CN103142583A - Levetiracetam-containing pharmaceutical composition and preparation method thereof - Google Patents
Levetiracetam-containing pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN103142583A CN103142583A CN2011104041666A CN201110404166A CN103142583A CN 103142583 A CN103142583 A CN 103142583A CN 2011104041666 A CN2011104041666 A CN 2011104041666A CN 201110404166 A CN201110404166 A CN 201110404166A CN 103142583 A CN103142583 A CN 103142583A
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Abstract
The invention provides a levetiracetam-containing pharmaceutical composition and a preparation method thereof. The levetiracetam-containing pharmaceutical composition comprises, by weight, 74 to 95 parts of levetiracetam, 2.5 to 25 parts of lactose, 0.01 to 9.0 parts of a disintegrating agent, 0.5 to 10 parts of a binder, and 0 to 10 parts of a lubricant. Compared with the prior art, the levetiracetam-containing pharmaceutical composition has the advantages that a wet granulation technology is adopted; a tablet prepared from the levetiracetam-containing pharmaceutical composition has good hardness and friability and satisfies tablet hardness and friability requirements; and the tablet prepared from the levetiracetam-containing pharmaceutical composition has good dissolution characteristics and a high dissolution degree above 90% in 15 minutes after being stood for 6 months.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, in particular to a kind of pharmaceutical composition that contains levetiracetam and preparation method thereof.
Background technology
Levetiracetam (Levetiracetam) is a kind of antiepileptic of high-efficiency broad spectrum, by the development of Belgian UCB. S.A. (BE) Bruxelles Belgium, commodity are called Levetiracetam, at present in EMEA (EMEA) and FDA (FDA) registration, and have been applied to clinical.The levetiracetam mechanism of action is unique, and curative effect lasting time is long, and untoward reaction is less, and safety and better tolerance can be used for add-on, adjuvant drug or the single therapy of polytype epilepsy, and potential applicability in clinical practice is widely arranged.
The chemistry of levetiracetam is by name: (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide; It is English by name: (S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide; Its molecular formula is: C
8H
14N
2O
2, molecular weight is: 170.21, and structural formula is suc as formula shown in (I):
The common formulations of levetiracetam is tablet, conventional preparation method is dry granulation, for example, put down in writing the prescription of the thin membrane coated tablet that contains 250mg, 500mg or 1000mg levetiracetam in Rote Liste Service Gmbh " Rote Liste 2003; 2002, ECV-Editio Cantor, Aulendorf; Germany ", composition is corn starch, 30 POVIDONE K 30 BP/USP
30, hypromellose, Macrogol 4000, titanium dioxide in Pulvis Talci, colloid anhydride silica, magnesium stearate and coating.
But in the prior art, prepare the technical problem that has following two aspects in the pharmaceutical composition that contains levetiracetam:
(1) because levetiracetam is crystalline powder, poor fluidity, compressibility is relatively poor, and be that the dosage specification is larger, the adjuvant ratio that can add is little, therefore is difficult to carry out suitability for industrialized production by the granulating process beyond dry granulation, but dry granulation complex technical process, the influence factor is various, and particularly the compactibility of prepared granule and particle size distribution can produce great impact to product quality, are unfavorable for the quality control of industrialized great production.Above effects limit the application of levetiracetam.
(2) in the process of placing, the stripping kinetics of the active component in the levetiracetam preparation---levetiracetam changes along with passage of time, this may cause the stripping of active component levetiracetam slack-off, and the stability of preparation is reduced, and one of result that this stability reduces is that medicine was more early lost efficacy.
Chinese patent application CN 200680001279.9 (applicant UCB Pharma SA) discloses and has contained pharmaceutical composition of levetiracetam and preparation method thereof.Said composition comprises as the levetiracetam of active component with respect to disintegrating agent, the fluidizer of 0.0～3.0% weight, the binding agent of 0.5～6.0% weight and the lubricant of 0.0～1.0% weight of 2.0～9.0% weight of pharmaceutical composition gross weight, and uses the technique of dry granulation to be prepared.Although in this Chinese patent application, disclosed method has improved the dynamic (dynamical) stability of drug-eluting to a certain extent, the method for its use remains dry granulation.
