JP2936553B2 - Nicergoline-containing tablets - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oral pharmaceutical preparation containing nicergoline, which has excellent storage stability.

[0002]

2. Description of the Related Art Nicergoline [Chemical name: (+)-10-]
Methoxy -1,6-dimethylergoline-8β-methanol-5-bromonicotinic acid ester] is a derivative of ergot alkaloid, and is an excellent drug as a therapeutic drug for sequelae of cerebrovascular disorders and peripheral circulatory disorders. However, this compound is easily decomposed in water, and when formulated using excipients or binders commonly used in this field, the compound is decomposed by moisture absorbed during storage, and There is a problem that the content in the inside decreases. Conventionally, mannitol and lactose are known excipients and polyethylene glycol is a known substance as a binder, but when these are blended with nicergoline, it is quite impossible to obtain a nicergoline-containing tablet with excellent storage stability. Was not known.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a tablet having excellent storage stability.

[0004]

To solve the above-mentioned problems, as a result of research, tablets obtained by mixing nicergoline with polyethylene glycol and further containing either or both mannitol and lactose have excellent stability (1). And (2) use of polyethylene glycol, which is liable to cause tableting troubles such as mannitol and sticking, which is conventionally considered to be inferior in moldability, because nicergoline serves as a binder. Without
The present inventors have found that a good preparation can be obtained without causing any trouble in the preparation of the preparation, and completed the present invention. That is, the present invention is a tablet comprising nicergoline and mannitol or / and lactose, and polyethylene glycol.

[0005] Nicergoline used in the present invention is a powder,
Any of crystals and lumps can be used, and mannitol and lactose are not particularly limited as long as they are commonly used for oral administration preparations. In addition, polyethylene glycol may also be used as long as it is usually used in a preparation for oral administration, and for example, has an average molecular weight of 1,000 to 20,000.
Those having 0, preferably 4,000 to 6,000 can be suitably used. Each of the above components may be appropriately blended according to the purpose, and the blending amount is not particularly limited. If one example is shown without limitation, the content of nicergoline in the tablet is about 1 to 1.
30% by weight, especially about 2 to 20% by weight, about 1 to 95% by weight of any of mannitol and lactose, especially about 1%
5 to 85% by weight, about 2 to 40 polyethylene glycol
%, Especially about 5 to 20% by weight. When lactose and mannitol are used in combination, the total of both components may be within the above range, but lactose is about 0.6 to 1 part by weight of mannitol.
More preferably, it is used within the range of 1.5 parts by weight.

[0006] The preparation of the present invention can be produced by a conventional method by compressing the above-mentioned components as powder or using a compression tableting machine after granulating once. The granules can be prepared, for example, by a heat granulation method, a wet granulation method or a dry granulation method. When using the heat granulation method, nicergoline, mannitol or (and) lactose, and polyethylene glycol are heated and mixed, and then cooled,
If necessary, it may be pulverized. In the case of the wet granulation method, a mixture of nicergoline and mannitol or (and) lactose is kneaded with a solution containing polyethylene glycol and granulated by a commercially available granulation device or the like. And drying. Examples of the solvent used in kneading include methanol, ethanol, water, and mixtures thereof. Furthermore, when using the dry granulation method, it can be carried out using a commercially available dry granulator. The compression molding is performed, for example, at a compression pressure of 50 to 250 kg / cm ² , especially 100 to 250 kg / cm ² .
It is preferably carried out under the condition of 150 kg / cm ² .

[0007] The tablet of the present invention thus obtained may be coated with a suitable light-shielding film. Such a film may be prepared by mixing a film-forming polymer compound with a light-shielding component. Can be used. As the film-forming polymer compound, for example, a hydrophobic polymer material, a water-soluble polymer material, an enteric polymer material, a gastrosoluble polymer material, a gastrointestinal compatible polymer material and the like can be suitably used.

