JP5534645B2 - Oral dosage formulation containing sarpogrelate hydrochloride with excellent stability in an unwrapped state - Google Patents

Oral dosage formulation containing sarpogrelate hydrochloride with excellent stability in an unwrapped state Download PDF

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JP5534645B2
JP5534645B2 JP2008003759A JP2008003759A JP5534645B2 JP 5534645 B2 JP5534645 B2 JP 5534645B2 JP 2008003759 A JP2008003759 A JP 2008003759A JP 2008003759 A JP2008003759 A JP 2008003759A JP 5534645 B2 JP5534645 B2 JP 5534645B2
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sarpogrelate hydrochloride
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JP2009167110A (en
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亮祐 井川
早世子 石瀬
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日医工株式会社
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  The present invention relates to a preparation for oral administration containing sarpogrelate hydrochloride.

Sarpogrelate hydrochloride has a selective antagonism against 5-HT 2 receptor, and is used in clinical practice as an ameliorating agent for various ischemic symptoms such as ulcer, pain and cold feeling associated with chronic arterial occlusion.
A preparation containing sarpogrelate hydrochloride as an active ingredient is commercially available as Amprag tablets (registered trademark), and no problem is observed in stability in the final packaging form.
However, it is known that sarpogrelate hydrochloride hydrolyzes when humidified.
Therefore, we examined the stability of the commercial preparation in the unwrapped state, and when it was stored for 2 months in the unwrapped state at 40 ° C. and 75% RH, the hydrolyzate produced about 3 to 4% of the active ingredient content. Turned out to be.
In recent years, there has been an increase in the number of hospitals that carry out single-packed preparations aimed at improving the compliance of outpatients, the increased handling of preparations after opening due to the widespread use of automatic tablet packaging machines, and a dramatic increase in long-term prescriptions. There is a demand for development of a formulation having excellent stability in a non-packaging state because of an increase in the number of reasons.
Japanese Patent Application Laid-Open No. 2007-56011 discloses a method for reducing the size of this preparation by incorporating a disintegrant in the preparation while ensuring the same dissolution property as that of a commercially available preparation.
However, this document does not mention the stability in the unwrapped state, although it shows fast dissolution and good storage stability in the packaged state.
Japanese Patent Laid-Open No. 2007-145733 discloses a method for improving the stability of a non-packaging state of a sarpogrelate hydrochloride-containing oral administration preparation by changing Mg stearate mixed in a commercial preparation to Ca stearate. However, miniaturization is insufficient.
Thus, an example of an orally administered preparation containing sarpogrelate hydrochloride that is stable in an unwrapped state while sufficiently miniaturizing the preparation has not yet been shown, and is stable even in an unwrapped state that can be used for a single-packed preparation, In addition, development of an oral administration preparation containing sarpogrelate hydrochloride that is excellent in ingestion has been desired.
For oral dosage forms containing sarpogrelate hydrochloride, increasing the drug content in the tablet with the aim of miniaturizing the dosage form affects the dissolution characteristics of the drug substance, especially the dissolution of JP Since gelation of the active ingredient occurs, it has been difficult to provide an orally administered preparation that exhibits rapid dissolution behavior.
In the above-mentioned JP-A-2007-56011, there is shown a method for reducing the size while ensuring the dissolution property equivalent to that of a commercially available preparation by blending a water-insoluble cellulose derivative as a disintegrant into the preparation.
However, as a result of studies by the present inventors, the water-insoluble cellulose derivative disclosed in the publication is in a state in which a large amount of water is absorbed in the unwrapped state, and hydrolysis of sarpogrelate hydrochloride is promoted, which adversely affects stability. It has been found.

JP 2007-56011 A JP 2007-145733 A

  An object of the present invention is to provide a miniaturized sarpogrelate hydrochloride-containing oral administration preparation that is excellent in storage stability under non-packaging conditions and exhibits a rapid dissolution rate as in the case of conventional commercial oral administration preparations.

