by weight of magnesium stearate.

In particular, in this further particular embodiment, the present invention relates to a pharmaceutical composition comprising, relative to the total weight of the pharmaceutical composition

80 to 95% by weight of levetiracetam,

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 2.5% by weight of polyethylene glycol 6000, and

0.0 to 0.50% by weight of magnesium stearate.

Preferably, in this further particular embodiment, the present invention relates to a pharmaceutical composition comprising, relative to the total weight of the pharmaceutical composition

85 to 93% by weight of levetiracetam,

3.0 to 7.0% by weight of croscarmellose sodium,

0.5 to 2.5% by weight of anhydrous colloidal silica,

0.7 to 1.8% by weight of polyethylene glycol 6000, and

0.05 to 0.25% by weight of magnesium stearate.

More preferably, in this further particular embodiment, the present invention relates to a pharmaceutical composition comprising, relative to the total weight of the pharmaceutical composition

90 to 92% by weight of levetiracetam,

3.0 to 5.0% by weight of croscarmellose sodium,

1.0 to 2.0% by weight of anhydrous colloidal silica,

0.8 to 1.6% by weight of polyethylene glycol 6000, and

0.08 to 0.15% by weight of magnesium stearate.

In one embodiment of the invention, the sum of disintegrant, glidant, binder and lubricant present in a pharmaceutical composition comprising levetiracetam as active ingredient is less than or equal to 20% by weight, preferably less than or equal to 15% by weight, more preferably less than or equal to 10% by weight, relative to the total weight of the pharmaceutical composition.

The above values of the sum of disintegrant, glidant, binder and lubricant provide the advantage of further reducing the size and weight of the pharmaceutical composition for a specific amount of active ingredient, thereby increasing the ease of administration to the patient.

Most preferably, the sum of croscarmellose sodium, anhydrous colloidal silicon dioxide, polyethylene glycol 6000 and magnesium stearate present in the pharmaceutical composition comprising levetiracetam according to the invention is preferably less than or equal to 10% by weight.

Preferably, the pharmaceutical composition according to the invention is administered orally.

Preferably, the pharmaceutical composition according to the invention is in solid form, preferably in tablet form.

The tablets may be uncoated or coated with a coating material.

In one embodiment, the pharmaceutical composition according to the invention comprises 1.0% to 6.0% by weight of coating material, preferably 2.0% to 5.0% by weight of coating material, more preferably 2.5% to 4.5% by weight of coating material, most preferably 2.9% of coating material, relative to the total weight of the pharmaceutical composition.

In a preferred embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and the amount thereof relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of a disintegrant,

0 to 3.0% by weight of a glidant,

0.5 to 6.0% by weight of a binder,

0.0 to 1.0% by weight of a lubricant, and

1.0 to 6.0% by weight of coating material.

Generally, in this preferred embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of a disintegrant,

0 to 3.0% by weight of a glidant,

0.5 to 4.0% by weight of a binder,

0.0 to 0.75% by weight of a lubricant, and

1.0 to 6.0% by weight of coating material.

In particular, in this preferred embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of a disintegrant,

0 to 3.0% by weight of a glidant,

0.5 to 2.5% by weight of a binder,

0.0 to 0.50% by weight of a lubricant, and

1.0 to 6.0% by weight of coating material.

Preferably, in this preferred embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

3.0 to 7.0% by weight of a disintegrant,

0.5 to 2.5% by weight of a glidant,

0.7 to 1.8% by weight of a binder,

0.05 to 0.25% by weight of a lubricant, and

2.0 to 5.0% by weight of coating material.

More preferably, in this preferred embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and the amount thereof relative to the total weight of the pharmaceutical composition

3.0 to 5.0% by weight of a disintegrant,

1.0 to 2.0% by weight of a glidant,

0.8 to 1.6% by weight of a binder,

0.08 to 0.15% by weight of a lubricant, and

2.5 to 4.5% by weight of coating material.

Examples of coating materials are ethyl cellulose, hydroxypropyl methylcellulose and methacrylic acid-alkyl acrylate copolymers.

The preferred coating material is an aqueous hydroxypropyl methylcellulose dispersion.

A more preferred coating material according to the invention is Opadry。

OpadryIs an aqueous hydroxypropyl methylcellulose dispersion. OpadryIs Opadry85F20694、Opadry85F32004、Opadry85F23452 and Opadry85F1 8422。

The coating material preferably comprises polyvinyl alcohol (PVA) so that the coating material ensures better flow of the tablets when packaged. More preferably, the coating material comprises partially hydrolyzed polyvinyl alcohol.