In addition, this Chinese patent application also discloses the compositions by the technique preparation of wet granulation, it comprises the levetiracetam as active component, with be equivalent to the pharmaceutical composition gross weight: 17.3% corn starch, 2.2% polyvinylpyrrolidone, 1.2% colloidal silica anhydrous, 1.5% Pulvis Talci, 0.1% magnesium stearate, and 3.0%
Coating material.And prove by experiment by after storing 6 months after the levetiracetam compositions blister package of this wet granulation technology preparation under 40 ℃ and relative humidity are 75% condition, the obvious variation of its stripping kinetics, dissolution when being in particular in 15 minutes significantly reduces, therefore have unsettled defective, those skilled in the art's content disclosed according to this Chinese patent application can draw to draw a conclusion: wet granulation be not suitable for preparing stable, meet the pharmaceutical composition that contains levetiracetam that pharmaceutics requires.
Chinese patent application CN 200910236406 discloses pharmaceutical composition of a kind of levetiracetam and preparation method thereof, this invention is by adding mobility mobility and the compressibility of excipient to improve principal agent preferably, adopt direct compression process to make tablet, or make capsule with the direct completion method of powder.The method easily causes flying dust, and environmental pollution is large, to the healthy generation of operator serious threat; And pressed powder easily causes sliver, and gained tablet or capsule weight differential are larger.
In addition, this Chinese patent application by add mobility preferably excipient realize direct compression with mobility and the compressibility of improving principal agent, but when the levetiracetam specification is increased to 500mg/ sheet or 1000mg/ sheet, the ratio of the amount of addible adjuvant will obviously reduce, thereby make the drug flow variation, tablet weight variation increases, and easily causes the problems such as sliver, even can't realize direct powder compression; The method need be equipped with special-purpose equipment simultaneously, and production cost increases greatly.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of levetiracetam medicinal composition applicable to wet granulation and preparation method thereof.
Particularly, the invention provides:
(1) a kind of pharmaceutical composition that contains levetiracetam, it comprises: in weight portion,
Levetiracetam 74-95 part;
Lactose 2.5-25 part;
Disintegrating agent 0.01-9.0 part;
Binding agent 0.5-10 part; And
Lubricant 0-10 part.
(2) pharmaceutical composition described according to (1), wherein, the content of described lactose is the 4-10 weight portion.
(3) pharmaceutical composition described according to (1), wherein, the content of described lactose is the 6-8 weight portion.
(4) pharmaceutical composition described according to (1), wherein, described binding agent is selected from one or more in water, alcohols, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvidone, methylcellulose, sucrose solution and starch slurry.
(5) pharmaceutical composition described according to (4), wherein, described binding agent is hydroxypropyl emthylcellulose.
(6) pharmaceutical composition described according to (1), wherein, described disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose.
(7) pharmaceutical composition described according to (6), wherein, described disintegrating agent is cross-linking sodium carboxymethyl cellulose.
(8) pharmaceutical composition described according to (1), wherein, described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, Macrogol 4000, polyethylene glycol 6000 and micropowder silica gel.
(9) according to the described pharmaceutical composition of any one in (1)-(8), wherein, described pharmaceutical composition prepares by wet granulation.
(10) according to the described pharmaceutical composition of any one in (1)-(9), wherein, the dosage form of described pharmaceutical composition is tablet or capsule.
(11) a kind of method for preparing according to the described pharmaceutical composition of (1)-(10) any one, it comprises:
1) with the described filler of the described levetiracetam of formula ratio, formula ratio with after accounting for the described disintegrating agent mix homogeneously of x% of its formula ratio, add the described binding agent of formula ratio, granule processed is also dry; And
2) with step 1) the described mix lubricant of the described disintegrating agent of the dried granule of gained and (100-x) % that accounts for its formula ratio and optional formula ratio, make mixture;
Wherein, the numerical range of described x is 0-100.