As a result of repeated investigations to obtain a rapid drug release without using a water-insoluble cellulose derivative having a property of absorbing a large amount of water, the present inventors have reached the present invention.
The oral administration preparation containing sarpogrelate hydrochloride having excellent stability in a non-packaging state according to the present invention contains a water-soluble cellulose derivative as a binder, but does not contain a water-insoluble cellulose derivative as a disintegrant. It is characterized by.
In the present invention, the blending amount of the water-soluble cellulose derivative used as the binder is preferably 0.5% by mass to 3% by mass of the formulation mass.
When the blending amount is less than 0.5% by mass, granulation does not proceed sufficiently and tableting troubles such as sticking occur at the time of production, the commercial value is remarkably impaired, and the production becomes difficult.
Further, when the amount of the binder is more than 3% by mass, it is not preferable because the release rate of the drug from the preparation may be delayed and sufficient bioavailability may not be ensured.
The water-soluble cellulose derivative used in the present invention is preferably any of hydroxypropyl cellulose, hypromellose, and methyl cellulose.
In the present invention, orally administrable pharmaceutical additives such as excipients and lubricants can be used as a binder in addition to a water-soluble cellulose derivative.
Examples of the excipient include lactose, D-mannitol, potato starch, corn starch, calcium hydrogen phosphate, light anhydrous silicic acid, citric acid and the like.
Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, hydrogenated oil, talc and the like.
In the present invention, it is possible to reduce the size of the preparation, and 40 to 95% by mass of salpoglaate hydrochloride is contained per preparation.
In the present invention, it is possible to produce an oral administration preparation containing sarpogrelate hydrochloride by a known method. For example, direct tableting method, dry granulation method, fluidized bed granulation method, stirring granulation method, rolling fluidized bed Examples thereof include a granulation method, an extrusion granulation method, a melt granulation method, etc., preferably a fluidized bed granulation method, a stirring granulation method, a rolling fluidized bed granulation method, and an extrusion granulation method, more preferably. A stirring granulation method may be mentioned.
For example, when the fluidized bed granulation method is used, granulation is performed by spraying the binder solution according to the present invention to a powder mixed with sarpogrelate hydrochloride, excipient, and the like.
When the stirring granulation method is used, granulation is performed by adding the binder solution according to the present invention to a powder mixed with sarpogrelate hydrochloride, excipient, and the like to obtain a granulated product.
Further, it is possible to obtain a granulated product by granulating by adding purified water to a powder mixed with sarpogrelate hydrochloride, an excipient and a binder.
The target tablet can be obtained by mixing a lubricant and the like with the granulated product obtained by these methods and then tableting.
In the present invention, it is also possible to film-coat the tablets produced as described above for the purpose of masking the original bitterness.
As the additive that can be used for film coating in the present invention, those usually used when producing film-coated tablets can be used, and it is desirable to use hypromellose or hydroxypropylcellulose.
Moreover, a plasticizer, a talc, a titanium oxide, a pigment | dye, etc. can be mix | blended in a film coating layer.

A small size that is stable in an unwrapped state by using a water-soluble cellulose derivative as a binder and not adding a water-insoluble cellulose derivative as a disintegrating agent in an oral administration preparation containing sarpogrelate hydrochloride and having excellent dosing properties An oral administration preparation containing sarpogrelate hydrochloride can be obtained.
Thereby, the handleability and compliance of the packaged preparation and the preparation after opening are improved.

Examples and comparative examples will be described below in detail.
However, the present invention is not limited to these.
Formulations (Examples 1 and 2 and Comparative Examples 1 and 2) having the formulations shown in the table of FIG. 1 were produced by a fluidized bed granulation method.
Sarpogrelate hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo), and potato starch (refined and dried sterilized potato starch, manufactured by Matsutani Chemical Industry) were added to a fluidized bed granulator (FL-mini, manufactured by Freund Sangyo). In Examples, hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda), citric acid (manufactured by Kosuge Pharmaceutical), in comparative examples, polyvinyl alcohol (Gosenol, manufactured by Nippon Synthetic Chemical Industry), citric acid (manufactured by Kosuge Pharmaceutical), or After sprayed with povidone (Kollidon K30, manufactured by BASF Japan) and citric acid (manufactured by Kominato Pharmaceutical), it was dried and sized to obtain a fluidized bed granulated product.
After mixing the fluidized bed granulated product with light anhydrous silicic acid (ADSOLIDER-101, manufactured by Freund Corporation) and magnesium stearate (magnesium stearate-S, manufactured by NOF Corporation), a diameter of 7.5 mm (Example 1, comparative example) 1, 2) or a tablet with a diameter of 6.5 mm (Example 2), and tableted to obtain a preparation containing 50 mg of sarpogrelate hydrochloride.

