CN104042582A - Levetiracetam sustained-release agent composition and preparation method - Google Patents
Levetiracetam sustained-release agent composition and preparation method Download PDFInfo
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- CN104042582A CN104042582A CN201310085307.1A CN201310085307A CN104042582A CN 104042582 A CN104042582 A CN 104042582A CN 201310085307 A CN201310085307 A CN 201310085307A CN 104042582 A CN104042582 A CN 104042582A
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- levetiracetam
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Abstract
The invention provides a levetiracetam sustained-release agent composition which comprises levetiracetam which accounts for 50-88% of the total weight of the composition, a sustained-release material which accounts for 10-45% of the total weight of the composition, and a lubricant which accounts for 1.5-9% of the total weight of the composition. The sustained-release material is selected from ethyecellulose, stearic acid, hydrogenated castor oil, hydroxypropyl methylcellulose or a group formed by the above combination. The lubricant is selected from magnesium stearate, aerosil, talcum powder or a group formed by the above combination. The invention also provides a method for preparing the levetiracetam sustained-release agent composition. The composition has a simple formula. Addition of auxiliary materials such as a filler, a disintegrating agent and the like that are needed in production of conventional preparations is not required. A sustained-release preparation which has advantages of stable curative effect, lasting effect and convenient administration is provided for clinic. In comparison with the prior art, the invention provides a simple and effective production method of levetiracetam sustained-release tablets. The preparation technology is very simple and easy for enlargement.
Description
Technical field
The present invention relates to levetiracetam slow release agent composition and method of making the same.
Background technology
Levetiracetam (levetiracetam) is a kind of pyrrolidinone derivatives, and its chemical name is (-)-(S)-2-ethyl-2-oxo-1-pyrrolidine acetamide, and molecular formula is C
8h
14n
2o
2, molecular weight is 170.21.Character is white to light yellow crystalline powder, and water solubility is 104mg/ml.It is easily molten in chloroform (65.3g/100ml) and methanol (53.6g/100ml), solvable in ethanol (16.5g/100ml), slightly soluble in acetonitrile (5.7g/100ml) and dissolving hardly in normal hexane.Structure expression is as follows:
Levetiracetam is combined the exploitation of chemical industry (UCB) company limited by Belgium, external, in vivo test shows, levetiracetam suppresses Hippocampal epilepsy sample burst electric discharge, and on normal neuronal excitability without impact, prompting levetiracetam may optionally suppress the supersynchronous property of epileptic burst electric discharge and the propagation of epilepsy.Sold (trade name Keppra) in 1999 by U.S. FDA approval, at first for the partial seizures of being grown up, ratified again its oral tablet and the solution auxiliary treatment for 4 years old or above child's partial seizures in 2005.Levetiracetam is very easily in dissolving and having high osmosis compound, is linear metabolism, individual in and interindividual variation little; Multiple dosing does not affect its clearance rate, and asexuality, race and circadian rhythm difference.After levetiracetam oral administration, absorb rapidly, oral absolute bioavailability approaches 100%, is difficult for being combined with plasma protein (<10%).After oral administration, 1.3 hours post sales blood drug level reach maximum, soak time and dosage indifference, pickuping food does not affect infiltration rate.In levetiracetam clinical treatment, modal untoward reaction has drowsinessly, weak and dizzy, often occurs in incipient stage for the treatment of.Pass in time, the adverse reaction rate that central nervous system is relevant and the order of severity can decrease, and untoward reaction and dosage do not have obvious dependency.
Levetiracetam is described in patent EP0162036, US4696942 and US6107492 at first.The patent CN200680001279.9 of UCB Pharma SA's application discloses and has contained pharmaceutical composition of levetiracetam and preparation method thereof.Said composition comprises as the levetiracetam of active component with respect to the disintegrating agent of 2.0 to 9.0% weight of pharmaceutical composition gross weight, fluidizer, the binding agent of 0.5% to 6.0% weight and the lubricant of 0.0 to 1.0% weight of 0.0 to 3.0% weight, and preparation method thereof.
But, levetiracetam drug dose is larger, consider that the compliance in clinical use is subject to sheet shape and the heavy impact of sheet, the adjuvant amount that can use in tablet is limited, the use amount that levetiracetam slow release agent compositions provided by the invention can effectively reduce adjuvant ensures that levetiracetam granule has good mechanical compressibility simultaneously, utilize existing production equipment can meet Production requirement, be beneficial to industrialization promotion.