The hydrophobic polymer substance is not particularly limited as long as it has a film forming ability and is insoluble in water but soluble in an organic solvent miscible with water. Such hydrophobic polymer substances include, for example, cellulose ether,
Examples include cellulose esters, polyvinyl esters, and acrylic acid polymers having a quaternary ammonium alkyl group. Specifically, for example, ethylcellulose, butylcellulose; cellulose acetate, cellulose propionate; polyvinyl acetate, polyvinyl butyrate; Eudrakid RS (trade name of Rohm Pharma Co., Ltd .; chemical name; ethyl acrylate / methyl methacrylate / methacrylic) Trimethylammonium ethyl chloride copolymer) and the like. Ethyl cellulose,
Butyl cellulose, polyvinyl acetate or Eudragg RS are preferred, and ethyl cellulose and polyvinyl acetate are particularly preferred.

Examples of the water-soluble polymer substance include polysaccharides which may have a sulfate group such as pullulan, dextrin and alkali metal alginate, and hydroxyalkyl such as hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose. And polysaccharides having a carboxyalkyl group, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol.
Of these, hydroxypropylmethylcellulose, hydroxypropylcellulose and the like are preferable, and hydroxypropylmethylcellulose is particularly preferable.

The enteric polymer substance may be any polymer substance capable of forming a film by dissolving in water having a pH of 5 or more. For example, (1) carboxyalkyl cellulose ether, (2) dibasic acid Examples thereof include a cellulose derivative having a monoester bond, (3) a polyvinyl derivative having a monoester bond of a dibasic acid, (4) a maleic acid-vinyl copolymer, and (5) an acrylic acid polymer. Specific examples of (1) include carboxymethyl ethyl cellulose, and specific examples of (2) include cellulose acetate phthalate, cellulose acetate succinate, methyl cellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, and hydroxy. Examples thereof include propyl methylcellulose acetate succinate, and specific examples of (3) include polyvinyl alcohol phthalate, polyvinyl butyrate phthalate, and polyvinyl acetoacetal phthalate.
Specific examples of (4) include vinyl acetate / maleic anhydride copolymer, vinyl butyl ether / maleic anhydride copolymer, and styrene / maleic acid monoester copolymer. Specific examples of (5) Examples are methyl acrylate / methacrylic acid copolymer, styrene / acrylic acid copolymer, methyl acrylate / methacrylic acid / octyl acrylate copolymer, Eudragg L and S (trade names of Rohm Pharma, methacrylic acid / meth Methyl acrylate copolymer) and the like. Of these, carboxymethylethylcellulose, hydroxypropyl methylcellulose acetate succinate or Eudragit L are preferred.

Further, as the gastric soluble polymer substance, pH 6
Any polymer substance capable of forming a film by dissolving in the following water may be used, for example, (a) a cellulose derivative having a mono- or di-substituted amino group, (b) a polyvinyl derivative having a mono- or di-substituted amino group, (c) ) Acrylic acid polymers having monosubstituted amino groups. Specific examples of (a) include aminocelluloses such as benzylaminomethylcellulose, diethylaminomethylcellulose and piperidyl-ethyl-hydroxyethylcellulose, and aminocellulose esters such as cellulose-acetate-diethylaminoacetate. Specific examples of (b) include vinylamine compounds such as vinyl diethylamine / vinyl acetate copolymer, vinylbenzylamine / vinyl acetate copolymer, polyvinyl acetal / diethylamino acetate, vinyl piperidyl acetoacetal / vinyl acetate copolymer and the like. Examples include aminovinyl acetal compounds and polydiethylaminomethylstyrene. Specific examples of (c) include Eudragg E (trade name of Rohm Pharma Co., Ltd .; methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate). Polymer), polydimethylaminoethyl methacrylate and the like. Among them, polyvinyl acetal / diethylamino acetate or Eudrakid E is preferred. These polymer substances can be used alone or in combination of two or more as appropriate. Examples of the light-shielding component include titanium oxide. Further, upon coating, if desired,
Talc, synthetic aluminum silicate and the like can be added as an anti-agglomeration agent.