(12) method described according to (11), wherein, described method also comprises:
3) with step 2) mixture of gained carries out tabletting, thereby obtains levetiracetam tablet.
(13) method described according to (12), wherein, described method also comprises:
4) with step 3) levetiracetam tablet of gained carries out coating, thereby obtains the levetiracetam coated tablet.
(14) method described according to (11), wherein, described method also comprises:
3 ') with step 2) mixture of gained incapsulates, thus obtain containing the capsule of levetiracetam.
Pharmaceutical composition of the present invention and preparation method thereof compared with prior art has the following advantages and good effect:
1. the formula of the pharmaceutical composition of levetiracetam provided by the invention, by selecting suitable supplementary material and proportioning, improved greatly the micromeritis character of mixed material, solved in the prior art and can't make the technical barrier that meets production requirement and have the levetiracetam tablet of stripping dynamic stability by wet granulation.
2. the lactose of amount ranges of the present invention has obviously improved the compressibility of material, can make the tablet by the present invention's preparation have outstanding hardness and friability, has simultaneously outstanding stripping, even after long-term the placement, the tablet prepared according to the present invention still has outstanding dissolution.
3. tablet prepared in accordance with the present invention has outstanding dissolution characteristic, even after long-term the placement, the tablet prepared according to the present invention still has stripping dynamic stability preferably, places after 6 months, and the dissolution in the time of 15 minutes is still more than 90%.
Description of drawings
Fig. 1 is the comparison diagram of sheet X and sheet A and the instant stripping kinetics (t=0) of sheet E after preparation;
Fig. 2 is that sheet X and sheet A and sheet E are at the comparison diagram of the preparation stripping kinetics of rear six months (t=6 month);
Fig. 3 is the comparison diagram of sheet Y and sheet B and the instant stripping kinetics (t=0) of sheet F after preparation;
Fig. 4 is that sheet Y and sheet B and sheet F are at the comparison diagram of the preparation stripping kinetics of rear six months (t=6 month);
Fig. 5 is the comparison diagram of sheet Z and sheet D and the instant stripping kinetics (t=0) of sheet H after preparation;
Fig. 6 is that sheet Z and sheet D and sheet H are at the comparison diagram of the preparation stripping kinetics of rear six months (t=6 month);
Fig. 7 is commercially available Levetiracetam
Blood drug level-the time plot of the sheet X of 250mg tablet and embodiment 5 in Beagle dog body.
The specific embodiment
The below description by the specific embodiment and the invention will be further described with reference to accompanying drawing, but this is not to be limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within the scope of the present invention.
Unless otherwise indicated, herein term " wet granulation " is to add binding agent to prepare the method for granule after powder mix homogeneously with medicine and adjuvant.
Term herein " filler " also claims diluent, and Main Function is the weight and volume of filling tablet, thereby is convenient to tabletting.
Term herein " disintegrating agent " is to make tablet split rapidly the material that is broken into fine particle in gastro-intestinal Fluid.
Term herein " lubricant " refers to the general name of the lubricant of fluidizer, antiplastering aid, narrow sense; Fluidizer is to reduce frictional force between granule, thereby improves the material of powder flowbility; Antiplastering aid is to prevent that supplementary material is adhered to the material of punch head surface; The lubricant of narrow sense refers to reduce the material of frictional force between tablet and punch die hole wall.
Term herein " binding agent " comprises the binding agent of wetting agent, narrow sense; The liquid that can the viscosity that drug powder itself is intrinsic brings out out is called wetting agent; The binding agent of narrow sense refers to stickum that drug powder is combined.
Term herein " low-substituted hydroxypropyl cellulose " is cellulosic hydroxypropyl ether compound (hydroxypropyl content is 7%～19%).
