CN102871981A

CN102871981A - Tablet medicine compound containing levetiracetam

Info

Publication number: CN102871981A
Application number: CN2012104170534A
Authority: CN
Inventors: 李阅东; 唐建飞; 沈如杰; 何海珍; 刘玉艳; 赵福斌
Original assignee: HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Current assignee: HANGZHOU ZHUYANGXIN PHARMACEUTICAL CO Ltd
Priority date: 2012-10-25
Filing date: 2012-10-25
Publication date: 2013-01-16
Anticipated expiration: 2032-10-25
Also published as: CN102871981B

Abstract

The invention relates to a tablet medicine compound containing levetiracetam. Specifically, the medicine compound comprises levetiracetam, disintegrant, binder, glidant and lubricant. More specifically, the medicine compound comprises 500 parts by weight of levetiracetam, 10-50 parts by weight of disintegrant, 2 -10 parts by weight of binder, 1-5 parts by weight of glidant, and 1 -5 parts by weight of lubricant. The medicine compound has good pharmaceutical characteristics, and can be used for treating or preventing epilepsy, Parkinson's disease, dyskinesia, migraine, tremor, essential tremor, bipolar disorder, chronic pain, neuropathic pain, bronchia, asthma or allergic diseases.

Description

The tablet medicine compositions that comprises levetiracetam

Technical field

The present invention relates to the new tablet medicine composition and method of making the same that comprises levetiracetam.

Background technology

European patent EP 0162036B discloses a kind of levo-compound levetiracetam; its chemistry (S)-(-)-[α] by name-ethyl-2-oxo-1-pyrrolidine acetamide, this medicine can be used as the protective agent that treatment and prevention central nervous system's hypoxia and local ischemic-type are attacked.This chemical compound can effectively be treated epilepsy, there are not activity (AJ.Gowe etc., Eur.J.Pharmacol., 222 fully for verified its dextrorotation enantiomer (R)-(-)-[α]-ethyl-2-oxo-1-pyrrolidine acetamide of this treatment indication, 1992,193-203).

Levetiracetam is a kind of pyrrolidinone derivatives, its chemical constitution and existing antiepileptic non-correlation.In multiple epilepsy animal model, assessed the antiepileptic action of levetiracetam.Levetiracetam is shied the simple epilepsy unrestraint effect that the agent maximal stimulus is induced to electric current or multiple causing, and only shows faint activity in inferior maximal stimulus and Test of threshold.But the generalized seizures of focal attack's secondary that pilocarpine and red algae aminoacid are induced is observed protective effect, and these two kinds of chemical convulsivants can imitate some with the characteristic of the complex partial seizures of Secondary cases generalized seizure.Levetiracetam is to the ignition procedures of the rat kindling model of complex partial seizures and to light state all inhibited.These animal models are still not clear the predictive value of human body particular type epilepsy.

In the body, in vitro tests shows that levetiracetam suppresses the Hippocampal epilepsy sample and discharges suddenly, and on normal neuronal excitability without impact, the prompting levetiracetam may optionally suppress the propagation of the epileptic burst supersynchronous property of discharge and epilepsy.

Levetiracetam when concentration height to 10 μ M, to multiple known receptor without affinity, such as Benzodiazepines, GABA, glycine, NMDA, reuptake sites and second messenger system.In vitro tests show levetiracetam on the valtage-gated sodium-ion channel of neuron or T-type calcium current without impact.The direct facilitation GABA energy of levetiracetam neurotransmission, but studies show that neuron GABA and the sub-activity of glycine gating current negative regulator to cultivating have antagonism.In rat cerebral tissue, found saturable and the stereoselective neuron binding site of levetiracetam, but the evaluation of this binding site and function are still not clear at present.

The definite antiepileptic action mechanism of levetiracetam is still not exclusively clear and definite.Generally believe that at present its mechanism of action from Antiepileptic drugs is different, to Gabanergic and Glutamatergic Nervous pathway without direct effect, with benzodiazepine receptors without affinity, to neuronic Voltage-gated sodium channels, the T-shaped calcium channel of low-voltage gate without contacting directly.Mainly play a role by following approach: 1. with axoneuron in the synaptophysin 2A that extensively distributes have an effect, regulate the exocytosis function of synaptic vesicle and the release of presynaptic neurotransmitter.Zoopery shows that the SV2A knock out mice shows growth restriction, neuronal excitability increases and serious convulsions susceptibility.Levetiracetam and SV2A have very high affinity in brain, and closely related with the discharge of inhibition epilepsy.2. resist the gamma-aminobutyric acid receptor blocker, thus indirectly strengthen gamma-aminobutyric acid receptor effect, suppress Hippocampus CA 3 Region etc. and locate neuronic irritability.3. suppress the N-type calcium channel that high voltage activates, like potassium-channel is also had effect.4. some molecular studies show, neuronal excitability increase with Hippocampus in raise relevant for the synthesis of the mRNA level of Brain Derived Neurotrophic Factor and neuropeptide γ.Levetiracetam then can reduce the rise of these gene expressions, increases thereby suppress associated neuronal excitability.

" Aulendorf has put down in writing the thin membrane coated tablet that contains 250mg, 500mg or 1000mg levetiracetam among the Germany for Rote Liste 2003,2002, ECV-Editio Cantor at Rote Liste Service Gmbh.Composition is corn starch, PVP K30, Talcum, colloid anhydride silica, magnesium stearate, and is mixed with hydroxypropyl emthylcellulose, Macrogol 4000, titanium dioxide in the coating material.

Because the dosage of levetiracetam is larger, the single dose of oral formulations is 250mg, 500mg, 750mg, 1000mg usually.Therefore expectation has as far as possible little size and weight, the least possible interpolation pharmaceutic adjuvant when making preparation.

The particularly less film coating tablet of clothing material use quantity of tablet is made in the levetiracetam expectation, yet the inventor finds that the intrinsic character of plain sheet of coating does not have the impact of not expecting for tablet coating, for example might affect the impact of coated tablet yield rate.

Therefore, those skilled in the art expect to obtain the high levetiracetam coated tablet of a kind of coated tablet yield rate.

Summary of the invention

The object of the invention is to obtain a kind of levetiracetam coated tablet, expect that this tablet has the characteristics such as coated tablet yield rate.

Summary of the invention

In some embodiments, the invention provides:

[1], a kind of pharmaceutical composition, it comprises: levetiracetam, disintegrating agent, binding agent, fluidizer, lubricant.

[2], according to aforementioned each purpose pharmaceutical composition, it comprises:

Levetiracetam

500 weight portions,

Disintegrating agent	The 10-50 weight portion,
		Binding agent	The 2-10 weight portion,
Fluidizer	The 1-5 weight portion,
		Lubricant	The 1-5 weight portion.

[3], according to aforementioned each purpose pharmaceutical composition, wherein said disintegrating agent is selected from: sodium starch glycolate and cross-linked carboxymethyl cellulose sodium; Further, for the active component of per 500 weight portions, the amount of disintegrating agent is the 10-50 weight portion, for example 10-40 weight portion, for example 15-30 weight portion.