Summary of the invention
The present invention relates to levetiracetam slow release agent compositions and prepare the method for levetiracetam sustained-release tablets, the tablet that production obtains evenly slow release, to gastrointestinal tract, is the clinical slow releasing preparation that a kind of stable curative effect is provided, acts on lasting and convenient drug administration.Levetiracetam is mixed homogeneously with slow-release material, and levetiracetam can evenly be wrapped up by slow-release material, is attached on the skeleton of slow-release material, by selecting the rate of release of framework ingredient control levetiracetam, reaches the slow release effect of expection.
One aspect of the present invention provides a kind of levetiracetam slow release agent compositions, and described compositions comprises:
Account for the levetiracetam of described composition total weight 50-88%;
Account for the slow-release material of described composition total weight 10-45%, described slow-release material selects the group of free ethyl cellulose, stearic acid, castor oil hydrogenated, hypromellose or combinations thereof; And
Account for the lubricant of the 1.5-9% of described composition total weight, described lubricant selects the group of free magnesium stearate, micropowder silica gel, Pulvis Talci or combinations thereof.
In some embodiments, slow-release material is selected from ethyl cellulose or castor oil hydrogenated.
In some embodiments, lubricant is magnesium stearate.
In some embodiments, compositions of the present invention comprises:
Account for the levetiracetam of the 65-75% of described composition weight;
Account for the slow-release material of the 18-30% of described composition weight; And
Account for the lubricant of the 2-8% of described composition weight.
In some embodiments, compositions of the present invention comprises:
Account for the levetiracetam of the 70-75% of described composition weight;
Account for the slow-release material of the 20-26% of described composition weight; And
Account for the lubricant of the 3-6% of described composition weight.
In some embodiments, compositions of the present invention comprises:
Account for the levetiracetam of the 68-75% of described composition weight;
Account for the ethyl cellulose of the 18-25% of described composition weight; And
Account for the 2-8% magnesium stearate of described composition weight.
In some embodiments, compositions of the present invention comprises:
Account for 65% to 75% levetiracetam of described composition weight;
Account for 22% to 32% stearic acid of described composition weight; And
Account for 2% to 9% magnesium stearate of described composition weight.
In some embodiments, compositions of the present invention comprises:
Account for 65% to 75% levetiracetam of described composition weight;
Account for 20% to 32% castor oil hydrogenated of described composition weight; And
Account for 2% to 8% magnesium stearate of described composition weight.
Another aspect of the present invention provides a kind of method of preparing levetiracetam slow release agent compositions, said method comprising the steps of:
(1) by slow-release material melting or dissolving, and the slow-release material of melting or dissolving is mixed homogeneously with levetiracetam, obtain homogeneous mixture;
(2) described mixture is made to soft material, described soft material is sieved and dried, obtain the granule of described mixture;
(3) described granule evenly mixed and suppressed with lubricant, obtaining described compositions,
Wherein, levetiracetam accounts for the 50-88% of described composition weight; Described slow-release material accounts for the 10-45% of described composition weight, and described slow-release material selects group or its combination of free ethyl cellulose, stearic acid, castor oil hydrogenated, hypromellose composition; Described lubricant accounts for the 1.5-9% of described composition weight, and described lubricant is selected from group or its combination of magnesium stearate, micropowder silica gel, Pulvis Talci composition.
In some embodiments, be heating and melting by the method for slow-release material liquefaction.
In some embodiments, the solvent of the solution of slow-release material is ethanol.
In some embodiments, solvent is dehydrated alcohol.
In some embodiments, the melt temperature of slow-release material is not for higher than 120 DEG C.
Compared with prior art, prescription used is simple for compositions of the present invention, without adding required filler in conventional formulation production, the adjuvants such as disintegrating agent; Preparation technology is very simple and be easy to amplify; Because preparation specification (1.0g/ sheet) is larger, reduce to greatest extent tablet size, improve compliance.In addition, compared with prior art, the invention provides a kind of simple and effective levetiracetam sustained-release tablets production method.
Brief description of the drawings
Fig. 1 be the embodiment of the present invention 2 under USPII, 100rpm and 37 DEG C of conditions, the drug release characteristics figure in the 0.1Mol/L hydrochloric acid of described slow releasing tablet;
Fig. 2 is commercially available slow releasing tablet and the blood plasma level Characteristic Contrast figure of embodiment 2 in beasle dog (beagle).
Detailed description of the invention
The levetiracetam of mentioning in the present invention refers to (-)-(S)-2-ethyl-2-oxo-1-pyrrolidine acetamide.
The slow-release material of mentioning in the present invention is mainly ethyl cellulose, stearic acid, castor oil hydrogenated, hypromellose or their combination.Preferably, slow-release material is selected from ethyl cellulose or castor oil hydrogenated.
The lubricant of mentioning in the present invention is mainly magnesium stearate, micropowder silica gel, Pulvis Talci or its their combination.Preferably, lubricant is magnesium stearate.