The preparations prepared in Examples 1 and 2 and Comparative Examples 1 and 2 and commercially available preparations (50 mg tablets) were stored for 2 months at 40 ° C./75% RH / non-packaging conditions.
The amount of the related substance (hydrolyzate) was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in the table of FIG.
The commercial preparation contains polyvinyl alcohol.
In Example 2 in which the preparation was miniaturized from the formulations of Example 1 and Example 1, the amount of related substances in the preparation after the stability test was about ½ compared to Comparative Examples 1 and 2.

The preparations (Examples 3 to 5) having the formulations shown in the table of FIG. 3 were produced by the stirring granulation method.
Sarpogrelate hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo), and potato starch (refined and dried sterilized potato starch, manufactured by Matsutani Chemical Industry) were added to an agitating granulator (VG-01, manufactured by Paulek) and hydroxypropyl. Cellulose (HPC-L, manufactured by Nippon Soda), citric acid (manufactured by Kosuge Pharmaceutical), or hypromellose (TC-5EW, manufactured by Shin-Etsu Chemical), citric acid (manufactured by Kosuge Pharmaceutical), or methylcellulose (SM-4, Shin-Etsu Chemical) And citric acid (manufactured by Kominato Pharmaceutical Co., Ltd.) were added with stirring to perform granulation.
After completion of granulation, the mixture was dried and sized using a fluidized bed granulator (FL-mini, manufactured by Freund Corporation) to obtain a stirred granulated product.
This stirred granulated product is mixed with light anhydrous silicic acid (Adsolider-101, manufactured by Freund Corporation) and magnesium stearate (magnesium stearate-S, manufactured by Nippon Oil & Fats), and then tableted using a 6.5 mm diameter punch. Thus, a preparation containing 50 mg of sarpogrelate hydrochloride was obtained.

As Comparative Example 3, a preparation having the formulation shown in the table of FIG. 4 was produced by the stirring granulation method.
Sarpogrelate hydrochloride, crystalline cellulose (Theolas PH101, manufactured by Asahi Kasei Chemicals) and carmellose (NS-300, manufactured by Gotoku Pharmaceutical) were introduced into a stirring granulator (VG-01, manufactured by Paulek), and hydroxypropylcellulose (HPC-L, Japan). Soda) and citric acid (manufactured by Kosuge Pharmaceutical) were added, dried and sized to obtain a stirred granulated product.
This stirred granulated product is mixed with light anhydrous silicic acid (ADSOLIDER-101, manufactured by Freund Corporation) and magnesium stearate (magnesium stearate-S, manufactured by Nippon Oil & Fats), and then tableted using a 6.5 mm diameter punch. Thus, a preparation containing 50 mg of sarpogrelate hydrochloride was obtained.

The preparations prepared in Examples 3, 4, 5 and Comparative Example 3 and the commercially available preparation (50 mg tablet) were stored for 2 months under the conditions of 40 ° C., 75% RH and no packaging.
The amount of the related substance (hydrolyzate) was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in the table of FIG.
In Examples 3, 4 and 5, the amount of the related substance in the preparation after the stability test for 2 months was about 1/3 to 1/2 compared with Comparative Example 3 and the commercially available preparation.

The preparations (Examples 6 and 7) having the formulations shown in the table of FIG. 6 were produced by the stirring granulation method.
Sarpogrelate hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo), and potato starch (refined and dried sterilized potato starch, manufactured by Matsutani Chemical Industry) were added to an agitating granulator (VG-01, manufactured by Paulek) and hydroxypropyl. Cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and citric acid (manufactured by Kosuge Pharmaceutical Co., Ltd.) were added with stirring to perform granulation.
After completion of granulation, the mixture was dried and sized using a fluidized bed granulator (FL-mini, manufactured by Freund Corporation) to obtain a stirred granulated product.
This stirred granulated product is mixed with light anhydrous silicic acid (ADSOLIDER-101, manufactured by Freund Corporation) and magnesium stearate (magnesium stearate-S, manufactured by Nippon Oil & Fats), and then tableted using a 6.5 mm diameter punch. Thus, a preparation containing 50 mg of sarpogrelate hydrochloride was obtained.