[4], according to aforementioned each purpose pharmaceutical composition, wherein said fluidizer is selected from Pulvis Talci, starch, stearic acid and colloidal silica anhydrous; Further, for the active component of per 500 weight portions, the amount of fluidizer is the 1-5 weight portion, for example the 2-5 weight portion.

[5], according to aforementioned each purpose pharmaceutical composition, wherein said binding agent is selected from polyvidone (being called again polyvinylpyrrolidone, referred to as PVP) and all size (for example K15, K25, K30, K60, K90), Polyethylene Glycol, microcrystalline Cellulose, sucrose, mannitol or Sorbitol; Further, for the active component of per 500 weight portions, the amount of binding agent is the 2-10 weight portion, for example 3-10 weight portion, for example 4-10 weight portion.

[6], according to aforementioned each purpose pharmaceutical composition, wherein said lubricant is selected from Pulvis Talci, magnesium stearate or calcium stearate; Further, for the active component of per 500 weight portions, the amount of lubricant is the 1-5 weight portion, for example the 2-5 weight portion.

[7], according to aforementioned each purpose pharmaceutical composition, comprising active component levetiracetam and the following composition for the active component of per 500 weight portions:

Cross-linked carboxymethyl cellulose sodium is measured the weight portion into 10-50, for example 10-40 weight portion, for example 15-30 weight portion;

Micropowder silica gel is measured the weight portion into 1-5, for example the 2-5 weight portion;

PVP K30 is measured the weight portion into 2-10, for example 3-10 weight portion, for example 4-10 weight portion; And/or

Magnesium stearate is measured the weight portion into 1-5, for example the 2-5 weight portion.

[8], according to aforementioned each purpose pharmaceutical composition, comprising

Levetiracetam	500 weight portions,
		Cross-linked carboxymethyl cellulose sodium	The 10-40 weight portion,
PVP K30	The 2-8 weight portion,
		Micropowder silica gel	The 2-5 weight portion,
Magnesium stearate	The 2-5 weight portion.

[9], according to aforementioned each purpose pharmaceutical composition, comprising

Levetiracetam	500 weight portions,
		Cross-linked carboxymethyl cellulose sodium	The 15-30 weight portion,
PVP K30	The 3-6 weight portion,
		Micropowder silica gel	The 3-5 weight portion,
Magnesium stearate	The 2-4 weight portion.

[10], according to aforementioned each purpose pharmaceutical composition, the summation of disintegrating agent, fluidizer, binding agent and the lubricant that wherein exists is less than or equal to 20% weight with respect to the gross weight of pharmaceutical composition, preferably be less than or equal to 15% weight, be more preferably less than or equal 10% weight; Preferably, exist the summation of cross-linked carboxymethyl cellulose sodium, micropowder silica gel, PVP K30 and magnesium stearate preferably to be less than or equal to 10% weight in the described pharmaceutical composition.

[11], according to aforementioned each purpose pharmaceutical composition, its be not coating or with the tablet of coating material coating; Further, this pharmaceutical composition comprises the coating material with respect to pharmaceutical composition gross weight 1.0% to 6.0% weight, 2.0% to 5.0% weight, 2.5% to 4.5% weight; Further, coating material is selected from ethyl cellulose, hydroxypropyl emthylcellulose and methacrylic acid-alkyl acrylate copolymer; Further, coating material is the hydroxypropyl emthylcellulose aqueous dispersion; Further, coating material is

It is the hydroxypropyl emthylcellulose aqueous dispersion; Further, coating material is selected from

85F20694,

85F32004, 85F23452, 85G60978 and

85F18422.

[12], according to aforementioned each purpose pharmaceutical composition, it comprises:

Levetiracetam	500 weight portions,
		Disintegrating agent	The 10-40 weight portion,
Binding agent	The 2-8 weight portion,
		Fluidizer	The 2-5 weight portion,
Lubricant	The 2-5 weight portion, and

With respect to the coating material of pharmaceutical composition gross weight 1.0% to 6.0% weight, the coating material of preferred 2.0% to 5.0% weight, the more preferably coating material of 2.5% to 4.5% weight.

[13], according to aforementioned each purpose pharmaceutical composition, it comprises:

Levetiracetam	500 weight portions,
		Disintegrating agent	The 15-30 weight portion,
Binding agent	The 3-6 weight portion,
		Fluidizer	The 3-5 weight portion,
Lubricant	The 2-4 weight portion, and

[14], according to aforementioned each purpose pharmaceutical composition, in comprising the pharmaceutical composition of levetiracetam as active component, the summation of disintegrating agent, fluidizer, binding agent, lubricant and the coating material that exists is less than or equal to 20% weight with respect to the gross weight of pharmaceutical composition, preferably be less than or equal to 15% weight, be more preferably less than or equal 10% weight.

[15], according to aforementioned each purpose pharmaceutical composition, it comprises:

Levetiracetam	500 weight portions,
		Cross-linked carboxymethyl cellulose sodium	The 10-40 weight portion,
PVP K30	The 2-8 weight portion,
		Micropowder silica gel	The 2-5 weight portion,
Magnesium stearate	The 2-5 weight portion, and

Coating material with respect to pharmaceutical composition gross weight 1.0% to 6.0% weight

The coating material of preferred 2.0% to 5.0% weight

The more preferably coating material of 2.5% to 4.5% weight

[16], according to aforementioned each purpose pharmaceutical composition, it comprises:

Levetiracetam	500 weight portions,
		Cross-linked carboxymethyl cellulose sodium	The 15-30 weight portion,
PVP K30	The 3-6 weight portion,
		Micropowder silica gel	The 3-5 weight portion,
Magnesium stearate	The 2-4 weight portion, and

Coating material with respect to pharmaceutical composition gross weight 1.0% to 6.0% weight The coating material of preferred 2.0% to 5.0% weight

The more preferably coating material of 2.5% to 4.5% weight

[17], according to aforementioned each purpose pharmaceutical composition, the summation of the cross-linked carboxymethyl cellulose sodium in comprising the pharmaceutical composition of levetiracetam, PVP K30, micropowder silica gel (being silicon dioxide), magnesium stearate and Opadry@preferably is less than or equal to 10% weight with respect to the gross weight of pharmaceutical composition.

[18], aforementioned each purpose pharmaceutical composition of preparation method of tablet particularly, described pharmaceutical composition comprises

Levetiracetam	500 weight portions,
		Disintegrating agent	The 10-50 weight portion,
Binding agent	The 2-10 weight portion,
		Fluidizer	The 1-5 weight portion,

Lubricant

The 1-5 weight portion,

The method comprising the steps of: active component is mixed granulation with each adjuvant; The gained granule is pressed into tablet; Randomly, to above step gained pharmaceutical composition for example tablet carry out coating.