The coating can be performed by a usual coating method. For example, the film-forming polymer compound and the light-shielding component are water, ethyl alcohol,
Acetone, methylene chloride, coating solution dissolved or dispersed in a suitable solvent such as isopropyl alcohol,
For example, it can be easily carried out by spray coating the uncoated tablet with a through-drying type coating apparatus, a pan coating method or the like. For example, when using the pan coating method, put uncoated tablets in a coating pan,
While rotating the coating pan, a solution of the film-forming polymer compound is sprayed from a nozzle of a spray gun at an appropriate speed and then dried. Hereinafter, the present invention will be described in more detail with reference to Experimental Examples and Examples.

[0013]

[Action]

Experimental Example Stability was tested when nicergoline was combined with the excipients, binders and lubricants shown in Table 1 below.

[Preparation of tablets] 7 parts by weight of nicergoline, 41 parts by weight of mannitol, and 41 parts by weight of lactose were mixed, and the mixture was placed in a stirring granulator (Shinagawa mixer), and polyethylene glycol (average molecular weight: 6000) was added thereto. Water containing parts by weight is added and kneaded. This kneaded material is treated with a 20-mesh JIS standard sieve, and the material that has passed through the sieve is dried at 45 ° C. for 2 hours. After drying, 1 part by weight of calcium stearate is added and mixed, and the mixture is subjected to a rotary tableting machine (6.5 mm in diameter).
To obtain tablets of 100 mg per tablet. To 90% alcohol, 2 parts by weight of hydroxypropylmethylcellulose and 0.2 parts by weight of polyethylene glycol (average molecular weight: 6000) are added, stirred and dissolved. To this solution, 2 parts by weight of titanium oxide is added and dispersed to obtain a coating solution. The tablets of the present invention were obtained by placing the tablets in a coating pan and spraying the coating solution. Also, 7 parts by weight of nicergoline, 70 parts by weight of lactose, and 17 parts by weight of corn starch are put into a stirring granulator (Shinagawa mixer), and water containing 5 parts by weight of amicol is added and kneaded. A control tablet was obtained in the same manner as the tablet of the present invention.

[Storage Stability Test] In the experiment, the tablet of the present invention and the control tablet were stored at 50 ° C. for one month, and the amount of degraded nicergoline after storage was measured to examine the stability.

[Results] As shown in Table 1, nicergoline
It can be seen that the tablet of the present invention containing polyethylene glycol, mannitol and lactose has a lower content of degraded products and is superior in storage stability than the control tablet containing nicergoline, corn starch and amicol with lactose.

[0017]

[Table 1]

[0018]

【Example】

Example 1 5 parts by weight of nicergoline, 35 parts by weight of lactose, and 26.5 parts by weight of mannitol were mixed, and the mixture was agitated and granulated (Shinagawa mixer).
And polyethylene glycol (average molecular weight 6
000) Water containing 8 parts by weight is added and kneaded. This kneaded material is treated with a 20-mesh JIS standard sieve, and what has passed through the sieve is dried at 40 ° C. for 4 hours. After drying, 0.5 part by weight of calcium stearate is added and mixed, and the mixture is compression-molded with a rotary tableting machine (diameter 6 mm) to obtain a tablet of 75 mg per tablet. After 1 part by weight of vinyl acetate resin, 2 parts by weight of hydroxypropyl cellulose, and 1 part by weight of hydroxypropyl methyl cellulose are dissolved in 80% alcohol, 1 part by weight of synthetic aluminum silicate, 1 part by weight of titanium oxide, and 3 parts by weight of talc are added and dispersed. To make a coating solution. The tablets were placed in a through-drying type coating apparatus (High Coater manufactured by Freund) and sprayed with a coating solution to obtain film-coated tablets.