The object of the present invention is to provide a kind of compositions that contains levetiracetam, this pharmaceutical composition can be by being called the technique preparation of wet granulation on pharmaceutics.
The inventor finds by great many of experiments: by each component and content thereof in the pharmaceutical composition that changes levetiracetam, can improve the micromeritis character of mixed material and the compressibility of material, can't make the technical barrier that meets production requirement and have the levetiracetam tablet of stripping dynamic stability by wet granulation thereby solved in the prior art.Concrete technical scheme is as follows:
One aspect of the present invention provides a kind of pharmaceutical composition of levetiracetam, and wherein, described pharmaceutical composition comprises following weight portion
Levetiracetam 74-95 part,
Filler 2.5-25 part,
Disintegrating agent 0.01-9.0 part,
Binding agent 0.5-10 part, and
Lubricant 0-10 part.
Described pharmaceutical composition preferably contains the filler of 4-10 weight portion.Described pharmaceutical composition more preferably contains the filler of 6-8 weight portion.
Described filler can be selected from one or more in lactose, Icing Sugar, starch, pregelatinized Starch, microcrystalline Cellulose, inorganic calcium salt and mannitol.Described filler is preferably lactose.
Described binding agent can be selected from one or more in water, alcohols, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvidone, methylcellulose, sucrose solution and starch slurry.Described binding agent is preferably hydroxypropyl emthylcellulose.Described alcohols is preferably one or more in methanol, ethanol, isopropyl alcohol and/or propylene glycol.
One or more in the optional self-crosslinking sodium carboxymethyl cellulose of described disintegrating agent, carboxymethyl starch sodium, crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose.Described disintegrating agent is preferably cross-linking sodium carboxymethyl cellulose.
Described lubricant can be selected from one or more in magnesium stearate, Pulvis Talci, Macrogol 4000, polyethylene glycol 6000 and micropowder silica gel.
Preferably, described pharmaceutical composition prepares by wet granulation.
The dosage form of described pharmaceutical composition can comprise tablet or capsule.
Another aspect of the present invention provides the method for preparing described pharmaceutical composition, and it comprises:
1) with the filler of the levetiracetam of formula ratio, formula ratio with after accounting for the disintegrating agent mix homogeneously of x% of its formula ratio, add the binding agent of formula ratio, granule processed is also dry; And
2) with step 1) the described mix lubricant of the disintegrating agent of the dried granule of gained and (100-x) % that accounts for its formula ratio and optional formula ratio, make mixture;
Wherein, the numerical range of described x is 0-100.
In one embodiment of the invention, described method comprises:
1) after the disintegrating agent mix homogeneously with the filler of the levetiracetam of formula ratio, formula ratio, formula ratio, add the binding agent of formula ratio, granule processed is also dry; And
2) with step 1) the dried granule of gained and the mix lubricant of formula ratio, make mixture.(be x=100.)
In another embodiment of the invention, described method comprises:
1) after the filler mix homogeneously with the levetiracetam of formula ratio, formula ratio, add the binding agent of formula ratio, granule processed is also dry; And
2) with step 1) the dried granule of gained and the disintegrating agent of formula ratio and the mix lubricant of formula ratio, make mixture.(be x=0.)
In another embodiment of the invention, described method comprises:
1) with the filler of the levetiracetam of formula ratio, formula ratio, account for the disintegrating agent mix homogeneously of its formula ratio 5-95% after, add the binding agent of formula ratio, granule processed is also dry; And
2) with step 1) the dried granule of gained with account for the disintegrating agent of its formula ratio 95-5% and the mix lubricant of formula ratio, make mixture.
Preferably, described method also comprises: 3) with step 2) mixture of gained carries out tabletting, thereby obtains levetiracetam tablet.More preferably, described method also comprises: 4) with step 3) levetiracetam tablet of gained carries out coating, thereby obtains the levetiracetam coated tablet.