[19], aforementioned each purpose pharmaceutical composition of preparation method of tablet particularly, described pharmaceutical composition comprises

Levetiracetam	500 weight portions,
		Disintegrating agent	The 10-50 weight portion,
Binding agent	The 2-10 weight portion,
		Fluidizer	The 1-5 weight portion,
Lubricant	The 1-5 weight portion,

The method comprising the steps of:

I) levetiracetam, disintegrating agent, binding agent, fluidizer are fully mixed, with the mixture compacted that obtains;

Ii) with step I) compacting mixture that obtains pulverizes; With

Iii) to step I i) add lubricant in the gained crushed mixture, mix homogeneously becomes for example tablet of pharmaceutical composition of the present invention with its compressed shape; Randomly

Iv) to above step gained pharmaceutical composition for example tablet carry out coating and (for example will comprise hydroxypropyl emthylcellulose

Suspension is sprayed to mixture that above step obtains for example on the tablet, to the gained pharmaceutical composition for example tablet carry out coating),

Perhaps, the method comprising the steps of:

I) levetiracetam, disintegrating agent, binding agent, fluidizer are fully mixed;

Ii) add lubricant;

Iii) fully mix levetiracetam, disintegrating agent, binding agent, fluidizer and lubricant;

Iv) compacting is at step I ii) in the mixture (becoming block) that obtains;

V) compacting mixture pulverising step iv) (formation can be crossed the particle of 20 mesh sieves);

Vi) mixture compression step v) forms for example tablet of pharmaceutical composition of the present invention; Randomly

Vii) to above step gained pharmaceutical composition for example tablet carry out coating and (for example will comprise hydroxypropyl emthylcellulose

Perhaps, the method comprising the steps of:

I) levetiracetam, disintegrating agent, fluidizer are fully mixed, with 0 ~ 85% ethanol binder solution is made in the binding agent dissolving, with this binder solution soft material processed, wet granular processed, dry (measuring loss on drying to dried granule under 105 ° of C is lower than 5% and particularly is lower than 3%) gets dried granule;

Ii) to step I) add lubricant in the gained crushed mixture, mix homogeneously becomes for example tablet of pharmaceutical composition of the present invention with its compressed shape; Randomly

Iii) to above step gained pharmaceutical composition for example tablet carry out coating and (for example will comprise hydroxypropyl emthylcellulose

Perhaps, the method comprising the steps of:

I) levetiracetam, disintegrating agent are fully mixed, with 0 ~ 85% ethanol binder solution is made in the binding agent dissolving, with this binder solution soft material processed, wet granular processed, dry (measuring loss on drying to dried granule under 105 ° of C is lower than 5% and particularly is lower than 3%) gets dried granule;

Ii) to step I) add fluidizer and lubricant in the gained crushed mixture, mix homogeneously becomes for example tablet of pharmaceutical composition of the present invention with its compressed shape; Randomly

Suspension is sprayed to mixture that above step obtains for example on the tablet, to the gained pharmaceutical composition for example tablet carry out coating).

[20], aforementioned each purpose pharmaceutical composition of preparation method of tablet particularly, described pharmaceutical composition comprises

Levetiracetam	500 weight portions,
		Cross-linked carboxymethyl cellulose sodium	The 10-40 weight portion,
PVP K30	The 2-8 weight portion,
		Micropowder silica gel	The 2-5 weight portion,
Magnesium stearate	The 2-5 weight portion,

The method comprising the steps of:

Ii) with step I) compacting mixture that obtains pulverizes; With

Perhaps, the method comprising the steps of:

Ii) add lubricant;

Iv) compacting is at step I ii) in the mixture (becoming block) that obtains;

Perhaps, the method comprising the steps of:

Perhaps, the method comprising the steps of:

Iii) to above step gained pharmaceutical composition for example tablet carry out coating and (for example will comprise hydroxypropyl emthylcellulose Suspension is sprayed to mixture that above step obtains for example on the tablet, to the gained pharmaceutical composition for example tablet carry out coating).

[21], aforementioned each purpose pharmaceutical composition of preparation method of tablet particularly, described pharmaceutical composition comprises

Levetiracetam	500 weight portions,
		Cross-linked carboxymethyl cellulose sodium	The 10-40 weight portion,
PVP K30	The 2-8 weight portion,

Micropowder silica gel	The 2-5 weight portion,
		Magnesium stearate	The 2-5 weight portion, and

The coating material of preferred 2.0% to 5.0% weight

The more preferably coating material of 2.5% to 4.5% weight

The method comprising the steps of:

Ii) with step I) compacting mixture that obtains pulverizes; With

Iii) to step I i) add lubricant in the gained crushed mixture, mix homogeneously becomes for example tablet of pharmaceutical composition of the present invention with its compressed shape;

Perhaps, the method comprising the steps of:

Ii) add lubricant;

Iv) compacting is at step I ii) in the mixture (becoming block) that obtains;

Vi) mixture compression step v) forms for example tablet of pharmaceutical composition of the present invention;

Perhaps, the method comprising the steps of:

Ii) to step I) add lubricant in the gained crushed mixture, mix homogeneously becomes for example tablet of pharmaceutical composition of the present invention with its compressed shape;

Iii) to above step gained pharmaceutical composition for example tablet carry out coating and (for example will comprise hydroxypropyl emthylcellulose Suspension is sprayed to mixture that above step obtains for example on the tablet, to the gained pharmaceutical composition for example tablet carry out coating),

Perhaps, the method comprising the steps of:

[22], according to aforementioned each purpose pharmaceutical composition or aforementioned arbitrary project approach gained pharmaceutical composition, wherein do not comprise coating described pharmaceutical composition (for example face granular material before the tabletting, not coating plain sheet or through the label of coating) have 55 ~ 95 ° contact angle, particularly have 60 ~ 85 ° contact angle.

[23], aforementioned each purpose pharmaceutical composition is in the purposes that is selected from for the preparation for the treatment of or prevention in the medicine of following disease or disease: cause the Epileptic disease, the epilepsy disease, faint from fear, parkinson, the dyskinesia that is brought out by the dopamine replacement therapy, by using the stable drug-induced tardive dyskinesia of class, Huntington Chorea and other neurological disorder comprise bipolar disorder, manic, depressed, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, trigeminal neuralgia and other neuralgias, chronic pain, neuropathic pain, cerebral ischaemia, arrhythmia, myotonia, cocaine abuse, apoplexy, myoclonus, tremble, essential tremor, simple type or complexity are twitched, tourette syndrome, restless leg syndrome and other movement disorder, neonatal apoplexy, amyotrophic lateral sclerosis, spasticity and degenerative disease, bronchial asthma, status asthmaticus and allergic bronchitis, Asthma Syndrome, bronchial hyperreactivity and bronchospastic syndromes and anaphylaxis and vasomotor rhinitis and nose conjunctivitis; Particularly in the purposes that is selected from for the preparation for the treatment of or prevention in the medicine of following disease or disease: epilepsy, parkinson, the dyskinesia, migraine, tremble, essential tremor, bipolar disorder, chronic pain, neuropathic pain or bronchus, asthma or irritated disease.

Detailed Description Of The Invention

First aspect present invention provides a kind of pharmaceutical composition, and it comprises: levetiracetam, disintegrating agent, binding agent, fluidizer, lubricant.

According to the pharmaceutical composition of first aspect present invention, it comprises:

Levetiracetam	500 weight portions,
		Disintegrating agent	The 10-50 weight portion,

Binding agent	The 2-10 weight portion,
		Fluidizer	The 1-5 weight portion,
Lubricant	The 1-5 weight portion.

