CN106511306B

CN106511306B - Levo-oxiracetam sustained-release capsule and preparation method thereof

Info

Publication number: CN106511306B
Application number: CN201510579849.3A
Authority: CN
Inventors: 叶雷
Original assignee: Chongqing Runze Pharmaceutical Co Ltd
Current assignee: Chongqing Runze Pharmaceutical Co Ltd
Priority date: 2015-09-11
Filing date: 2015-09-11
Publication date: 2020-08-11
Anticipated expiration: 2035-09-11
Also published as: CN106511306A

Abstract

The levo-oxiracetam slow-release capsule is characterized by being prepared from the following raw and auxiliary materials in parts by weight, namely 1 part of levo-oxiracetam, 1.5-3.5 parts of slow-release framework material, 0.2-0.8 part of retarder, 0.05-0.20 part of lubricant and 1-2 parts of adhesive, wherein the levo-oxiracetam slow-release capsule prepared according to the invention has good content uniformity, the RSD of the main drug content is less than 1% in the mixing process, the release speed is slow, and the release period is as long as 12 hours, so that the levo-oxiracetam slow-release capsule can reduce the taking times compared with the traditional preparation and can be taken once a day; meanwhile, the product has good stability, the shelf life is as long as 24 months, the preparation process is simple and feasible, and the product is worthy of market popularization.

Description

Levo-oxiracetam sustained-release capsule and preparation method thereof

Technical Field

The invention mainly relates to the technical field of pharmacy, and in particular relates to a levo-oxiracetam sustained-release capsule and a preparation method thereof.

Background

Oxiracetam (oxiracetam, CAS No.: 62613-82-5) has the chemical name of 4-hydroxy-2-oxo-1-pyrrolidine acetamide, is an anti-hypoxia nootropic drug (the compound is disclosed in US4118396) which is synthesized for the first time in 1974 by ISFS. P.A. company of Italy, is a cyclic GABOB derivative, can promote the synthesis of phosphorylcholine and phosphorylethanolamine, promote brain metabolism, penetrate blood brain barrier, has stimulation effect on specific central nervous pathways, can improve intelligence and memory, has better curative effect on cerebrovascular diseases, brain trauma, brain tumor, intracranial infection, brain degeneration diseases and the like, and has extremely low toxicity, no mutagenic effect, carcinogenic effect and reproductive toxicity. The chemical structure and preparation of oxiracetam is disclosed in US4118396 by Giorgio et al, and the pharmaceutical efficacy of oxiracetam in the S configuration (levo) is shown in the clinical results in WO9306826A by Chiodini et al, which is stronger than that in the R configuration (dextro), with oxiracetam and levooxiracetam structures shown below.

The existing oxiracetam oral preparation mainly has the technical problems that the release degree can not be well controlled, the requirements of a sustained-release preparation can not be met, the content uniformity of a main drug in the preparation process is poor, and the like.

Disclosure of Invention

The invention aims to provide a levo-oxiracetam sustained-release capsule with good release degree and stability.

The invention also aims to provide a preparation method of the levo-oxiracetam sustained-release capsule.

The aim of the invention is realized by the following technical measures:

a levo-oxiracetam sustained-release capsule is characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 1.5 to 3.5 parts of sustained-release framework material, 0.2 to 0.8 part of retarder, 0.05 to 0.20 part of lubricant and 1 to 2 parts of adhesive; wherein the slow release skeleton material is one or more of hydroxypropyl methylcellulose, ethyl cellulose, polyethylene, polypropylene, polysiloxane, polyoxyethylene, lactose, fructose, sucrose, mannitol, sodium alginate, agar, chitin and galactose; the retarder is one or more of fat, beeswax, carnauba wax, hydrogenated vegetable oil, stearyl alcohol and glyceryl monostearate; the lubricant is one or more of magnesium stearate, talcum powder, silicon dioxide and stearyl alcohol; the adhesive is one of ethanol solution, starch slurry, sucrose solution, water, polyvidone ethanol solution, etc.

The inventor finds that the sustained-release matrix material consisting of lactose and hydroxypropyl methylcellulose K4M in a certain proportion is selected, and a certain amount of carnauba wax, octadecanol and ethanol solution with a specific volume percentage concentration are matched, so that the release speed of the levo-oxiracetam sustained-release capsule can reach 12 hours, and the levo-oxiracetam sustained-release capsule is characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.5-1.2 parts of lactose, 1.0-2.3 parts of hydroxypropyl methylcellulose, 0.3-0.7 part of carnauba wax, 0.06-0.18 part of octadecanol and 1-1.8 parts of ethanol solution with volume fraction of 50-80%.