Example 2 7 parts by weight of nicergoline and 72 parts by weight of mannitol were mixed and placed in a stirring granulator (Shinagawa mixer), and hydrous ethanol containing 10 parts by weight of polyethylene glycol (average molecular weight: 6000) was added thereto. In addition, it is kneaded. The kneaded material was treated with a 20 mesh JIS standard sieve, and the
Dry at 0 ° C. for 2 hours. After drying, 1 part by weight of magnesium stearate was added and mixed, and the mixture was compression-formed with a rotary tableting machine (6.5 mm in diameter) to obtain 9 tablets per tablet.
0 mg tablets are obtained. Hydroxypropyl methylcellulose 2 parts by weight, polyethylene glycol 0.2 parts by weight ,
One part by weight of titanium oxide and 2 parts by weight of talc are dissolved or dispersed in 80% alcohol to prepare a coating solution. The tablets were placed in an air-drying type coating apparatus (High Coater, manufactured by Freund Corporation) and sprayed with a coating solution to obtain film-coated tablets.

Example 3 3 parts by weight of nicergoline and 62 parts by weight of lactose were mixed and placed in a stirring granulator (Shinagawa mixer), and to this was added hydrated ethanol containing 9 parts by weight of polyethylene glycol (average molecular weight 4000). Knead. Use a 20 mesh J
The product is treated with an IS standard sieve, and the product that has passed through the sieve is dried at 40 ° C. for 2 hours. After drying, 1 part by weight of magnesium stearate is added and mixed. Thereafter, a film-coated tablet is obtained in the same manner as in Example 1.

Example 4 Nicergoline 4 parts by weight, Mannit 23 parts by weight, Lactose 2
3 parts by weight and polyethylene glycol (average molecular weight 60
00) 5 parts by weight were mixed and put into a high-speed stirring granulator (high speed mixer manufactured by Fukae Kogyo Co., Ltd.), and the external bath temperature was 75
Heat granulation at ℃. The granulated product is cooled to room temperature, treated with a 20-mesh JIS standard sieve, and 1 part by weight of calcium stearate is added to and passed through the sieve and mixed. The mixture is compression-molded on a rotary tablet press (diameter 7 mm) to give tablets of 120 mg per tablet.

Example 5 Nicergoline 5 parts by weight, Mannit 60 parts by weight, Lactose 4
0 parts by weight and 10 parts by weight of sucrose are mixed and put into a fluidized bed granulator (Flocoater manufactured by Freund Corporation), and water containing 7 parts by weight of polyethylene glycol (average molecular weight 4000) is added thereto, and granulation is performed. dry. The dried granules are crushed with a power mill and sieved with a 32 mesh JIS standard sieve. Then, 0.5 part by weight of magnesium stearate is added and mixed, and the mixture is compression-molded by a rotary tableting machine (diameter 7 mm) to obtain a tablet of 120 mg per tablet.

[0023]

The oral pharmaceutical preparation of the present invention comprising the pharmaceutically active ingredient nicergoline and mannitol or (and) lactose and polyethylene glycol is stable as the pharmaceutical active ingredient for a long period of time, and is excellent as a pharmaceutical preparation. It has the property which was. Furthermore, according to the present invention, since nicergoline serves as a binder, despite the fact that polyethylene glycol which is apt to cause tableting troubles such as mannitol and sticking, which is conventionally said to be inferior in moldability, is used, its formulation Since a good preparation can be obtained without causing any trouble in the preparation, an oral pharmaceutical preparation which is simple and economical and has excellent storage stability can be obtained.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ identification code FI A61K 47/34 A61K 47/34 J (58) Investigated field (Int.Cl. ⁶ , DB name) A61K 31/48 A61K 9 / 20 A61K 9/30 A61K 47/10 A61K 47/26 A61K 47/34 CA (STN)

Claims (2)

(57) [Claims] 1. A tablet comprising nicergoline and mannitol or / and lactose, and polyethylene glycol. 2. A tablet obtained by film-coating the tablet of claim 1.