As described herein, levetiracetam is used for the present composition as active component, and term " active component " is defined as the material with therapeutic effect.

The amount of the active component that exists in pharmaceutical composition of the present invention can change according to the compositions mammal of using and the disease for the treatment of.

This paper term " disintegrating agent " is defined as in water or promotes the material that disintegration of tablet or active component disperse in the gastro-intestinal Fluid.Disintegrating agent can exist with the form of single compound or the form of compound mixture in compositions.

The representative instance of disintegrating agent is starch or derivatives thereof, cross-linked carboxymethyl cellulose sodium (being also referred to as cross-linking sodium carboxymethyl cellulose) etc.Preferred disintegrating agent is sodium starch glycolate and cross-linked carboxymethyl cellulose sodium according to the present invention.Preferred disintegrating agent is cross-linked carboxymethyl cellulose sodium according to the present invention.

Preferably, pharmaceutical composition according to the present invention comprises disintegrating agent, and for the active component of per 500 weight portions, the amount of disintegrating agent is the 10-50 weight portion, for example 10-40 weight portion, for example 15-30 weight portion.

This paper term " fluidizer " is defined as the material that can improve powder flowbility and therefore can be packed into the tablet machine discharge chambe.Fluidizer can exist with the form of single compound or the form of compound mixture in compositions.

The example of fluidizer is Pulvis Talci, starch, stearic acid and colloidal silica anhydrous (also being called silicon dioxide or micropowder silica gel).

Preferably, pharmaceutical composition according to the present invention comprises fluidizer, and for the active component of per 500 weight portions, the amount of fluidizer is the 1-5 weight portion, for example the 2-5 weight portion.

As used herein, term " binding agent " be defined as can be bonding can not be only the material of granule by the compression stress combination.Binding agent can exist with the form of single compound or the form of compound mixture in compositions.

The example of binding agent is polyvidone (being called again polyvinylpyrrolidone, referred to as PVP) and all size (for example K15, K25, K30, K60, K90), Polyethylene Glycol, microcrystalline Cellulose, sucrose, mannitol or Sorbitol.Preferred binding agent is polyvidone according to the present invention.Most preferred binding agent is PVP K30 according to the present invention.

Preferably, pharmaceutical composition according to the present invention comprises binding agent, and for the active component of per 500 weight portions, the amount of binding agent is the 2-10 weight portion, for example 3-10 weight portion, for example 4-10 weight portion.

As used herein, term " lubricant " is defined as and can reduces powder to the material of frictional force between the adhesion of drift and the granule.Lubricant can exist with the form of single compound or the form of compound mixture in compositions.The example of lubricant is magnesium stearate or calcium stearate; Preferred lubricant is magnesium stearate.

Preferably, pharmaceutical composition according to the present invention comprises lubricant, and for the active component of per 500 weight portions, the amount of lubricant is the 1-5 weight portion, for example the 2-5 weight portion.

Preferably, it is basicly stable to guarantee to pass in time the release of active component according to pharmaceutical composition of the present invention.

Preferably, as far as possible little size and weight can be arranged so that the patient takes according to pharmaceutical composition of the present invention.Yet be size and the weight of dwindling medicine, the formulation excipients that can add will be restricted, and preparations shaping may encounter difficulties, and for example needs to make the tablet of compacting to keep enough mechanical performances.

Preferably, pharmaceutical composition according to the present invention comprises cross-linked carboxymethyl cellulose sodium, and for the active component of per 500 weight portions, the amount of cross-linked carboxymethyl cellulose sodium is the 10-50 weight portion, for example 10-40 weight portion, for example 15-30 weight portion.

Preferably, pharmaceutical composition according to the present invention comprises micropowder silica gel, and for the active component of per 500 weight portions, the amount of micropowder silica gel is the 1-5 weight portion, for example the 2-5 weight portion.

Preferably, pharmaceutical composition according to the present invention comprises PVP K30, and for the active component of per 500 weight portions, the amount of PVP K30 is the 2-10 weight portion, for example 3-10 weight portion, for example 4-10 weight portion.

Preferably, pharmaceutical composition according to the present invention comprises magnesium stearate, and for the active component of per 500 weight portions, the amount of magnesium stearate is the 1-5 weight portion, for example the 2-5 weight portion.

Levetiracetam	500 weight portions,
		Disintegrating agent	The 10-40 weight portion,
Binding agent	The 2-8 weight portion,
		Fluidizer	The 2-5 weight portion,
Lubricant	The 2-5 weight portion.

Levetiracetam	500 weight portions,
		Disintegrating agent	The 15-30 weight portion,
Binding agent	The 3-6 weight portion,
		Fluidizer	The 3-5 weight portion,
Lubricant	The 2-4 weight portion.

In a specific embodiment, according to the pharmaceutical composition of first aspect present invention, it comprises:

Levetiracetam	500 weight portions,
		Cross-linked carboxymethyl cellulose sodium	The 10-40 weight portion,

PVP K30	The 2-8 weight portion,
		Micropowder silica gel	The 2-5 weight portion,
Magnesium stearate	The 2-5 weight portion.

In one embodiment of the invention, the summation of disintegrating agent, fluidizer, binding agent and the lubricant that exists in comprising the pharmaceutical composition of levetiracetam as active component is less than or equal to 20% weight with respect to the gross weight of pharmaceutical composition, preferably be less than or equal to 15% weight, be more preferably less than or equal 10% weight.

The value of the summation of above-mentioned disintegrating agent, fluidizer, binding agent and lubricant provides the advantage of further minimizing pharmaceutical composition size and weight for the active component of specific quantity, increases thus the ease for use that is applied to the patient.

Most preferably, according to existing the summation of cross-linked carboxymethyl cellulose sodium, micropowder silica gel, PVP K30 and magnesium stearate preferably to be less than or equal to 10% weight in the pharmaceutical composition that comprises levetiracetam of the present invention.

Preferably, oral administration is according to pharmaceutical composition of the present invention.

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

Tablet can be not coating or use the coating material coating.

In one embodiment, pharmaceutical composition according to the present invention comprises the coating material with respect to pharmaceutical composition gross weight 1.0% to 6.0% weight, the coating material of preferred 2.0% to 5.0% weight, the more preferably coating material of 2.5% to 4.5% weight.

The example of coating material is ethyl cellulose, hydroxypropyl emthylcellulose and methacrylic acid-alkyl acrylate copolymer.

Preferred coating material is the hydroxypropyl emthylcellulose aqueous dispersion.

Preferred coating material is according to the present invention

It is the hydroxypropyl emthylcellulose aqueous dispersion.

Example be

85F20694,

85F32004,

85F23452,

85G60978 and

85F18422.In the specific embodiments, such as not in addition explanation, used hereinafter

Concrete model be

85G60978.

In a specific embodiment according to the present invention, the summation of disintegrating agent, fluidizer, binding agent, lubricant and the coating material that exists in comprising the pharmaceutical composition of levetiracetam as active component is less than or equal to 20% weight with respect to the gross weight of pharmaceutical composition, preferably be less than or equal to 15% weight, be more preferably less than or equal 10% weight.

