CN108434110B - Misoprostol composition, tablet and application thereof - Google Patents

Abstract

The invention discloses a misoprostol composition, a tablet and an application thereof. The composition is prepared by directly compressing the formulation of microcrystalline cellulose with different particle sizes, which effectively avoids the separation of materials in the tableting process during production. layer problem. The misoprostol tablet prepared according to the invention has the characteristics of rapid disintegration and dissolution, uniform content, simple production process and is suitable for industrial production.

Description

Misoprostol composition, tablet and use thereof

technical field

The invention relates to a misoprostol composition, tablet and application thereof.

Background technique

Misoprostol belongs to a kind of artificially synthesized active prostaglandin derivatives. It was developed and marketed by Searle, UK in 1985. It was initially clinically used to treat duodenal ulcer and gastric ulcer caused by non-steroidal anti-inflammatory drugs. , and later combined with mifepristone sequentially for the termination of early pregnancy within 49 days of menopause.

Powder direct compression method refers to the method of directly compressing the mixture of drug and excipients without going through the granulation process. The powder direct compression process avoids the granulation process, which has the advantages of saving time and energy, simple process, less procedures, and is suitable for drugs that are unstable in humidity and heat, but it also has high requirements for material fluidity, compressibility and formability , The material is easy to mix unevenly, and the excipients are prone to stratification during the tableting process, resulting in uneven tablet content and other problems.

U.S. Food and Drug Administration (FDA) on December 27, 1988, review data (Review) page 79 disclosed the prescription misoprostol hypromellose 20.2mg of the original research drug, microcrystalline cellulose 175.8mg, Sodium carboxymethyl starch 3.0mg, hydrogenated castor oil 1.0mg. During the research, it was found that when microcrystalline cellulose with an average particle size (D50) of 180 μm was used, the content uniformity of the tablet during the tableting process was unqualified, and the material tended to be stratified, but the dissolution curve could be consistent with the original research; when using When the average particle size (D50) of microcrystalline cellulose is 50 μm, the content uniformity of the tablet is qualified during the tableting process, and the material is not separated, but the dissolution curve is not consistent with the original research, and it is obviously slower. Using one kind of microcrystalline cellulose alone cannot meet the requirements of content uniformity and dissolution curve.

The instruction sheet of the original research drug produced by PHARMACIA in the UK shows that the product is rapidly absorbed after oral administration, and the plasma concentration of its active metabolite reaches the peak after 30 minutes, and the plasma clearance half-life of the active metabolite is 20-40 minutes. The dissolution rate of the original drug is very fast. In order to meet the requirements of bioequivalence, the dissolution rate of the generic drug should also be very fast and consistent with the trend of the original drug. During the research process, the inventors found that microcrystalline cellulose with a single particle size cannot be used for both uniform content and rapid dissolution when preparing tablets according to the previously described prescription.

Contents of the invention

The purpose of the present invention is to solve the problem that the current misoprostol composition is in a liquid state at room temperature, and is unstable when exposed to water. The powder direct compression method material is easy to mix unevenly, and the adjuvant is prone to stratification during the tablet process, resulting in tablet content. Uneven technical issues.

To achieve the above object of the invention, in a first aspect, the present invention provides a misoprostol composition, comprising the following components:

Wherein, the misoprostol content in the misoprostol hydroxypropyl methylcellulose complex is 1%, the average particle diameter (D50) of the microcrystalline cellulose 1 is 50-90 μm, and the microcrystalline cellulose The average particle size (D50) of prime 2 is 160-180 μm.

Further, the average particle diameter (D50) of the misoprostol-hypromellose complex is 50-200 μm, preferably 80-150 μm.

Further, the mass ratio of the microcrystalline cellulose 2 to the microcrystalline cellulose 1 is 3.4:1-1:1, preferably 2:1-1:1.

Further, the disintegrant includes but is not limited to one or a mixture of starch, sodium starch glycolate, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; The lubricant includes, but is not limited to, one or a mixture of talc, stearic acid, hydrogenated castor oil, and polyethylene glycol.

Second aspect, the present invention provides a kind of misoprostol tablet, comprises following component in every 10,000 misoprostol tablets:

Wherein, the average particle diameter (D50) of the microcrystalline cellulose 1 is 50-90 μm, and the average particle diameter (D50) of the microcrystalline cellulose 2 is 160-180 μm.

In a third aspect, the present invention provides a misoprostol tablet, and every ten thousand misoprostol tablets comprises the following components:

Wherein, the average particle diameter (D50) of the microcrystalline cellulose 1 is 50-90 μm, and the average particle diameter (D50) of the microcrystalline cellulose 2 is 160-180 μm.