The dissolution test of the preparations prepared in Examples 6 and 7 and the commercial preparation (50 mg tablet) was carried out according to the Japanese dissolution test method method 2 (paddle method) (test solution: Japanese Pharmacopoeia disintegration test solution solution 1 (pH 1. 2) Test solution volume: 900 mL, paddle rotation speed: 50 rpm).
The results are shown in the table of FIG.
Both the preparations of Examples 6 and 7 showed rapid dissolution behavior equivalent to that of the commercially available preparation.

The preparations (Examples 8 to 10) having the formulations shown in the table of FIG. 8 were produced by the stirring granulation method.
Sarpogrelate hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo), and potato starch (refined and dried sterilized potato starch, manufactured by Matsutani Chemical Industry) were added to an agitating granulator (VG-01, manufactured by Paulek) and hydroxypropyl. Cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and citric acid (manufactured by Kosuge Pharmaceutical Co., Ltd.) were added with stirring to perform granulation.
After completion of granulation, the mixture was dried and sized using a fluidized bed granulator (FL-mini, manufactured by Freund Corporation) to obtain a stirred granulated product.
This stirred granulated product is mixed with light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industries) and magnesium stearate (magnesium stearate-S, manufactured by Nippon Oil & Fats), and then tableted using a 7.5 mm diameter punch. Thus, a preparation containing 100 mg of sarpogrelate hydrochloride was obtained.

The preparations prepared in Examples 8, 9, and 10 and the commercial preparation (100 mg tablet) were stored for 2 months under the conditions of 40 ° C., 75% RH and no packaging.
The amount of the related substance (hydrolyzate) was measured for the stored preparation, and the content ratio of the amount of the related substance to the main drug content was determined.
The results are shown in the table of FIG.
In Examples 8, 9, and 10, the amount of related substances in the preparation after the stability test for one month was about ½ compared to the commercially available preparation.

The dissolution test of the preparations prepared in Examples 8, 9, and 10 and the commercial preparation (100 mg tablet) was performed according to the Japanese dissolution test method 2 (paddle method) (Test solution: Japanese Pharmacopoeia Disintegration Test Solution 1 ( pH 1.2), test solution volume: 900 mL, paddle rotation speed: 50 rpm).
The results are shown in the table of FIG.
Also in the dissolution behavior of the 100 mg tablet, as in the case of the 50 mg tablet, the preparations of Examples 8, 9, and 10 all showed rapid dissolution behavior equivalent to that of the commercially available preparation.
As described above, the present invention was found to be stable in an unwrapped state and effective for downsizing the preparation.

The formulation example of a 50 mg tablet by a fluidized bed granulation method is shown. The measurement results of related substances generated under non-packaging conditions are shown. The formulation example of formulation by the stirring granulation method is shown. A prescription example for comparison is shown. The measurement results of related substances generated under non-packaging conditions are shown. The other formulation example of formulation by the stirring granulation method is shown. The dissolution test result of a 50 mg tablet is shown. The other formulation example of the 100 mg tablet by a stirring granulation method is shown. The measurement results of related substances generated under non-packaging conditions are shown. The dissolution test result of a 100 mg tablet is shown.

Claims (1)

  1. In a mixture of sarpogrelate hydrochloride in an amount of 40 to 95% by mass per formulation and D-mannitol or / and potato starch as an excipient,
    It is formulated in a granulated product granulated using a solution selected from the group of hydroxypropylcellulose, hypromellose, methylcellulose or a mixed solution of them and citric acid as a binder ,
    The binder contains 0.5 to 3% by mass per formulation,
    An oral administration preparation containing sarpogrelate hydrochloride having excellent stability in a non-packaging state, which does not contain a water-insoluble cellulose derivative as a disintegrant .
JP2008003759A 2008-01-11 2008-01-11 Oral dosage formulation containing sarpogrelate hydrochloride with excellent stability in an unwrapped state Active JP5534645B2 (en)

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JPH09309829A (en) * 1996-05-22 1997-12-02 Taiyo Yakuhin Kogyo Kk Oral administration preparation containing nitrendipine and its production
RU2201215C2 (en) * 1998-01-14 2003-03-27 Дайити Фармасьютикал Ко., Лтд. Disintegrating agent
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JP4567640B2 (en) * 2005-07-29 2010-10-20 田辺三菱製薬株式会社 Miniaturized sarpogrelate hydrochloride oral dosage form
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