The coating material of preferred 2.0% to 5.0% weight

The more preferably coating material of 2.5% to 4.5% weight

Levetiracetam

500 weight portions,

Cross-linked carboxymethyl cellulose sodium	The 15-30 weight portion,
		PVP K30	The 3-6 weight portion,
Micropowder silica gel	The 3-5 weight portion,
		Magnesium stearate	The 2-4 weight portion, and

The coating material of preferred 2.0% to 5.0% weight The more preferably coating material of 2.5% to 4.5% weight

In another specific embodiment, the summation of the cross-linked carboxymethyl cellulose sodium in comprising the pharmaceutical composition of levetiracetam, PVP K30, micropowder silica gel (being silicon dioxide), magnesium stearate and Opadry@preferably is less than or equal to 10% weight with respect to the gross weight of pharmaceutical composition.

Randomly, can contain diluent or filler according to pharmaceutical composition of the present invention.

As used herein, term " diluent " or " filler " are defined as the inert material for increasing weight and/or the size of pharmaceutical composition, for example when for tablet.

The form that diluent or filler can single compounds in compositions or the form of compound mixture exist.

Preferably, when can not obtaining the tablet of suitable size very little, the amount of active component and other excipient adds diluent or filler.

Example according to diluent of the present invention or filler is starch, lactose, mannitol, sugar or mineral salt.

Can determine according to conventional method well known to those skilled in the art the percetage by weight of according to the present invention necessary diluent of pharmaceutical composition or filler.

Randomly, can contain sweeting agent according to pharmaceutical composition of the present invention, for example sucrose or glucide, coloring agent or flavoring agent.

Randomly, can comprise odor mask according to pharmaceutical composition of the present invention.

Preferably, pharmaceutical composition according to the present invention comprises the coating material with taste masking feature.

Therefore, on the other hand, the present invention relates to prepare the particularly method of pharmaceutical composition of the present invention of a kind of pharmaceutical composition, described pharmaceutical composition comprises

In a specific embodiment, the present invention relates to prepare the particularly method of pharmaceutical composition of the present invention of a kind of pharmaceutical composition, described pharmaceutical composition comprises

The method comprising the steps of:

Ii) with step I) compacting mixture that obtains pulverizes; With

Perhaps, the method comprising the steps of:

Ii) add lubricant;

Iv) compacting is at step I ii) in the mixture (becoming block) that obtains;

Perhaps, the method comprising the steps of:

Perhaps, the method comprising the steps of:

As used herein, term " compacting " is defined as the sample (coherent specimen) that powder is converted to the compactness of designated shape by compression (for example passing through roller press), for example powder is pressed into the tablet of bulk in advance by suitable machinery, the tablet of this bulk can be used for follow-up pulverizing to prepare the suitable granule that tabletting is used when making tablet.

As used herein, " pulverizing " is defined as by screening and reduces granular size with term.

As used herein, the drift that term " compression " is defined as by tablet machine is compressed into tablet in the enough power of powder application with it, that is " tabletting " in tablet process industry operation.

Preferably, at least aly in levetiracetam, disintegrating agent, fluidizer or the binding agent before mixing, stand depolymerization (desagglomeration) and process.

As used herein, term " depolymerization " is defined as the division of agglomerate in the powder, that is before various mixing of materials, first raw material is pulverized, such as being crushed to particle footpath less than 80 orders etc.

Preferably, by less than 5mm, be more preferably less than 3mm, most preferably finish pulverising step on the screen cloth less than 1.5mm.

Preferably, the method comprises further coating steps, and wherein with water, preferred pure water is added in the coating material and medicinal mixture that the gained suspension is sprayed to gained of the present invention particularly on the tablet.

Preferred coating material is

Preferred coating material is selected from 85F20694, Opadry@85F32004,

85F23452,

85G60978 and

85F18422.

The invention further relates to the method for making pharmaceutical composition, this pharmaceutical composition comprises preferred as defined above, the levetiracetam of preferred and most preferred percetage by weight, as above definition is suitable for these pharmaceutical composition disintegrating agents, fluidizer, binding agent, lubricant and coating material, and the method comprises as mentioned above various preparation embodiments.

At pharmaceutical composition of the present invention particularly in some embodiments of tablet, the label of described tablet (being plain sheet) is by levetiracetam, disintegrating agent and binding agent three are mixed granulation, and then gained granule and fluidizer and lubricant are mixed together rear tabletting make.

At pharmaceutical composition of the present invention particularly in some embodiments of tablet, the label of described tablet (being plain sheet) is by levetiracetam, disintegrating agent and binding agent three are mixed granulation, and then gained granule and fluidizer and lubricant are mixed together rear tabletting make.The plain sheet that obtains thus can carry out coating further.

The method comprising the steps of:

Ii) with step I) compacting mixture that obtains pulverizes; With

Iv) to above step gained pharmaceutical composition for example tablet carry out coating and (for example will comprise hydroxypropyl emthylcellulose Suspension is sprayed to mixture that above step obtains for example on the tablet, to the gained pharmaceutical composition for example tablet carry out coating),

Perhaps, the method comprising the steps of:

Ii) add lubricant;

Iv) compacting is at step I ii) in the mixture (becoming block) that obtains;

Perhaps, the method comprising the steps of:

Perhaps, the method comprising the steps of:

The coating material of preferred 2.0% to 5.0% weight The more preferably coating material of 2.5% to 4.5% weight The method comprising the steps of:

Ii) with step I) compacting mixture that obtains pulverizes; With

Perhaps, the method comprising the steps of:

Ii) add lubricant;

Iv) compacting is at step I ii) in the mixture (becoming block) that obtains;

Perhaps, the method comprising the steps of:

Perhaps, the method comprising the steps of:

The invention further relates to the method for making pharmaceutical composition, this pharmaceutical composition comprise the levetiracetam of common, specific, preferred, preferred and most preferred percetage by weight, as defined above be fit to these pharmaceutical compositions cross-linked carboxymethyl cellulose sodium, silicon dioxide, PVP K30, magnesium stearate and

The method comprises the step that defines in as above each method.

The present invention relates in yet another aspect be used for the treatment of and prophylactic pharmaceutical composition, this pharmaceutical composition comprises

Levetiracetam	500 weight portions,
		Disintegrating agent	The 10-50 weight portion,
Binding agent	The 2-10 weight portion,
		Fluidizer	The 1-5 weight portion,
Lubricant	The 1-5 weight portion.

And optional, with respect to the coating material of pharmaceutical composition gross weight 1.0% to 6.0% weight

The coating material of preferred 2.0% to 5.0% weight

The more preferably coating material of 2.5% to 4.5% weight

In the present invention, the active component levetiracetam has following chemical structural formula:

The pharmaceutical composition tablet particularly according to the present invention, its label (for uncoated tablets, refers to whole; For coated tablet, refer to strike off fully the slice, thin piece inner core that the clothing layer obtains) measure loss on drying (105 ° of C are dried to constant weight) after grinding and be lower than 5%, particularly be lower than 3%.