In a fourth aspect, the present invention provides a misoprostol tablet, and every 10,000 misoprostol tablets comprise the following components:

Wherein, the average particle diameter (D50) of the microcrystalline cellulose 1 is 50-90 μm, and the average particle diameter (D50) of the microcrystalline cellulose 2 is 160-180 μm.

In a fifth aspect, the present invention provides a use of a misoprostol composition, wherein any misoprostol composition described in the first aspect is sequentially combined with mifepristone for terminating menopause within 49 days early pregnancy.

In addition, the present invention also provides a kind of preparation method of misoprostol composition, comprises the following steps:

1) mix the misoprostol hydroxypropyl methylcellulose complex and the disintegrant evenly;

2) Add microcrystalline cellulose 1 with a smaller particle size to the above materials and mix evenly;

3) Add microcrystalline cellulose 2 with a larger particle size to the above materials and mix evenly;

4) adding hydrogenated castor oil to the above-mentioned materials and mixing uniformly to obtain total mixed particles;

5) Place the above-mentioned blended granules in a high-speed rotary tablet press for tableting.

Further, the misoprostol tablet prepared by using the composition scheme and preparation method of the present invention has specifications including but not limited to 0.1 mg and 0.2 mg, and its main purpose is to sequentially combine with mifepristone for terminating menopause Early pregnancy within 49 days.

Compared with prior art, the beneficial effect of the present invention is:

The present invention adopts two kinds of microcrystalline cellulose with different particle sizes, which can effectively solve the problem of material layering in the tableting process, and the content uniformity of the prepared tablet meets the requirements of the Chinese Pharmacopoeia, and the dissolution curve is similar to that of the imported original drug produced by PHARMACIA in the United Kingdom. Consistent; the misoprostol tablet prepared according to the present invention has the characteristics of rapid disintegration and dissolution and uniform content, and is suitable for industrial production.

Description of drawings

Fig. 1 is the stripping curve of comparative example and original research drug in aqueous medium (paddle method, 500ml water, 30 turns);

Fig. 2 is the stripping curve of embodiment and original research drug in aqueous medium (paddle method, 500ml water, 30 revolutions).

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

Comparative Example 1

components Dosage Misoprostol Hypromellose Complex 200g Microcrystalline Cellulose 1 352g Microcrystalline Cellulose 2 1408g Sodium carboxymethyl starch 30g hydrogenated castor oil 10g

The average particle diameter (D50) of microcrystalline cellulose 1 was 70 μm, and the average particle diameter (D50) of microcrystalline cellulose 2 was 170 μm.

Preparation:

1) Misoprostol hydroxypropyl methylcellulose complex and sodium carboxymethyl starch are mixed evenly;

2) Add microcrystalline cellulose 1 to the above materials, and mix well;

3) Add microcrystalline cellulose 2 to the above materials, and mix well;

4) adding hydrogenated castor oil to the above materials and mixing uniformly to obtain a total blend material;

5) Put the above-mentioned materials into a high-speed tablet press for tableting. The evaluation process of 10,000 tablets of misoprostol tablets with a specification of 0.1 mg:

(1) Changes in content uniformity during tablet compression

Divide the entire tableting process into three sections: front, middle, and back according to the time period, and take samples at the discharge port of the tablet machine before each section starts, according to the content uniformity inspection method of the Chinese Pharmacopoeia 2015 edition four 0941 (A+2.2S< =15) Detect the content uniformity of the tablet.

(2) Dissolution

According to the dissolution test method (Chinese Pharmacopoeia 2015 edition four 0931 dissolution and release test method second method).

Comparative Example 2

components Dosage Misoprostol Hypromellose Complex 200g Microcrystalline Cellulose 1 978g Microcrystalline Cellulose 2 782g Sodium carboxymethyl starch 30g hydrogenated castor oil 10g

The average particle diameter (D50) of microcrystalline cellulose 1 was 51 μm, and the average particle diameter (D50) of microcrystalline cellulose 2 was 180 μm.

Preparation:

1) Misoprostol hydroxypropyl methylcellulose complex and sodium carboxymethyl starch are mixed evenly;

2) Add microcrystalline cellulose 1 to the above materials, and mix well;

3) Add microcrystalline cellulose 2 to the above materials, and mix well;

4) adding hydrogenated castor oil to the above materials and mixing uniformly to obtain a total blend material;

5) Put the above-mentioned materials into a high-speed tablet press for tableting. Make 10,000 tablets, and the evaluation process of the misoprostol tablet whose specification is 0.1 mg is consistent with Comparative Example 1.

Comparative example 1, the content uniformity result of comparative example 2 is as follows:

The comparison results of the dissolution curves of the comparative examples are shown in Figure 1.

the result shows:

When the ratio of microcrystalline cellulose 2 to microcrystalline cellulose 1 is 4:1, stratification occurs during the preparation process, and the uniformity of the obtained misoprostol tablets is unqualified, but the dissolution profile is consistent with the original drug .