Levetiracetam slow release agent compositions of the present invention does not need to comprise disintegrating agent.
More than 35-55%, 55-70% and 85% that the release of levetiracetam sustained-release tablets vitro release of the present invention 2 hours, 6 hours and 12 hours is labelled amount.In compositions, in the time that slow-release material is excessive, the release of levetiracetam is slow, within first 2 hours, discharges lower than 30%, cannot meet clinical application demand.
Carry out animal drugs for test for levetiracetam sustained-release tablets of the present invention: 6 of beasle dogs, average body quality (9.0 ± 0.8) Kg, this test adopts the random trial design of binary cycle, and be spaced apart 7 days two cycle times.6 beasle dogs are divided into 2 groups at random, and fasting is subject to respectively test preparation and reference preparation after 12 hours.Before administration after (0h) and administration 0.25,0.5,0.75,1.0,2.0,3.0,4.0,6.0,8.0,24.0,48.0h is by back leg small saphenous vein blood sampling 1ml.Adopt LC-MS/MS to detect.Animal drugs proves for test data: levetiracetam sustained-release tablets of the present invention has excellent slow release effect.
Following lifted illustrative embodiment, only in order to illustrate, does not cause restriction to the present invention.Therefore, protection scope of the present invention is not limit by following examples, is only as the criterion with the scope of appending claims.
The preparation of embodiment 1 levetiracetam sustained-release tablets
Table 1 levetiracetam sustained-release tablets (100) formula
| Composition | Dosage (100) |
| Levetiracetam | 100.0g |
| Ethyl cellulose | 15.0g |
| Magnesium stearate | 1.0g |
| Silicon dioxide | 1.5g |
| Ethanol | In right amount |
Preparation method: first take ethyl cellulose 15g, add appropriate dissolve with ethanol, add recipe quantity levetiracetam, stir and granulate, 50 DEG C of oven dry, and be cooled to room temperature, cross 30 mesh sieves, add lubricant, tabletting and get final product.
The preparation of embodiment 2 levetiracetam sustained-release tablets
Table 2 levetiracetam sustained-release tablets (100) formula
| Composition | Dosage (100) |
| Levetiracetam | 100.0g |
| Castor oil hydrogenated | 25.0g |
| Magnesium stearate | 2.0g |
| Silicon dioxide | 1.5g |
Preparation method: first take castor oil hydrogenated 25.0g, be heated to 60 DEG C, and continue to stir and make melting, add recipe quantity levetiracetam, stir and be cooled to room temperature, cross 30 mesh sieves, add lubricant, tabletting and get final product.
Embodiment 3 drug release determinations
Measure levetiracetam sustained-release tablets prepared by the invention process row 2 according to drug release determination method (Chinese Pharmacopoeia 2010 editions), respectively taking 1000ml0.1mol/L hydrochloric acid solution, pH6.8 phosphate buffer solution, pH4.5 hac buffer and water as medium, rotating speed is per minute 100 to turn, sample at regular intervals 10ml, filter, get subsequent filtrate 5ml, directly detect by high performance liquid chromatography.Separately get commercially available slow releasing tablet, be measured in the same method.The drug release determination data of the levetiracetam sustained-release tablets of embodiment 2 are in table 3, and release profiles is shown in Fig. 1.Levetiracetam sustained-release tablets is in USP device II under 100rpm, and in 0.1MHCL, 37 DEG C have following stripping feature:
The release of table 3 levetiracetam sustained-release tablets
| Time (hour) | The average release (%) of levetiracetam |
| 2 | <40 |
| 5 | 40-60 |
| 12 | >80 |
Claims (13)
1. a levetiracetam slow release agent compositions, is characterized in that described compositions comprises:
Account for the levetiracetam of described composition total weight 50-88%;
Account for the slow-release material of described composition total weight 10-45%, described slow-release material is selected from the group of ethyl cellulose, stearic acid, castor oil hydrogenated, hypromellose or combinations thereof; And
Account for the lubricant of the 1.5-9% of described composition total weight, described lubricant is selected from the group of magnesium stearate, micropowder silica gel, Pulvis Talci or combinations thereof.
2. levetiracetam slow release agent as claimed in claim 1, is characterized in that described slow-release material is selected from ethyl cellulose or castor oil hydrogenated.
3. levetiracetam slow release agent as claimed in claim 1, is characterized in that described lubricant is magnesium stearate.
4. compositions as claimed in claim 1, is characterized in that described compositions comprises:
Account for the levetiracetam of the 65-75% of described composition weight;
Account for the slow-release material of the 18-30% of described composition weight; And
Account for the lubricant of the 2-8% of described composition weight.