Preferably, described method also comprises: 3 ') with step 2) mixture of gained incapsulates, thus obtain containing the capsule of levetiracetam.
Below further explain and describe content of the present invention by example, but these examples are not to be construed as limiting the scope of the invention.
In following examples, levetiracetam used and various adjuvants etc. are known in the art, can be commercially available.For example, can adopt available from Shanghai Ka Lekang (Colorcon) company in coated tablet of the present invention
Coating materials also can adopt available from the beautiful TM coating materials of easily releasing of Tianjin Ai Leyi medical material Science and Technology Ltd.; Levetiracetam used in the present invention can be available from Shanghai Yaben Chemical Co., Ltd; Microcrystalline Cellulose can be available from Japanese Asahi Kasei Corporation; Lactose can be available from the abundant safe food additive company limited in Henan; Carboxymethyl starch sodium can be available from sweetening treatment company limited in Hangzhou; Magnesium stearate can be available from Zhengzhou blue space chemical industry company limited; Micropowder silica gel can be available from Zhengzhou Fu Run moral biological engineering company limited.
Embodiment 1 (levetiracetam tablet 250mg specification)
Prescription
| Levetiracetam | 250mg |
| Lactose | 84.5mg |
| Carboxymethyl starch sodium | 1.69 |
| 30 |
1.69mg |
Preparation method:
After levetiracetam and lactose mix homogeneously, adding concentration is the 30 POVIDONE K 30 BP/USP of 3% (mass percentage concentration)
30Alcoholic solution granule processed and dry; With gained granule and carboxymethyl starch sodium mix homogeneously, tabletting gets tablet.
Embodiment 2 (levetiracetam tablet 250mg specification)
Prescription
| Levetiracetam | 250mg |
| Lactose | 46.9mg |
| Crospolyvinylpyrrolidone | 6mg |
| Micropowder silica gel | 0.3mg |
| Hydroxypropyl cellulose | 9.1mg |
Preparation method:
After crospolyvinylpyrrolidone mix homogeneously with levetiracetam and lactose and 50% formula ratio, adding concentration is the alcoholic solution soft material processed of the hydroxypropyl cellulose of 3% (mass percentage concentration), the granulation of sieving, and drying gets granule; With tabletting after the crospolyvinylpyrrolidone of above-mentioned granule and surplus, micropowder silica gel mix homogeneously, get tablet.
Embodiment 3 (levetiracetam capsule 250mg specification)
Prescription
| Levetiracetam | 250mg |
| Lactose | 29.1mg |
| Low-substituted hydroxypropyl cellulose | 2.9mg |
| Pulvis Talci | 1.5mg |
| Sodium carboxymethyl cellulose | 7.5mg |
Preparation method:
After levetiracetam and lactose mix homogeneously, adding concentration is the aqueous solution soft material processed of the sodium carboxymethyl cellulose of 2% (mass percentage concentration), the granulation of sieving, and drying gets granule; Fill after above-mentioned granule and low-substituted hydroxypropyl cellulose, Pulvis Talci mix homogeneously to capsule, is got capsule.
Embodiment 4 (levetiracetam tablet 250mg specification)
Prescription
| Levetiracetam | 250mg |
| Lactose | 19.5mg |
| Cross-linking sodium carboxymethyl cellulose | 2.5mg |
| Carboxymethyl starch sodium | 1.2mg |
| Magnesium stearate | 0.6mg |
| Hypromellose | 4.2mg |
Preparation method:
After levetiracetam and lactose and cross-linking sodium carboxymethyl cellulose mix homogeneously, adding concentration is the alcoholic solution soft material processed of the hypromellose of 7% (mass percentage concentration), the granulation of sieving, and drying gets granule; With above-mentioned granule and carboxymethyl starch sodium and magnesium stearate mix homogeneously, tabletting gets tablet.