The presence of polyvinyl alcohol in the coating material also ensures better adhesion of the coating to the tablet. Also, higher concentrations of coating material may be used.

In another embodiment, the pharmaceutical composition according to the invention comprises 1.0 to 6.0% by weight of the coating material comprising polyvinyl alcohol, preferably 2.0 to 5.0% by weight of the coating material comprising polyvinyl alcohol, more preferably 2.5 to 4.5% by weight of the coating material comprising polyvinyl alcohol, most preferably 2.9% by weight of the coating material comprising polyvinyl alcohol, relative to the total weight of the pharmaceutical composition.

In this embodiment, the polyvinyl alcohol is preferably partially hydrolyzed.

In a particular embodiment according to the invention, the sum of disintegrant, glidant, binder, lubricant and coating material present in a pharmaceutical composition comprising levetiracetam as active ingredient is less than or equal to 20% by weight, preferably less than or equal to 15% by weight, more preferably less than or equal to 10% by weight, relative to the total weight of the pharmaceutical composition.

In a more preferred embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and the amount thereof relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 6.0% by weight of polyethylene glycol 6000, and

0.0 to 1.0% by weight of magnesium stearate,

1.0 to 6.0% by weight of Opadry。

In general, in this particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 4.0% by weight of polyethylene glycol 6000, and

0.0 to 0.75% by weight of magnesium stearate,

1.0 to 6.0% by weight of Opadry。

In particular, in this particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 2.5% by weight of polyethylene glycol 6000, and

0.0 to 0.50% by weight of magnesium stearate,

1.0 to 6.0% by weight of Opadry。

Preferably, in this particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and, relative to the total weight of the pharmaceutical composition

3.0 to 7.0% by weight of croscarmellose sodium,

0.5 to 2.5% by weight of anhydrous colloidal silica,

0.7 to 1.8% by weight of polyethylene glycol 6000, and

0.05 to 0.25% by weight of magnesium stearate,

2.0 to 5.0% by weight of Opadry。

More preferably, in this particular embodiment, the invention relates to a pharmaceutical composition comprising levetiracetam as active ingredient and relative to the total weight of the pharmaceutical composition

3.0 to 5.0% by weight of croscarmellose sodium,

1.0 to 2.0% by weight of anhydrous colloidal silica,

0.8 to 1.6% by weight of polyethylene glycol 6000, and

0.08 to 0.15% by weight of magnesium stearate,

2.5 to 4.5% by weight of Opadry。

In the above-mentioned pharmaceutical composition, OpadryPreferably comprising polyvinyl alcohol. More preferably, OpadryIncluding partially hydrolyzed polyvinyl alcohol.

In another specific embodiment, croscarmellose sodium, anhydrous colloidal silicon dioxide, in a pharmaceutical composition comprising levetiracetam,Polyethylene glycol 6000, magnesium stearate and OpadryPreferably less than or equal to 10% by weight relative to the total weight of the pharmaceutical composition.

Optionally, the pharmaceutical composition according to the invention may contain a diluent or a filler.

As used herein, the term "diluent" or "filler" is defined as an inert material used to increase the weight and/or size of a pharmaceutical composition, for example when a tablet.

The diluent or filler may be present in the composition as a single compound or as a mixture of compounds.

Preferably, a diluent or filler is added when the amount of active ingredient and other excipients is too small to obtain a tablet of suitable size.

Examples of diluents or fillers according to the invention are starch, lactose, mannitol, sugars or mineral salts.

The weight percentage of diluent or filler necessary for the pharmaceutical composition according to the invention can be determined according to conventional methods well known to the person skilled in the art.

Optionally, the pharmaceutical composition according to the invention may contain sweetening agents, such as sucrose or saccharin, coloring agents or flavoring agents.

Optionally, the pharmaceutical composition according to the invention may comprise a taste-masking agent.

Preferably, the pharmaceutical composition according to the invention comprises a coating material having taste masking characteristics.

Generally, the existing pharmaceutical compositions comprising levetiracetam are prepared by wet granulation methods according to conventional methods well known to those skilled in the art.

Such wet granulation methods may cause degradation of the active ingredient when contacted with a liquid phase. Moreover, such a process requires a drying step, which is time consuming and increases the cost of production due to the presence of a heat source.