The inventor discovers a specific raw and auxiliary material proportioning relationship through a large number of experiments, and can obviously improve the content uniformity of the main medicament and enable the main medicament to be mixed more uniformly by matching with a specific main medicament pretreatment method, and the levorotatory oxiracetam slow-release capsule is characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.6 to 1.0 part of lactose, 1.2 to 2.2 parts of hydroxypropyl methylcellulose K4M 1.2, 0.3 to 0.6 part of carnauba wax, 0.08 to 0.13 part of octadecanol and 1.2 to 1.6 parts of ethanol solution with the volume fraction of 50 to 80 percent; dissolving the main drug of the levo-oxiracetam into a solution by using 3-7 times of water for later use; taking the sustained-release framework material and the retarder with the prescription amount, adding the levo-oxiracetam aqueous solution, stirring and mixing for 10-15 min, placing in a forced air drying oven, setting the temperature to 40-60 ℃, drying until the water content is less than or equal to 3%, taking out, placing in a mixing crusher, mixing and crushing into fine powder (the total amount of the fine powder passing through a No. 5 sieve and the amount of the fine powder passing through a No. 6 sieve is not less than 95% of the total amount), and sieving to obtain the composition.

Further, the levo-oxiracetam slow-release capsule is characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.7 to 0.9 part of lactose, 1.5 to 1.8 parts of hydroxypropyl methylcellulose K4M 1.5, 0.3 to 0.5 part of carnauba wax, 0.09 to 0.11 part of octadecanol and 1.3 to 1.5 parts of ethanol solution with the volume fraction of 50 to 80 percent; dissolving the levo-oxiracetam into a solution by using 3-7 times of water for later use; taking the sustained-release framework material and the retarder with the prescription amount, adding the levo-oxiracetam aqueous solution, stirring and mixing for 10-15 min, placing in a forced air drying oven, setting the temperature to 40-60 ℃, drying until the water content is less than or equal to 3%, taking out, placing in a mixing crusher, mixing and crushing into fine powder (the total amount of the fine powder passing through a No. 5 sieve and the amount of the fine powder passing through a No. 6 sieve is not less than 95% of the total amount), and sieving to obtain the composition.

A preparation method of a levorotatory oxiracetam sustained-release capsule is characterized by comprising the following steps:

1. pretreatment of raw materials and auxiliary materials: dissolving the main drug of the levo-oxiracetam into a solution by using 3-7 times of water for later use; taking the sustained-release framework material and the retarder with the prescription amount, adding the levo-oxiracetam aqueous solution, stirring and mixing for 10-15 min, placing in a forced air drying oven, setting the temperature to 40-60 ℃, drying until the water content is less than or equal to 3%, taking out, placing in a mixing crusher, mixing and crushing into fine powder (the amount of all the fine powder passing through a No. 5 sieve and the amount of the fine powder passing through a No. 6 sieve are not less than 95% of the total amount), and sieving;

2. and (3) granulating: adding an adhesive, mixing and granulating by using a 18-mesh sieve, placing the prepared wet granules in a hot air oven, setting the temperature to be 40-60 ℃, drying until the moisture of the granules is less than or equal to 3%, and finishing the granules (sieving by using the 18-mesh sieve) for later use;

3. total mixing: crushing the lubricant, sieving the crushed lubricant with a 100-mesh sieve, adding the crushed lubricant into the granules, and mixing the mixture for 10 to 20 minutes by using a three-dimensional motion mixer;

4. filling: filling with full-automatic capsule filling agent, adjusting the filling amount to 0.5 g/capsule, and controlling the relative humidity below 50% in the whole filling process;

5. and (3) aluminum-plastic packaging: subpackaging with aluminum-plastic blister packaging machine, wherein 10 granules are packaged in each plate, and the relative humidity of an operating room must be lower than 50%;

6. and (5) coating the mixture outside to obtain the finished product.

The invention has the following beneficial effects:

the levo-oxiracetam sustained-release capsule has good content uniformity, the RSD of the content of the main drug in the mixing process is less than 1%, the release speed is slow, and the release period is as long as 12 hours, so that compared with the traditional preparation, the levo-oxiracetam sustained-release capsule can reduce the taking frequency and can be taken once a day; meanwhile, the product has good stability, the shelf life is as long as 24 months, the preparation process is simple and feasible, and the product is worthy of market popularization.