5. compositions as claimed in claim 2, is characterized in that described compositions comprises:
Account for the levetiracetam of the 70-75% of described composition weight;
Account for the slow-release material of the 20-26% of described composition weight; And
Account for the lubricant of the 3-6% of described composition weight.
6. compositions as claimed in claim 1, is characterized in that described compositions comprises:
Account for the levetiracetam of the 68-75% of described composition weight;
Account for the ethyl cellulose of the 18-25% of described composition weight; And
Account for the 2-8% magnesium stearate of described composition weight.
7. compositions as claimed in claim 1, is characterized in that described compositions comprises:
Account for 65% to 75% levetiracetam of described composition weight;
Account for 22% to 32% stearic acid of described composition weight; And
Account for 2% to 9% magnesium stearate of described composition weight.
8. compositions as claimed in claim 1, is characterized in that described compositions comprises:
Account for 65% to 75% levetiracetam of described composition weight;
Account for 20% to 32% castor oil hydrogenated of described composition weight; And
Account for 2% to 8% magnesium stearate of described composition weight.
9. a method of preparing levetiracetam slow release agent compositions, said method comprising the steps of:
(1) by slow-release material melting or dissolving, and the slow-release material of melting or dissolving is mixed homogeneously with levetiracetam, obtain homogeneous mixture;
(2) described mixture is made to soft material, described soft material is sieved and dried, obtain the granule of described mixture;
(3) described granule evenly mixed and suppressed with lubricant, obtaining described compositions;
Wherein, levetiracetam accounts for the 50-88% of described composition weight; Described slow-release material accounts for the 10-45% of described composition weight, and described slow-release material selects group or its combination of free ethyl cellulose, stearic acid, castor oil hydrogenated, hypromellose composition; Described lubricant accounts for the 1.5-9% of described composition weight, and described lubricant is selected from group or its combination of magnesium stearate, micropowder silica gel, Pulvis Talci composition.
10. method as claimed in claim 9, is characterized in that by the method for slow-release material liquefaction be heating and melting.
11. methods as claimed in claim 9, the solvent that it is characterized in that the solution of described slow-release material is ethanol.
12. methods as claimed in claim 11, is characterized in that described solvent is dehydrated alcohol.
13. methods as claimed in claim 9, the melt temperature that it is characterized in that slow-release material is not for higher than 120 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310085307.1A CN104042582A (en) | 2013-03-15 | 2013-03-15 | Levetiracetam sustained-release agent composition and preparation method |
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| CN201310085307.1A CN104042582A (en) | 2013-03-15 | 2013-03-15 | Levetiracetam sustained-release agent composition and preparation method |
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| CN104042582A true CN104042582A (en) | 2014-09-17 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030714A (en) * | 2015-07-06 | 2015-11-11 | 长春中医药大学 | Aniracetam sustained release tablet and preparation method thereof |
| CN109692166A (en) * | 2017-10-23 | 2019-04-30 | 重庆润泽医药有限公司 | The enteric slow release particle and preparation method thereof for treating epilepsy |
| CN109718222A (en) * | 2017-10-27 | 2019-05-07 | 重庆润泽医药有限公司 | Oxiracetam enteric coated preparations and preparation method thereof |
-
2013
- 2013-03-15 CN CN201310085307.1A patent/CN104042582A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030714A (en) * | 2015-07-06 | 2015-11-11 | 长春中医药大学 | Aniracetam sustained release tablet and preparation method thereof |
| CN109692166A (en) * | 2017-10-23 | 2019-04-30 | 重庆润泽医药有限公司 | The enteric slow release particle and preparation method thereof for treating epilepsy |
| CN109718222A (en) * | 2017-10-27 | 2019-05-07 | 重庆润泽医药有限公司 | Oxiracetam enteric coated preparations and preparation method thereof |
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Address after: 201319 Shanghai city Pudong New Area indigo Road No. 1199 building 203 room 1 Applicant after: JS INNO PHARM (SHANGHAI) Ltd. Address before: 201201 Shanghai City, Pudong New Area Zhangjiang hi tech Industrial District Ruiqinglu No. 590 building 6 Room 302 Applicant before: JS INNO PHARM (SHANGHAI) Ltd. |
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Effective date of registration: 20170825 Address after: 201319 Shanghai city Pudong New Area indigo Road No. 1199 building 502 room 1 Applicant after: ATHENA DRUG DELIVERY SOLUTIONS Pvt.,Ltd. Address before: 201319 Shanghai city Pudong New Area indigo Road No. 1199 building 203 room 1 Applicant before: JS INNO PHARM (SHANGHAI) Ltd. |
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Application publication date: 20140917 |