Thus, in another aspect, the present invention relates to a process for the preparation of a pharmaceutical composition comprising levetiracetam as active ingredient and relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of a disintegrant,

0.0 to 3.0% by weight of a glidant,

0.5 to 6.0% by weight of a binder, and

0.0 to 1.0% by weight of a lubricant,

the method comprises the following steps:

i) mixing levetiracetam, glidant, disintegrant and adhesive,

ii) adding a lubricant to the mixture,

iii) mixing levetiracetam, glidant, disintegrant, binder and lubricant;

iv) compacting the mixture obtained in step iii),

v) comminuting the mixture of step iv), and

vi) compressing the mixture in step v).

As used herein, the term "compaction" is defined as the transformation of a powder into a compact specimen (coherent specimen) of a specified shape by compression, for example by a roller compactor.

As used herein, the term "comminution" is defined as reduction of particle size by sieving.

As used herein, the term "compressing" is defined as compressing a powder into a tablet by applying sufficient force on the powder through the punches of a tablet press.

Preferably, at least one of the levetiracetam, disintegrant, glidant, or binder is subjected to a depolymerization (deagglomeration) process prior to mixing.

As used herein, the term "deagglomeration" is defined as the breaking up of agglomerates in a powder.

Preferably, the comminution step is accomplished by sieving through a sieve of less than 5mm, more preferably less than 3mm, most preferably less than 1.5 mm.

The process according to the invention comprises fewer steps than the wet granulation process, thus ensuring lower production costs. Moreover, the above process avoids degradation of the active ingredient when in contact with the liquid phase.

Preferably, the process comprises a further coating step, wherein water, preferably pure water, is added to the coating material and the resulting suspension is sprayed onto the mixture obtained in step vi).

The preferred coating material is Opadry. More preferably the coating material is selected from Opadry85F20694、Opadry85F32004、Opadry85F23452 and Opadry85F 18422. The most preferred coating material comprises polyvinyl alcohol.

The present invention further relates to a process for the manufacture of a pharmaceutical composition comprising preferred, more preferred and most preferred weight percentages of levetiracetam as defined above, disintegrants, glidants, binders, lubricants and coating materials as defined above for these pharmaceutical compositions, which process comprises steps i) to vi) as defined above.

In a preferred embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising levetiracetam as active ingredient and relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 6.0% by weight of polyethylene glycol 6000, and

0.0 to 1.0% by weight of magnesium stearate,

the method comprises the following steps:

i) mixing levetiracetam, anhydrous colloidal silicon dioxide, croscarmellose sodium and polyethylene glycol 6000,

ii) adding magnesium stearate to the mixture,

iii) mixing levetiracetam, anhydrous colloidal silicon dioxide, croscarmellose sodium and polyethylene glycol 6000 and magnesium stearate;

iv) compacting the mixture obtained in step iii),

v) comminuting the mixture of step iv), and

vi) compressing the mixture in step v).

In a more preferred embodiment, the present invention relates to a process for preparing a pharmaceutical composition comprising levetiracetam as an active ingredient and levetiracetam relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 6.0% by weight of polyethylene glycol 6000, and

0.0 to 1.0% by weight of magnesium stearate,

1.0 to 6.0% by weight of Opadry

With respect to the total weight of the pharmaceutical composition,

the method comprises the following steps:

i) mixing levetiracetam, anhydrous colloidal silicon dioxide, croscarmellose sodium and polyethylene glycol 6000,

ii) adding magnesium stearate to the mixture,

iii) mixing levetiracetam, anhydrous colloidal silicon dioxide, croscarmellose sodium and polyethylene glycol 6000 and magnesium stearate;

iv) compacting the mixture obtained in step iii),

v) comminuting the mixture of step iv),

vi) compressing the mixture of step v), and

vii) will include OpadrySpraying the hydroxypropylmethylcellulose suspension of (a) onto the mixture obtained in step vi).

In a more preferred embodiment, OpadryPreferably comprising polyvinyl alcohol.

The invention further relates to a process for the manufacture of a pharmaceutical composition comprising the usual, specific, preferred, more preferred and most preferred weight percentages of levetiracetam, suitable for this as defined aboveThe pharmaceutical compositions croscarmellose sodium, anhydrous colloidal silicon dioxide, polyethylene glycol 6000, magnesium stearate and OpadryThe method comprises steps i) to vii) as defined above.

In another aspect the present invention relates to a pharmaceutical composition for the treatment and prevention of diseases comprising levetiracetam as active ingredient and relative to the total weight of the pharmaceutical composition

2.0 to 9.0% by weight of a disintegrant,

0 to 3.0% by weight of a glidant,

0.5 to 6.0% by weight of a binder, and

0.0 to 1.0% by weight of a lubricant.