Detailed Description

The present invention is described in detail below by way of examples, it being necessary to note that the following examples are provided only for illustrating the present invention and are not to be construed as limiting the scope of the present invention, and modifications or substitutions of the method, steps or conditions of the present invention may be made without departing from the spirit and spirit of the present invention.

Example 1

A levo-oxiracetam sustained-release capsule is prepared by the following steps:

composition (I)	Dosage of
		Levo-oxiracetam	1 part of
Lactose	0.7 portion of
		Carboxypropylmethyl cellulose K4M	1.5 parts of
Carnauba wax	0.3 part
		Stearyl alcohol	0.09 part
70% ethanol solution	1.3 parts of

Making into 1000 pieces

The preparation process comprises the following steps:

6. and (5) coating the mixture outside to obtain the finished product.

For a better understanding of the present invention, the following stability tests are provided to further illustrate the beneficial effects of the inventive agents, but not to limit the present invention.

Test one: content uniformity measurement

1. Test materials: example 1 sample after total mixing during preparation

2. The test method comprises the following steps: example 1 after the total mixing was completed for 15 minutes, 5g of the mixture was sampled from each of the upper, middle, lower, left, and right points of the three-dimensional moving mixer, and the content was measured by the content measuring method, and the content RSD of each sample point was calculated to evaluate whether the mixture was uniformly mixed or not;

3. and (3) test results:

4. and (4) test conclusion: as can be seen from the test results in the table above, the product has good content uniformity and RSD less than 1%

And (2) test II: measurement of Release degree

1. Test materials: test samples of example 1 were taken

2. The test method comprises the following steps: taking the prepared sustained-release capsule as a sample, adopting a device of a dissolution determination method second method according to a release degree inspection method (the second method of appendix X D of the second part of the 2010 version of Chinese pharmacopoeia), taking 900ml of water as a release medium, operating according to the method at the rotating speed of 100 revolutions per minute, taking 10ml of the release solution after 1, 2, 4, 6, 8 and 12 hours, filtering by using a 0.45 mu m microporous filter membrane, taking a subsequent filtrate as a test solution, and timely supplementing 10ml of the release medium in an operating container. And precisely weighing about 10mg of the levo-oxiracetam reference substance into a 25ml measuring flask, dissolving the levo-oxiracetam reference substance with water, diluting the levo-oxiracetam reference substance to a scale, and shaking up the solution to obtain a reference substance solution. Respectively and precisely measuring 20 μ l of the reference solution and the sample solution, and measuring according to chromatographic conditions for content measurement. The release rate (referred to as cumulative release rate) of each particle was calculated.

3. And (3) test results: the results of the measurements of the release rate of the sustained-release capsule samples of the present invention are shown in the following table

4. And (4) test conclusion: the main medicine of the levo-oxiracetam slow release capsule is levo-oxiracetam which is slowly released for 12 hours, and can meet the requirements of a slow release preparation.

And (3) test III: stability experiment of levo-oxiracetam sustained-release capsule

Experimental materials:

levo-oxiracetam sustained-release capsule: prepared for example 1.

The accelerated test method comprises the following steps: the levo-oxiracetam sustained-release capsules prepared in example 1 are packaged on the market, put in an acceleration experiment box, sampled for a certain time and inspected for the items to be examined.

Accelerated test temperature: 40 +/-2 DEG C

Humidity: RH 75% +/-5%

Investigation time: 0. months 1, 2, 3 and 6

And (4) investigation indexes are as follows:

property, water content, related substances, release rate, content, and microbial limit

Recording the stability of the accelerated test:

the results of accelerated experiments show that: the quality of each detection index of the sample in the accelerated 6 months is equivalent to that of the sample in the 0 month, which shows that the product has stable quality and better stability in the accelerated experiment for 6 months.

The long-term experimental method comprises the following steps: the levo-oxiracetam sustained-release capsules prepared in example 1 are packaged on the market, placed in a long-term sample box, sampled for a certain time and inspected for the items to be examined.

Accelerated test temperature: 25 +/-2 DEG C

Humidity: RH 60% +/-10%

Investigation time: 0.3, 6, 9, 12, 18, 24 months

Long-term test stability recording:

long-term tests show that: the product has no significant change in character, water content, related substances, release degree, content and microorganism limit after long-term test for 24 months, and all meet the relevant regulations of quality standard draft for production. The product has stable quality for 24 months in long-term test, so the product has a minimum effective period of 24 months, and the long-term test is still in the process of continuous investigation.