Embodiment 5 (sheet X, levetiracetam coated tablet 250mg specification)
Prescription
Preparation method:
Levetiracetam and lactose is slightly mixed, mixture is pulverized, sieve, adding concentration is the alcoholic solution soft material processed of the hypromellose of 8% (mass percentage concentration), the granulation of sieving, drying gets granule; With above-mentioned granule and cross-linking sodium carboxymethyl cellulose, magnesium stearate mix homogeneously, tabletting gets tablet, uses
Coating gets the levetiracetam coated tablet.
Embodiment 6 (sheet Y, levetiracetam coated tablet 500mg specification)
Prescription
Preparation method:
Levetiracetam and lactose and cross-linking sodium carboxymethyl cellulose is slightly mixed, mixture is pulverized, sieve, adding concentration is the alcoholic solution soft material processed of the hypromellose of 10% (mass percentage concentration), the granulation of sieving, drying gets granule; With above-mentioned granule and magnesium stearate mix homogeneously, tabletting gets tablet, uses
Coating gets the levetiracetam coated tablet.
Embodiment 7 (levetiracetam tablet 500mg specification)
Prescription
| Levetiracetam | 500mg |
| Lactose | 44.5mg |
| Carboxymethyl starch sodium | 5.9mg |
| Starch slurry | 5.6mg |
Preparation method:
The carboxymethyl starch sodium of levetiracetam and lactose and 50% formula ratio is slightly mixed, mixture is pulverized, sieve, adding concentration is the starch slurry soft material processed of 10% (mass percentage concentration), the granulation of sieving, drying gets granule; With the carboxymethyl starch sodium mix homogeneously of above-mentioned granule and surplus, tabletting gets tablet.
Embodiment 8 (levetiracetam tablet 500mg specification)
Prescription
| Levetiracetam | 500mg |
| Lactose | 26.6mg |
| Crospolyvinylpyrrolidone | 0.3mg |
| Macrogol 4000 | 0.3mg |
| Sucrose | 4.8mg |
Preparation method:
Levetiracetam and lactose and crospolyvinylpyrrolidone is slightly mixed, mixture is pulverized, sieve, adding concentration is the aqueous solution soft material processed of the sucrose of 8% (mass percentage concentration), the granulation of sieving, drying gets granule; With above-mentioned granule and Macrogol 4000 mix homogeneously, tabletting gets tablet.
Embodiment 9 (sheet Z, levetiracetam coated tablet 1000mg specification)
Prescription
| Levetiracetam | 1000mg |
| Lactose | 78mg |
| Cross-linking sodium carboxymethyl cellulose | 110mg |
| Magnesium stearate | 26mg |
| Hypromellose | 79mg |
| Easily release beautiful TM | 52mg |
Preparation method:
Levetiracetam and lactose is slightly mixed, mixture is pulverized, sieve, adding concentration is the aqueous solution soft material processed of the hypromellose of 5% (mass percentage concentration), the granulation of sieving, drying gets granule; With above-mentioned granule and cross-linking sodium carboxymethyl cellulose, magnesium stearate mix homogeneously, tabletting gets tablet, and is beautiful with easily releasing
TMCoating gets the levetiracetam coated tablet.
Embodiment 10 (levetiracetam tablet 1000mg specification)
Prescription
| Levetiracetam | 1000mg |
| Lactose | 27mg |
| Crospolyvinylpyrrolidone | 5.5mg |
| Magnesium stearate | 12mg |
| Methylcellulose | 11mg |
Preparation method:
Granulate: levetiracetam and lactose is slightly mixed, mixture is pulverized, sieve, adding concentration is the aqueous solution soft material processed of the methylcellulose of 5% (mass percentage concentration), the granulation of sieving, drying gets granule; With above-mentioned granule and crospolyvinylpyrrolidone, magnesium stearate mix homogeneously, tabletting gets tablet.