The present invention unexpectedly finds, the tablet label that the present composition is prepared into, has beat all advantage, and these labels can be selected all multiple coating materials, for example can film coating, for example the material of this film-coat can (wherein can add an amount of polyvinyl alcohol, for example commercial prod take hydroxypropyl emthylcellulose as main component

Series), certainly, for the object of the invention, also can use other coating material, for example the coating material take ethyl cellulose as main component.Therefore, for the object of the invention, can be not the coating material of the present composition be construed as limiting.

In addition, beat all discovery, the pharmaceutical composition that the present invention obtains, wherein do not comprise coating described pharmaceutical composition (for example face granular material before the tabletting, not coating plain sheet or through the label of coating) have a contact angle of 55 ~ 95 °, for example hereinafter the tablet (plain sheet or label) that obtains of each embodiment has 60 ~ 85 ° contact angle, and for example embodiment 1,3 contact angle are respectively 77 ° and 71 °; And hereinafter tablet (plain sheet or the label) contact angle that obtains of each comparative example less than 55 ° or greater than 90 °.Contact angle refers to the contact angle with water.Particularly, contact angle refers to drip the angle that contacts with the compositions surface in the water droplet on the solid preparation compositions surfaces such as tablet.Those skilled in the art know the method and apparatus that many mensuration contact angles are arranged, and in the present invention, an exemplary assay method is as follows: (for example model is SNSO52/026 at syringe needle; HAMILTON company produces, stainless steel, internal diameter 0.26mm, external diameter 0.52mm; Perhaps also available syringe needle with similar specification) needle point forms 1 μ l pure water (MILLI-Q; MILLIPORE company) drop is again by contact angle determination device (OCA-15 type for example, Data physics company; The contact angle determination device that perhaps has other brand or the model of similar functions) measures contact angle after water droplet is added to 60 milliseconds of tablet surface.When tablet surface has curvature, measure again contact angle after when resolving, will proofreading and correct as straight line; Normally measure under the room temperature.In the present invention, such as not in addition explanation, contact angle of the present invention is measured by following methods: at room temperature, and at syringe needle (SNSO52/026; HAMILTON company produces, stainless steel, internal diameter 0.26mm, external diameter 0.52mm) needle point form 1 μ l pure water (MILLI-Q; MILLIPORE company) drop is measured contact angle after water droplet is added to 60 milliseconds of tablet surface by contact angle determination device (OCA-15 type, Data physics company) again.Owing to measure the contact angle that obtains with above-mentioned conditions of similarity, at varying environment (for example different experiments chamber), distinct device (the contact angle determination device that for example uses other company to produce), these results do not have obvious difference, therefore when the contact angle of definition compositions of the present invention, need not concrete mensuration process and the condition determination of contact angle are construed as limiting.For the solid preparation that is not tablet, such as capsule, granule, powder etc., powder that can be by will containing in the preparation, granule, semi-solid material etc. are pressed into figure of tablet, measure again, for example for capsule, can be by taking out capsule 's content, get wherein that about 200mg is pressed into having an even surface of diameter 8mm, thickness 3.5mm and smooth tablet is measured contact angle.Even for the tablet that can not effectively reflect its real property, the tablet of film coating, enteric coating or sugar-coat for example, also can be by the clothing layer on the tablet surface be scraped off, and then tablet ground, refer again to the mode of above-mentioned capsule, tablet is ground measure again after the gained powder is suppressed in flakes again.For the present composition, it is not suppressed when in blocks in preparation, can get an amount of compacting of powder laggard row in blocks and measure; It can directly be measured when being prepared into the plain sheet of coating not; It, can scrape off the clothing layer on the tablet surface when making coated tablet coated, and then tablet is ground, and measures after the gained powder being suppressed again in flakes again.

Via term " disease ", we understand disease and are selected from: cause Epileptic disease (perhaps can be understood as epilepsy), the epilepsy disease, faint from fear, parkinson, the dyskinesia that is brought out by the dopamine replacement therapy, by using the stable drug-induced tardive dyskinesia of class, Huntington Chorea and other neurological disorder comprise bipolar disorder, manic, depressed, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, trigeminal neuralgia and other neuralgias, chronic pain, neuropathic pain, cerebral ischaemia, arrhythmia, myotonia, cocaine abuse, apoplexy, myoclonus, tremble, essential tremor, simple type or complexity are twitched, tourette syndrome, restless leg syndrome and other movement disorder, neonatal apoplexy, amyotrophic lateral sclerosis, spasticity and degenerative disease, bronchial asthma, status asthmaticus and allergic bronchitis, Asthma Syndrome, bronchial hyperreactivity and bronchospasticsyndromes and anaphylaxis and vasomotor rhinitis and nose conjunctivitis (rhinoconj unctivitis).

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

The effectiveness that refers to treat the symptom that obstacle or disease showing effect via term " healing ".

Refer to that via " preventative " obstacle or disease occur or the prevention of recurrence.

The invention still further relates to by using the method for medicine composite for curing human patients.

The invention still further relates to the pharmaceutical composition as the medicament of curing above-mentioned disease.

The invention still further relates to the pharmaceutical composition preparation is used for the treatment of the medicament of application in above-mentioned disease purposes.

Preferably, above-mentioned disease is selected from: cause Epileptic disease, parkinson, the dyskinesia, migraine, tremble, essential tremor, bipolar disorder, chronic pain, neuropathic pain or bronchus, asthma or irritated disease.More preferably above-mentioned disease is epilepsy.

The invention still further relates to preparation is used for the treatment of the medicament of application in above-mentioned disease method, it is characterized in that using according to pharmaceutical composition of the present invention.

The invention still further relates to the method for by the drug administration compositions mankind being treated to alleviate disease.

The specific embodiment

The following examples that provide only are used for task of explanation rather than are used for, and also should not be interpreted as limiting by any way the present invention.Those skilled in the art will recognize that in the situation that does not surmount the spirit or scope of the present invention can make conventional the variation and modification to following examples.Below the tablet of each embodiment and comparative example compacting, such as in addition explanation, tablet is all suppressed (the oval shallow concave punch that uses the suitable heavily about 500 ~ 550mg of sheet) with the tablet machine of same model.And various tablets are in when compacting, the hardness of tablet all is controlled at 5-6kgf (namely (uses the tablet hardness tester mensuration tablet hardness of same model) in 49 ~ 59N) the scope.Below in the example of preparation compositions, such as not in addition explanation, with for example amount preparation of (sheet) of 50,000 unit formulations that feeds intake, every contains active component is 500mg.Below in the example of preparation compositions, such as not in addition explanation, various materials are all pulverized before use and can be by 80 mesh sieves.Below in the example of preparation compositions, wet granulation in this way, such as in addition explanation, binding agent is that water or 0 ~ 85% ethanol are mixed with 8% solution and use.

Embodiment

Embodiment 1: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Opadry is mixed with 14% aqueous suspensions and uses, 3% expression is because coating makes weight (being drying material weight) that tablet increases with respect to the percent of pharmaceutical composition gross weight behind the coating in the prescription, and preparing below in the embodiment of compositions and the comparative example all has identical meanings.