By the term "disease" we understand a disease selected from the group consisting of epileptic induction disorders (epiletogenesis), seizure disorders, convulsions, parkinson's disease, dyskinesias induced by dopamine replacement therapy, tardive dyskinesia induced by administration of neuroleptic drugs, huntington's chorea and other neurological disorders including bipolar disorder, mania, depression, anxiety, attention deficit disorder (ADHD), migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmias, myotonia, cocaine abuse, stroke, myoclonus, tremor, essential tremor, simple or complex tics, tourette's syndrome, restless leg syndrome and other dyskinesias, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasticity and degenerative diseases, bronchial asthma, asthma persisting and allergic bronchitis, asthma syndrome, bronchial hyperresponsiveness and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis (rhinoconjunctivitis).

As used herein, the term "treatment" refers to both curative and prophylactic treatment.

By the term "curative" is meant the efficacy of treating the symptoms of the disorder or condition that is occurring.

By "prophylactic" is meant prevention of the occurrence or recurrence of a disorder or condition.

The invention also relates to methods of treating human patients by using the pharmaceutical compositions.

The invention also relates to pharmaceutical compositions for use as medicaments for curing the above mentioned diseases.

The invention also relates to the use of a pharmaceutical composition for the preparation of a medicament for therapeutic application in the above mentioned diseases.

Preferably, the above mentioned diseases are selected from the group consisting essentially of epilepsy, parkinson's disease, dyskinesias, migraine, tremor, essential tremor, bipolar disorders, chronic pain, neuropathic pain, or bronchial, asthma or allergic conditions. More preferably the disease is epilepsy.

The invention also relates to a method for the preparation of a medicament for therapeutic use in the above-mentioned diseases, characterized in that a pharmaceutical composition according to the invention is used.

The invention also relates to methods of treating humans to alleviate disease by administering the pharmaceutical compositions.

Fig. 1 shows a flow chart of a method according to the invention.

FIG. 2 shows a flow diagram of a wet granulation process.

Figure 3 shows a comparison of the immediate dissolution kinetics of the pharmaceutical composition a according to the invention of example 1 with the known pharmaceutical composition E of example 2 after preparation.

Figure 4 shows a comparison of the dissolution kinetics of compound a of example 1 according to the invention with the known compound E of example 2 six months after preparation.

Figure 5 shows a comparison of the immediate dissolution kinetics of the pharmaceutical composition B according to the invention of example 1 with the known pharmaceutical composition F of example 2 after preparation.

Figure 6 shows a comparison of the dissolution kinetics of compound B of example 1 according to the invention with the known compound F of example 2 six months after preparation.

Figure 7 shows a comparison of the instant dissolution kinetics of compound C of example 1 according to the invention after preparation with the known compound G of example 2.

Figure 8 shows a comparison of the dissolution kinetics of compound C according to the invention from example 1 with the known compound G of example 2 six months after preparation.

Figure 9 shows a comparison of the immediate dissolution kinetics of the pharmaceutical composition D according to the invention of example 1 with the known pharmaceutical composition H of example 2 after preparation.

Figure 10 shows a comparison of the dissolution kinetics of compound D of example 1 according to the invention with the known compound H of example 2 six months after preparation.

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

Examples

Example 1

Table I shows four pharmaceutical compositions (a, B, C and D) with different amounts of the active ingredient levetiracetam, prepared according to the process disclosed in fig. 1, which is called dry granulation.

TABLE I

Example 2

Table II shows four pharmaceutical compositions (E, F, G and H) with different amounts of the active ingredient levetiracetam, prepared according to the process disclosed in fig. 2, which is called wet granulation. These compositions are outside the scope of the present invention and are made for comparative studies.

TABLE II

Example 3

The kinetics of active ingredient release were determined for compositions a through H. The kinetics of all compositions were determined immediately after preparation and six months after preparation. The pharmaceutical composition was kept in the blister at 40 ℃ and 75% relative humidity for these six months.

Dissolution testing was performed in USP apparatus 2 (paddle apparatus) with a volume of 900mL, speed 50rpm, temperature 37 ℃.

Figures 3 to 10 show pharmaceutical compositions prepared according to the dry granulation method of the present invention, which dissolve the potcentages more stable than compositions prepared according to the wet granulation method. This suggests that pharmaceutical compositions a to D are more stable than pharmaceutical compositions E to H.

Example 4

The following six pharmaceutical compositions were prepared according to the process disclosed in fig. 1, which is called dry granulation.

Composition I, comprising 1000mg levetiracetam, 40mg polyvinylpyrrolidone, 60mg sorbitol and 5mg magnesium stearate.