Embodiment 11 (levetiracetam tablet 1000mg specification)
Prescription
| Levetiracetam | 1000mg |
| Lactose | 100mg |
| Crospolyvinylpyrrolidone | 45mg |
| Polyethylene glycol 6000 | 128mg |
| Water | 58mg |
Preparation method:
Granulate: levetiracetam and lactose is slightly mixed, mixture is pulverized, sieve, add entry soft material processed, the granulation of sieving, drying gets granule; With above-mentioned granule and crospolyvinylpyrrolidone, polyethylene glycol 6000 mix homogeneously, tabletting gets tablet.
Comparative example 1
Prepare sheet E, F, H in sheet A, B, D and embodiment 2 in embodiment 1 by the described method of Chinese patent application 200680001279.9.
Test example 1 (dissolution determination)
Measure the dissolution of levetiracetam in sheet A, B, D and sheet E, F in tablet X, Y, Z and the comparative example 1 that the embodiment of the present invention 5,6,9 obtains respectively, H, all compositionss are at the preparation instant and preparation dissolution of rear 6 months afterwards.This six the middle of the month tablet be to preserve under 75% condition at 40 ± 2 ℃ and relative humidity.
Press the dissolution of Chinese Pharmacopoeia two appendix XC the second methods of version (slurry method) mensuration levetiracetam in 2010, liquor capacity is 900ml, and rotating speed is 50rpm, 37 ℃ of temperature.
Fig. 1 to Fig. 6 represents pharmaceutical composition prepared in accordance with the present invention, compares with the compositions of the described wet granulation preparation of Chinese patent application 200680001279.9, and the pharmaceutical composition of the present invention's preparation has better stripping dynamic stability; Compare with the compositions of the described dry granulation preparation of Chinese patent application 200680001279.9, the pharmaceutical composition of the present invention's preparation has similar stripping dynamic stability, the more important thing is that preparation process is simple, the influence factor is few, is beneficial to the quality control of the large production of commercialization.
Test example 2 (friability inspection)
According to 2010 editions two appendix of Chinese Pharmacopoeia measure the tablets of the embodiment of the present invention 1,2,4,7,8,10 preparations friability, and by the friability of the sheet A (not coating) of disclosed embodiment 1 preparation in Chinese patent application 200680001279.9, and by the friability of disclosed embodiment 1 in Chinese patent application 200910236406, the results are shown in Table 1.
Table 1 friability check result
| Friability (%) | |
| Embodiment 1 | 0.02 |
| Embodiment 2 | 0.03 |
| Embodiment 4 | 0.05 |
| Embodiment 7 | 0.04 |
| |
0.03 |
| |
0.03 |
| Embodiment 11 | 0.04 |
| Sheet A in Chinese patent application 200680001279.9 | 0.09 |
| In Chinese patent application 200910236406.9, embodiment 1 | 0.03 |
Result: pharmaceutical composition prepared in accordance with the present invention, to compare with the compositions of the described dry granulation preparation of Chinese patent application 200680001279.9, the friability of the pharmaceutical composition of the present invention's preparation is lower; Compare with the tablet of embodiment 1 in the Chinese patent application 200910236406.9 that adopts the direct powder compression preparation and have similar even lower less loss weight.
Test example 3 (blood drug level test in Beagle dog single-dose body)
As follows at Beagle dog drug disposition dynamic metabolism experimental technique: select 8 of healthy bull Beagle dogs, be divided at random two groups, 4 every group, the oral Levetiracetam of difference
The sheet X2 sheet that 2, tablet and the embodiment of the present invention 5 make.Behind interval 7 days, with the administration of same dose crossover.Carrying out blood drug level at official hour point (1 hour, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 hours, 72 hours) venous blood samples detects.Take the time as transverse axis, blood drug level is the longitudinal axis, draws blood drug level-time graph, as Fig. 7.
Although Fig. 7 can demonstrate two kinds of preparations adjuvant used clearly and preparation method is obviously different, two kinds of preparations blood drug level variation tendency along with passage of time in Beagle dog body is identical, the area under curve there was no significant difference.