Method for making:

The method comprising the steps of:

Ii) with step I) compacting mixture that obtains pulverizes; With

Iii) to step I i) add lubricant in the gained crushed mixture, mix homogeneously becomes medicinal composition tablets of the present invention with its compressed shape, and it can be called label or plain sheet;

Iv) above step gained tablet is carried out coating, obtain medicinal composition tablets of the present invention, it is coated tablet.

Embodiment 2: prepare pharmaceutical composition of the present invention (tablet)

Prescription: with embodiment 1.

Method for making:

Ii) add lubricant;

Iv) compacting is at step I ii) in the mixture (becoming block) that obtains;

Vi) mixture compression step v) forms medicinal composition tablets of the present invention, and it can be called label or plain sheet;

Vii) above step gained tablet is carried out coating, obtain medicinal composition tablets of the present invention, it is coated tablet.

Embodiment 3: prepare pharmaceutical composition of the present invention (tablet)

Prescription: with embodiment 1.

Method for making:

I) levetiracetam, disintegrating agent, fluidizer are fully mixed, with 50% ethanol binder solution is made in the binding agent dissolving, with this binder solution soft material processed, wet granular processed, dry (measure loss on drying to dried granule under 105 ° of C and be lower than 3%) gets dried granule;

Ii) to step I) add lubricant in the gained crushed mixture, mix homogeneously becomes medicinal composition tablets of the present invention with its compressed shape, and it can be called label or plain sheet;

Iii) above step gained tablet is carried out coating, obtain medicinal composition tablets of the present invention, it is coated tablet.

Embodiment 4: prepare pharmaceutical composition of the present invention (tablet)

Prescription: with embodiment 1.

Method for making:

I) levetiracetam, disintegrating agent are fully mixed, water is made binder solution with the binding agent dissolving, and with this binder solution soft material processed, wet granular processed, dry (measure loss on drying to dried granule under 105 ° of C and be lower than 3%) gets dried granule;

Ii) to step I) add fluidizer and lubricant in the gained crushed mixture, mix homogeneously becomes medicinal composition tablets of the present invention with its compressed shape, and it can be called label or plain sheet;

Embodiment 5: prepare pharmaceutical composition of the present invention (tablet)

Prescription: with embodiment 1.

Method for making:

I) levetiracetam, disintegrating agent are fully mixed, with 50% ethanol binder solution is made in the binding agent dissolving, with this binder solution soft material processed, wet granular processed, dry (measure loss on drying to dried granule under 105 ° of C and be lower than 3%) gets dried granule;

Embodiment 6: prepare pharmaceutical composition of the present invention (tablet)

Prescription: with embodiment 1.

Method for making:

I) levetiracetam, disintegrating agent are fully mixed, with 85% ethanol binder solution is made in the binding agent dissolving, with this binder solution soft material processed, wet granular processed, dry (measure loss on drying to dried granule under 105 ° of C and be lower than 3%) gets dried granule;

Embodiment 7: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Method for making: the method according to embodiment 2 is carried out.

Embodiment 8: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Method for making: the method according to embodiment 4 is carried out.

Embodiment 9: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Method for making: the method according to embodiment 6 is carried out.

Embodiment 10: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Method for making: the method according to embodiment 2 is carried out.

Embodiment 11: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Method for making: the method according to embodiment 4 is carried out.

Embodiment 12: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Method for making: the method according to embodiment 6 is carried out.

Embodiment 13: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Method for making: the method according to embodiment 4 is carried out.

Embodiment 14: prepare pharmaceutical composition of the present invention (tablet)

Prescription:

Method for making: the method according to embodiment 4 is carried out.

Comparative example 1:Every tablet recipe amount: levetiracetam 500mg, cross-linking sodium carboxymethyl cellulose 21.50mg, polyethylene glycol 6000 be 5.00mg, colloidal silica anhydrous 10.375mg, magnesium stearate 0.625mg,

Be 16.125mg.Method for making: with embodiment 2.

Comparative example 2:Prescription is with comparative example 1.Method for making: with embodiment 4.

Comparative example 3:Prescription is with comparative example 1.Method for making: with embodiment 6.

Comparative example 4:It is basically identical with embodiment 1 to write out a prescription, but cross-linked carboxymethyl cellulose sodium is wherein replaced with sodium starch glycolate.Method for making: with embodiment 2.

Comparative example 5:Prescription is with comparative example 4.Method for making: with embodiment 4.

Comparative example 6:It is basically identical with embodiment 1 to write out a prescription, but PVP K30 is wherein replaced with 30 POVIDONE K 30 BP/USP 15.Method for making: with embodiment 2.

Comparative example 7:Prescription is with comparative example 6.Method for making: with embodiment 4.

Comparative example 8:It is basically identical with embodiment 1 to write out a prescription, but PVP K30 is wherein replaced with 30 POVIDONE K 30 BP/USP 60.Method for making: with embodiment 2.

Comparative example 9:Prescription is with comparative example 8.Method for making: with embodiment 4.

Comparative example 10:Except the consumption of disintegrating agent changes into 50 weight portions, prescription and method for making are with embodiment 4.

Comparative example 11:Except the consumption of disintegrating agent changes into 5 weight portions, prescription and method for making are with embodiment 4.

Comparative example 12:Except the consumption of binding agent changes into 10 weight portions, prescription and method for making are with embodiment 4.

Comparative example 13:Except the consumption of binding agent changes into 1 weight portion, prescription and method for making are with embodiment 4.

Comparative example 14:Except the consumption of fluidizer changes into 8 weight portions, prescription and method for making are with embodiment 4.

Test example 1: the friability of tablet

Get the above tablet (all getting the not plain sheet of coating) of embodiment and comparative example preparation, check their friability.Carry out according to the method under " tablet friability inspection technique " item among two appendix XG of Pharmacopoeia of the People's Republic of China version in 2010, calculating subtracts weight loss (%), and whether the observation tablet has the abnormal conditions such as fracture, be full of cracks and/or pulverizing.

The result shows, each sample of each embodiment subtracts weight loss (%) all between 0.15% ~ 0.5%, there are no abnormal conditions such as fracture, be full of cracks and/or pulverizing, for example the weight loss (%) that subtracts of embodiment 1,2,4,6 each sample is respectively 0.33%, 0.16%, 0.42%, 0.27%.The sample of each comparative example subtracts weight loss (%) all between 1.1% ~ 1.8%, and some sample has the abnormal conditions such as fracture, be full of cracks and/or pulverizing.For example comparative example 2,3,5,7,9, each sample of 13 subtract weight loss (%) all between 1.2% ~ 1.5%, and reference examples 2,5, each sample of 7 have the abnormal conditions such as fracture, be full of cracks and/or pulverizing.

Test example 2: coated tablet Performance

(tablet surface is normal with the coated tablet of above embodiment and comparative example preparation, the clothing layer is flawless), at least 250 on each sample places 55 ℃ of temperature, relative humidity to place 30 days for 75% time, and whether tablet surface clothing layer slight crack occurred after observation was disposed 30 days thus.Calculate every Lot sample slight crack rate (being the percent that slight crack occurs, is sheet number that slight crack occurs is counted gained divided by the used total sheet of test percent).The result shows, the sample slight crack rate of each embodiment is all between 1 ~ 5%, and for example embodiment 1,4,6,9 slight crack rate are respectively 3.7%, 2.1%, 3.4%, 1.4%; And the sample slight crack rate of each comparative example is all between 8 ~ 17%, and for example comparative example 2,4,7,8,12 slight crack rate are respectively 13.3%, 12.1%, 8.8%, 10.5%.