Composition J, comprising 1000mg levetiracetam, 30mg sodium carboxymethylcellulose, 30mg starch, 30mg macrogol and 1mg magnesium stearate.

Composition K, comprising 1000mg levetiracetam, 40mg croscarmellose sodium, 60mg microcrystalline cellulose, 5mg colloidal silicon dioxide and 5mg calcium stearate.

Composition L, comprising 1000mg levetiracetam, 40mg polyvinylpyrrolidone, 10mg colloidal silicon dioxide, 15mg talc and 20mg macrogol.

Composition M, comprising 1000mg levetiracetam, 37.5mg sodium starch glycolate, 10mg colloidal silicon dioxide, 20mg macrogol and 1.25mg magnesium stearate.

Composition N, comprising 1000mg levetiracetam, 30mg polyvinylpyrrolidone, 20mg colloidal silicon dioxide, 60mg mannitol and 5mg magnesium stearate.

These compositions are coated with an aqueous hydroxypropyl methylcellulose dispersion or an aqueous polyvinyl alcohol dispersion.

These 6 compositions are stable.

Claims (12)

1. A tablet pharmaceutical composition comprising a total amount of a pharmaceutical composition

80 to 95% by weight of levetiracetam as active ingredient,

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 6.0% by weight of polyethylene glycol 6000, and

0.0 to 1.0% by weight of magnesium stearate;

the tablet pharmaceutical composition is prepared by a dry granulation method, and the preparation method of the pharmaceutical composition comprises the following steps:

i) mixing levetiracetam, anhydrous colloidal silicon dioxide, croscarmellose sodium and polyethylene glycol 6000,

ii) adding magnesium stearate to the mixture,

iii) mixing levetiracetam, anhydrous colloidal silicon dioxide, croscarmellose sodium and polyethylene glycol 6000 and magnesium stearate,

iv) compacting the mixture obtained in step iii),

v) comminuting the mixture obtained in step iv), and

vi) compressing the mixture obtained in step v).

2. Pharmaceutical composition according to claim 1, comprising the amount of the active ingredient relative to the total weight of the pharmaceutical composition

80 to 95% by weight of levetiracetam,

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 4.0% by weight of polyethylene glycol 6000, and

0.0 to 0.75% by weight of magnesium stearate.

3. Pharmaceutical composition according to claim 1, comprising the amount of the active ingredient relative to the total weight of the pharmaceutical composition

80 to 95% by weight of levetiracetam,

2.0 to 9.0% by weight of croscarmellose sodium,

0.0 to 3.0% by weight of anhydrous colloidal silica,

0.5 to 2.5% by weight of polyethylene glycol 6000, and

0.0 to 0.5% by weight of magnesium stearate.

4. Pharmaceutical composition according to claim 1, comprising the amount of the active ingredient relative to the total weight of the pharmaceutical composition

85 to 93% by weight of levetiracetam,

3.0 to 7.0% by weight of croscarmellose sodium,

0.5 to 2.5% by weight of anhydrous colloidal silica,

0.7 to 1.8% by weight of polyethylene glycol 6000, and

0.05 to 0.25% by weight of magnesium stearate.

5. Pharmaceutical composition according to claim 1, comprising the amount of the active ingredient relative to the total weight of the pharmaceutical composition

90 to 92% by weight of levetiracetam,

3.0 to 5.0% by weight of croscarmellose sodium,

1.0 to 2.0% by weight of anhydrous colloidal silica,

0.8 to 1.6% by weight of polyethylene glycol 6000, and

0.08 to 0.15% by weight of magnesium stearate.

6. A pharmaceutical composition according to any preceding claim comprising a coating material.

7. The pharmaceutical composition according to claim 6, wherein the coating material comprises polyvinyl alcohol.

8. The pharmaceutical composition according to claim 6, wherein the coating material is an aqueous hydroxypropyl methylcellulose dispersion.

9. The pharmaceutical composition according to claim 7, wherein the coating material is an aqueous hydroxypropyl methylcellulose dispersion.

10. The pharmaceutical composition according to claim 1, wherein the coating material is sprayed onto the mixture obtained in step vi) as a suspension of hydroxypropylmethylcellulose.

11. The pharmaceutical composition according to claim 10, wherein the coating material comprises polyvinyl alcohol.

12. Use of a pharmaceutical composition according to any one of claims 1 to 9 in the manufacture of a medicament for the treatment of epilepsy, parkinson's disease, dyskinesias, migraine, tremor, essential tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial asthma or allergic conditions.