Claims (14)
1. pharmaceutical composition that contains levetiracetam, it comprises: in weight portion,
Levetiracetam 74-95 part;
Lactose 2.5-25 part;
Disintegrating agent 0.01-9.0 part;
Binding agent 0.5-10 part; And
Lubricant 0-10 part.
2. pharmaceutical composition according to claim 1, wherein, the content of described lactose is the 4-10 weight portion.
3. pharmaceutical composition according to claim 1, wherein, the content of described lactose is the 6-8 weight portion.
4. pharmaceutical composition according to claim 1, wherein, described binding agent is selected from one or more in water, alcohols, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvidone, methylcellulose, sucrose solution and starch slurry.
5. pharmaceutical composition according to claim 4, wherein, described binding agent is hydroxypropyl emthylcellulose.
6. pharmaceutical composition according to claim 1, wherein, described disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose.
7. pharmaceutical composition according to claim 6, wherein, described disintegrating agent is cross-linking sodium carboxymethyl cellulose.
8. pharmaceutical composition according to claim 1, wherein, described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, Macrogol 4000, polyethylene glycol 6000 and micropowder silica gel.
9. the described pharmaceutical composition of any one according to claim 1-8, wherein, described pharmaceutical composition prepares by wet granulation.
10. the described pharmaceutical composition of any one according to claim 1-9, wherein, the dosage form of described pharmaceutical composition is tablet or capsule.
11. a method for preparing the described pharmaceutical composition of any one according to claim 1-10, it comprises:
1) with the described filler of the described levetiracetam of formula ratio, formula ratio with after accounting for the described disintegrating agent mix homogeneously of x% of its formula ratio, add the described binding agent of formula ratio, granule processed is also dry; And
2) with step 1) the described mix lubricant of the described disintegrating agent of the dried granule of gained and (100-x) % that accounts for its formula ratio and optional formula ratio, make mixture;
Wherein, the numerical range of described x is 0-100.
12. method according to claim 11, wherein, described method also comprises:
3) with step 2) mixture of gained carries out tabletting, thereby obtains levetiracetam tablet.
13. method according to claim 12, wherein, described method also comprises:
4) with step 3) levetiracetam tablet of gained carries out coating, thereby obtains the levetiracetam coated tablet.
14. method according to claim 11, wherein, described method also comprises:
3 ') with step 2) mixture of gained incapsulates, thus obtain containing the capsule of levetiracetam.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104041666A CN103142583A (en) | 2011-12-07 | 2011-12-07 | Levetiracetam-containing pharmaceutical composition and preparation method thereof |
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| CN104666263A (en) * | 2015-02-09 | 2015-06-03 | 海南华益泰康药业有限公司 | Tablet containing levetiracetam and preparation method of tablet |
| CN105434375A (en) * | 2014-05-30 | 2016-03-30 | 北大方正集团有限公司 | Levetiracetam tablet and preparation method thereof |
| JP2017206467A (en) * | 2016-05-19 | 2017-11-24 | エルメッド エーザイ株式会社 | Levetiracetam-containing pharmaceutical composition and method for producing the same, method for preventing delay of at least one of collapse and elution of levetiracetam-containing pharmaceutical composition, and agent for preventing delay of at least one of collapse and elution of levetiracetam-containing pharmaceutical composition |
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| CN105434375A (en) * | 2014-05-30 | 2016-03-30 | 北大方正集团有限公司 | Levetiracetam tablet and preparation method thereof |
| CN104666263A (en) * | 2015-02-09 | 2015-06-03 | 海南华益泰康药业有限公司 | Tablet containing levetiracetam and preparation method of tablet |
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| JP2017206467A (en) * | 2016-05-19 | 2017-11-24 | エルメッド エーザイ株式会社 | Levetiracetam-containing pharmaceutical composition and method for producing the same, method for preventing delay of at least one of collapse and elution of levetiracetam-containing pharmaceutical composition, and agent for preventing delay of at least one of collapse and elution of levetiracetam-containing pharmaceutical composition |
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