Experimental example 3: the coated tablet stripping property is investigated

Dissolution determination method: Chinese Pharmacopoeia two appendix XC the second methods of version (oar method) in 2010, take water 900ml as dissolution medium, rotating speed is that per minute 50 turns, sampling in the time of 15 minutes, filter, measure stripping quantity according to following HPLC chromatographic condition with the HPLC method, calculate every stripping quantity.

HPLC chromatographic condition: chromatographic column: C18 post, column temperature: 25 ℃, the potassium dihydrogen phosphate of mobile phase: 0.25g/L (potassium hydroxide solution with 2% is regulated pH value 5)-methanol (90:10), flow velocity: 1ml/min, detector: UV detects (wavelength 210nm), system suitability: number of theoretical plate calculates by the levetiracetam peak should be not less than 3000.

Coated tablet with the preparation of above embodiment and comparative example, place temperature 50 C, relative humidity 75% lower seal to preserve 4 months, measure each sample in without above-mentioned high-temperature treatment situation 20 minutes stripping percent, measure in addition each sample at 20 minutes stripping percent in above-mentioned high-temperature treatment situation, calculating is dissolution percent change (%, 20 minutes stripping percent of high-temperature treatment sample is divided by multiply by 100% without 20 minutes stripping percent of high-temperature treatment sample again) behind high-temperature treatment.The result shows that the sample dissolution percent change of each embodiment is all between 93 ~ 98%; But the sample dissolution percent change that a plurality of comparative examples (comparative example 2 ~ 5, comparative example 7, comparative example 9 ~ 13) are arranged is all between 68 ~ 83%, and for example comparative example 2,3,5 sample dissolution percent change are respectively 73%, 81%, 79%.

More than by preferred embodiment of the present invention spirit of the present invention has been done to elaborate.It will be appreciated by those skilled in the art that every according to the technology of the present invention essence to any modification, equivalent variations and modification that above embodiment does, all drop in protection scope of the present invention.

Claims

1. pharmaceutical composition, it comprises: levetiracetam, disintegrating agent, binding agent, fluidizer, lubricant.

2. according to claim 1 pharmaceutical composition, it comprises:

3. pharmaceutical composition according to claim 1-2, wherein:

Described disintegrating agent is selected from: sodium starch glycolate and cross-linked carboxymethyl cellulose sodium;

Described fluidizer is selected from Pulvis Talci, starch, stearic acid and colloidal silica anhydrous;

Described binding agent is selected from polyvidone (being called again polyvinylpyrrolidone, referred to as PVP) and all size (for example K15, K25, K30, K60, K90), Polyethylene Glycol, microcrystalline Cellulose, sucrose, mannitol or Sorbitol; And/or

Described lubricant is selected from Pulvis Talci, magnesium stearate or calcium stearate.

4. pharmaceutical composition according to claim 1-3, comprising active component levetiracetam and the following composition for the active component of per 500 weight portions:

5. pharmaceutical composition according to claim 1-4, comprising

Micropowder silica gel The 2-5 weight portion, Magnesium stearate The 2-5 weight portion;

Perhaps, comprising

6. pharmaceutical composition according to claim 1-5 is characterized in that:

The summation of disintegrating agent, fluidizer, binding agent and the lubricant that wherein exists is less than or equal to 20% weight with respect to the gross weight of pharmaceutical composition, preferably is less than or equal to 15% weight, is more preferably less than or equals 10% weight; Preferably, exist the summation of cross-linked carboxymethyl cellulose sodium, micropowder silica gel, PVP K30 and magnesium stearate preferably to be less than or equal to 10% weight in the described pharmaceutical composition;

Perhaps, it is characterized in that:

It is not coating or with the tablet of coating material coating; Further, this pharmaceutical composition comprises the coating material with respect to pharmaceutical composition gross weight 1.0% to 6.0% weight, 2.0% to 5.0% weight, 2.5% to 4.5% weight; Further, coating material is selected from ethyl cellulose, hydroxypropyl emthylcellulose and methacrylic acid-alkyl acrylate copolymer; Further, coating material is the hydroxypropyl emthylcellulose aqueous dispersion; Further, coating material is It is the hydroxypropyl emthylcellulose aqueous dispersion; Further, coating material is selected from 85F20694,

85F32004,

85F23452,

85G60978 and 85F18422.

7. pharmaceutical composition according to claim 1-6, it comprises:

The coating material of preferred 2.0% to 5.0% weight

The more preferably coating material of 2.5% to 4.5% weight

Perhaps, it comprises:

The coating material of preferred 2.0% to 5.0% weight

The more preferably coating material of 2.5% to 4.5% weight

Perhaps, the summation of the cross-linked carboxymethyl cellulose sodium in comprising the pharmaceutical composition of levetiracetam, PVP K30, micropowder silica gel (being silicon dioxide), magnesium stearate and Opadry@preferably is less than or equal to 10% weight with respect to the gross weight of pharmaceutical composition.

8. the pharmaceutical composition of the preparation claim 1-7 method of tablet particularly, described pharmaceutical composition comprises

9. the pharmaceutical composition of the preparation claim 1-7 method of tablet particularly, described pharmaceutical composition comprises

The method comprising the steps of:

Ii) with step I) compacting mixture that obtains pulverizes; With

Perhaps, the method comprising the steps of:

Ii) add lubricant;

Iv) compacting is at step I ii) in the mixture (becoming block) that obtains;

Perhaps, the method comprising the steps of:

Perhaps, the method comprising the steps of:

10. the pharmaceutical composition of claim 1-7 is in the purposes that is selected from for the preparation for the treatment of or prevention in the medicine of following disease or disease: cause the Epileptic disease, the epilepsy disease, faint from fear, parkinson, the dyskinesia that is brought out by the dopamine replacement therapy, by using the stable drug-induced tardive dyskinesia of class, Huntington Chorea and other neurological disorder comprise bipolar disorder, manic, depressed, anxiety, attention deficit hyperactivity disorder (ADHD), migraine, trigeminal neuralgia and other neuralgias, chronic pain, neuropathic pain, cerebral ischaemia, arrhythmia, myotonia, cocaine abuse, apoplexy, myoclonus, tremble, essential tremor, simple type or complexity are twitched, tourette syndrome, restless leg syndrome and other movement disorder, neonatal apoplexy, amyotrophic lateral sclerosis, spasticity and degenerative disease, bronchial asthma, status asthmaticus and allergic bronchitis, Asthma Syndrome, bronchial hyperreactivity and bronchospastic syndromes and anaphylaxis and vasomotor rhinitis and nose conjunctivitis; Particularly in the purposes that is selected from for the preparation for the treatment of or prevention in the medicine of following disease or disease: epilepsy, parkinson, the dyskinesia, migraine, tremble, essential tremor, bipolar disorder, chronic pain, neuropathic pain or bronchus, asthma or irritated disease.