Example 2

A levo-oxiracetam sustained-release capsule is prepared by the following steps:

composition (I)	Dosage of
		Levo-oxiracetam	1 part of
Lactose	0.9 portion
		Carboxypropylmethyl cellulose K4M	1.8 parts of
Carnauba wax	0.5 portion
		Stearyl alcohol	0.11 portion
70% ethanol solution	1.5 parts of

Making into 1000 pieces

The preparation process comprises the following steps: prepared according to the preparation process of example 1. According to the test method of the embodiment 1, content uniformity, release rate measurement and sample stability test are respectively carried out, the content uniformity test result shows that the product has good content uniformity, RSD is less than 1%, the release rate measurement test result shows that the levo-oxiracetam is slowly released, the release time is as long as 12 hours, the requirement of a sustained release preparation can be met, the stability test result shows that the sample quality is stable in 6 months, the quality is stable in 24 months, and the effective period of the product is at least 24 months.

Example 3

A levo-oxiracetam sustained-release capsule is prepared by the following steps:

composition (I)	Dosage of
		Levo-oxiracetam	1 part of
Lactose	0.8 portion of
		Carboxypropylmethyl cellulose K4M	1.6 parts of
Carnauba wax	0.4 portion of
		Stearyl alcohol	1.0 part
70% ethanol solution	1.3 parts of

Making into 1000 pieces

Examples 4 to 6: the levo-oxiracetam sustained-release capsule is prepared from the following raw and auxiliary materials in parts by weight, and the preparation method is the same as that in example 1:

according to the test method of the embodiment 1, a content uniformity test, a release rate test and a stability test are respectively carried out, the content uniformity test results of the samples of the embodiments 4, 5 and 6 show that the product has good content uniformity, the RSD is less than 1%, the release rate test results of the samples of the embodiments 4, 5 and 6 show that the levo-oxiracetam is slowly released, the release time is as long as 12 hours, the requirements of a sustained release preparation can be met, the stability test results of the samples of the embodiments 4, 5 and 6 show that the sample quality is stable in 6 months and the quality is stable in 24 months, so the effective period of the product is at least 24 months.

Claims

1. A levo-oxiracetam sustained-release capsule is characterized by being prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.6-1.0 part of lactose, 1.2-2.2 parts of hydroxypropyl methyl cellulose K4M 1.2, 0.3-0.6 part of carnauba wax, 0.08-0.13 part of octadecanol and 1.2-1.6 parts of ethanol solution with volume fraction of 50-80%;

the preparation method comprises the following steps:

A. pretreatment of raw materials and auxiliary materials: dissolving levo-oxiracetam into a solution by using 3-7 times of water for later use; taking formula amounts of slow-release framework materials including lactose, hydroxypropyl methylcellulose K4M and retarder carnauba wax, adding the levo-oxiracetam aqueous solution, stirring and mixing for 10-15 min, placing in a forced air drying oven at the set temperature of 40-60 ℃, drying until the water content is less than or equal to 3%, taking out, placing in a mixing and crushing machine, and mixing and crushing into fine powder; sieving the fine powder by a No. 5 sieve and the amount of the fine powder which can pass through a No. 6 sieve is not less than 95 percent of the total amount;

B. and (3) granulating: adding an ethanol solution with the volume fraction of the adhesive being 50% -80%, mixing and granulating with a 18-mesh sieve, placing the prepared wet granules in a hot air oven, setting the temperature to be 40-60 ℃, drying until the moisture of the granules is less than or equal to 3%, and sieving with the 18-mesh sieve to complete granules for later use;

C. total mixing: smashing octadecanol serving as a lubricant, sieving the smashed octadecanol with a 100-mesh sieve, adding the smashed octadecanol into the granules, and mixing the octadecanol and the granules for 10-20 min by using a three-dimensional motion mixer;

D. filling: filling with a full-automatic capsule filling machine, adjusting the filling amount to 0.5 g/capsule, and controlling the relative humidity below 50% in the whole filling process;

E. and (3) aluminum-plastic packaging: subpackaging with aluminum-plastic blister packaging machine, wherein 10 granules are packaged in each plate, and the relative humidity of an operating room must be lower than 50%;

F. and (5) coating the mixture outside to obtain the finished product.

2. The levo-oxiracetam sustained-release capsule as claimed in claim 1, which is prepared from the following raw and auxiliary materials in parts by weight: 1 part of levo-oxiracetam, 0.7-0.9 part of lactose, 1.5-1.8 parts of hydroxypropyl methyl cellulose K4M 1.5, 0.3-0.5 part of carnauba wax, 0.09-0.11 part of octadecanol and 1.3-1.5 parts of ethanol solution with volume fraction of 50-80%.