When the ratio of microcrystalline cellulose 2 to microcrystalline cellulose 1 is 0.8:1 for tablet compression, no delamination occurs, and the uniformity of the obtained misoprostol tablets is acceptable, but the dissolution curves are inconsistent with the original drug.

Example 1

components Dosage Misoprostol Hypromellose Complex 200g Microcrystalline Cellulose 1 400g Microcrystalline Cellulose 2 1360g Sodium carboxymethyl starch 30g hydrogenated castor oil 10g

The average particle diameter (D50) of microcrystalline cellulose 1 was 51 μm, and the average particle diameter (D50) of microcrystalline cellulose 2 was 180 μm.

Preparation method is the same as comparative example 1

evaluation process

Content uniformity and dissolution rate sampling and detection process are the same as Comparative Example 1.

Example 2

The average particle diameter (D50) of microcrystalline cellulose 1 was 70 μm, and the average particle diameter (D50) of microcrystalline cellulose 2 was 170 μm.

The preparation method, content uniformity and dissolution rate sampling and detection process are the same as in Example 1.

Example 3

components Dosage Misoprostol Hypromellose Complex 200g Microcrystalline Cellulose 1 820g Microcrystalline Cellulose 2 940g Sodium carboxymethyl starch 30g hydrogenated castor oil 10g

The average particle diameter (D50) of microcrystalline cellulose 1 was 61 μm, and the average particle diameter (D50) of microcrystalline cellulose 2 was 180 μm.

The preparation method, content uniformity and dissolution sampling and testing process are the same as in Example 1.

Example 4

components Dosage Misoprostol Hypromellose Complex 200g Microcrystalline Cellulose 1 820g Microcrystalline Cellulose 2 940g Sodium carboxymethyl starch 30g hydrogenated castor oil 10g

The average particle diameter (D50) of microcrystalline cellulose 1 was 89 μm, and the average particle diameter (D50) of microcrystalline cellulose 2 was 163 μm.

The preparation method, content uniformity and dissolution rate sampling and detection process are the same as in Example 1.

The content uniformity result of embodiment 1,2,3 and 4 is as follows table:

The results of comparison of the dissolution curves of Examples 1, 2, 3 and 4 are shown in Figure 2.

The result shows: according to the preparation method of the present invention, adopting the cellulose formulation of two particle size specifications can effectively solve the layering problem in the tableting process, after testing, and the uniformity of Examples 1, 2, 3, and 4 meets the Pharmacopoeia standard , the dissolution curves of the three formulations were basically consistent with those of the original drug.

Inspired by the above-mentioned ideal embodiment according to the present invention, through the above-mentioned description content, relevant workers can make various changes and modifications within the scope of not departing from the technical idea of the present invention. The technical scope of the present invention is not limited to the content in the specification, but must be determined according to the scope of the claims.

Claims (7)

1. Misoprostol composition, which is characterized in that include following component:

Wherein, Misoprostol content is 1% in the Misoprostol hypromellose compound, and the crystallite is fine Tieing up plain 1 average grain diameter (D50) is 50-90 μm, and 2 average grain diameter of microcrystalline cellulose (D50) is 160-180 μm.

2. Misoprostol composition according to claim 1, which is characterized in that the Misoprostol hydroxypropyl is fine The average grain diameter (D50) for tieing up plain compound is 50-200 μm.

3. Misoprostol composition according to claim 1, which is characterized in that the microcrystalline cellulose 2 and crystallite are fine The mass ratio of dimension element 1 is in 3.4:1-1:1.

4. Misoprostol composition according to claim 1, which is characterized in that the disintegrating agent includes but is not limited to form sediment One of powder, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone or its Mixture；The lubricant includes but is not limited to one of talcum powder, stearic acid, rilanit special and polyethylene glycol or it is mixed Close object.

5. Misoprostol tablet, which is characterized in that include following component in every 10,000 misoprostol tablets by LC-MS:

Wherein, the average grain diameter (D50) of the microcrystalline cellulose 1 is 50-90 μm, and the average grain diameter (D50) of microcrystalline cellulose 2 is 160-180μm。

6. Misoprostol tablet, which is characterized in that include following component in every 10,000 misoprostol tablets by LC-MS:

Wherein, the average grain diameter (D50) of the microcrystalline cellulose 1 is 50-90 μm, and the average grain diameter (D50) of microcrystalline cellulose 2 is 160-180μm。

7. Misoprostol tablet, which is characterized in that include following component in every 10,000 misoprostol tablets by LC-MS:

Wherein, the average grain diameter (D50) of the microcrystalline cellulose 1 is 50-90 μm, and the average grain diameter (D50) of microcrystalline cellulose 2 is 160-180μm。