JPH0463858B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a hydrogenated ergot alkaloid sustained release preparation and a method for producing the same. Hydrogenated ergot alkaloids have effects on the circulatory system; for example, dihydroergotoxine is used to treat cerebrovascular insufficiency, hypertension, etc., and dihydroergotamine is used to treat orthostatic hypotension, migraine, etc. . The therapeutic effects of drugs that act on the circulatory system are closely related to blood concentration, but the elimination half-life of hydrogenated ergot alkaloids from the blood is short, within about 4 hours.
It needs to be taken several times a day. Moreover, many patients who require treatment with hydrogenated ergot alkaloids are elderly, and compliance problems are likely to occur. In order to maintain the therapeutic effect of hydrogenated ergot alkaloids with a reduced number of doses, it is necessary to achieve sustained release of the formulation, but this is not always easy. For example, in Belgian patent No. 882913,
Formulations have been shown that release dihydroergotoxine gradually over a 12 hour period by coating with an enteric base. However, this formulation
The AUC (area under the one-hour blood concentration curve) is considerably smaller than that of the immediate-release formulation. In other words, hydrogenated ergot alkaloids are poorly absorbed from the gastrointestinal tract, and when attempts are made to achieve sustained release using conventional sustained release methods such as wax matrices, plastic matrices, and enteric-coated base coatings, sufficient blood concentration cannot be obtained. Not only is this not sustainable, but the bioavailability is significantly reduced. In order to improve these shortcomings,
Publication No. 87718 describes a solid enteric coating composition containing an ergot alkaloid and a polyalkoxyalkylene sterol ether in the core, which delays the time to reach the maximum blood concentration and improves bioavailability. It has been shown that However, this composition does not maintain blood concentration sufficiently, and polyalkoxyalkylene sterol ether is not preferred as an additive for oral administration from a safety standpoint. Furthermore, Japanese Patent Publication No. 58-54122 discloses that in order to improve the gastrointestinal absorption of ergot alkaloids, ergot alkaloids and solid polymers such as polyethylene glycol and polyvinylpyrrolidone are dissolved in a solvent, and after the solvent is distilled off, they are powdered. Formulations containing the resulting solid solutions are described. However, ergot alkaloids, especially their salts, are themselves soluble in water to some extent, and the absorption improvement effect is not based on improved solubility by solid solution formation with solid polymers such as polyethylene glycol and polybilylpyrrolidone. From this explanation, it is thought that converting the ergot alkaloid into a solid solution does not necessarily lead to improved absorption, but rather that the use of a specific solid polymer brings about the effect of improving absorption. On the other hand, it is known that ergot alkaloids are unstable in polyethylene glycol, and polyvinylpyrrolidone has strong hygroscopicity, and its solid solution is unstable against humidity and easily deteriorates over time. Furthermore, it is not practical on an industrial scale to dissolve the ergot alkaloid and solid polymer in a solvent to obtain a solid solution, evaporate the solvent from this solution to dryness, and then pulverize the residue. In view of these circumstances, the present inventors conducted research to develop a stable and easy-to-manufacture sustained-release preparation that can maintain blood concentration without impairing the bioavailability of hydrogenated ergot alkaloids. As a result, the present invention was completed. The present invention provides a coating consisting of a water-soluble gel polymer containing a hydrogenated ergot alkaloid and a coating consisting of an enteric base and/or ethyl cellulose on core particles obtained by granulating a water-soluble pharmaceutical additive. This is a hydrogenated ergot alkaloid sustained-release preparation. According to the present invention, it is possible to create a multiple unit formulation in which each granule is designed to have sustained release properties, and when administered orally, there is less variation in gastric emptying rate compared to tablets. Because of its small size, it is less susceptible to dietary influences and has less variation among patients, making it possible to obtain a good sustained-release preparation with stable and sustained action. The preparation of the present invention is produced by spraying an organic solvent solution containing a hydrogenated ergot alkaloid and a water-soluble gel polymer onto core particles obtained by granulating a water-soluble pharmaceutical additive, and then drying the resulting coating. coated with an enteric base and/or ethyl cellulose, or
Alternatively, it can be manufactured by applying both coatings in the reverse order. The formulation of the present invention can maintain a sustained blood concentration of hydrogenated ergot alkaloids without impairing their bioavailability. Furthermore, the water-soluble gel polymers used in the present invention, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose, do not cause deterioration of hydrogenated ergot alkaloids, making it possible to provide stable preparations. Furthermore, during production, the organic solvent solution of the hydrogenated ergot alkaloid and water-soluble gel polymer can be directly sprayed onto the core particles consisting of the water-soluble pharmaceutical additive and dried, so it can be used in fluidized bed granulation coaching equipment, pan coaching equipment, etc. By using , it is easy to produce on an industrial scale without any GMP problems. Examples of hydrogenated ergot alkaloids include dihydroergotamine, dihydroergocornine, dihydroergocristine, α- and β-dihydroergocriptine, and the like. Although they can be used individually, it is preferred to use dihydroergotoxin and dihydroergotamine, which are equal mixtures of dihydroergocornine, dihydroergocristine, α- and β-dihydroergocriptine. These may be free bases, organic acid salts such as methanesulfonic acid, ethanesulfonic acid, tartaric acid, citric acid, acetic acid, or inorganic acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid. The core particles in the present invention include, for example, lactose, sucrose,
Adding bonds such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, gum arabic, etc. to water-soluble pharmaceutical additives such as glucose, mannitol, and sorbitol,
It can be produced by granulation using commonly used methods such as extrusion granulation, fluidized bed granulation, and rolling granulation. The amounts of water-soluble pharmaceutical additives and binders used are not particularly limited and may be the same as in the case of normal granulation. Furthermore, a surfactant etc. can also be added. Further, spherical fine particles (so-called nonpareil seeds) made of crystalline lactose, crystalline sucrose, etc. can also be used as core particles. There is no limit to the size of the core particle, but it is 0.1~
2 mm is preferred. The water-soluble gel polymer used in the present invention may be one that is easily soluble in water and forms a film when the solution is dried, such as hydropropyl cellulose,
It is preferable to use cellulose derivatives such as hydroxypropyl methylcellulose and methylcellulose. Hydroxypropylcellulose is JP No. 10 "Hydroxypropylcellulose", and hydroxypropylmethylcellulose is "Hydroxypropylmethylcellulose 2208, 2906,"
Examples of methylcellulose include ``Methylcellulose''. The blending ratio of hydrogenated ergot alkaloid and water-soluble gel polymer is 1:1 to 20 (weight ratio), preferably 1:2 to 10 (weight ratio). To coat core particles with a water-soluble gel polymer containing hydrogenated ergot alkaloids, dissolve a predetermined amount of each in an organic solvent, and apply the core particles or coat while maintaining this solution in a fluid or rotating state. What is necessary is to uniformly spray the core particles and dry them. Organic solvents include methanol, ethanol, acetone,
Those that can dissolve hydrogenated ergot alkaloids and water-soluble gel polymers, such as methylene chloride, trichloroethane, and mixtures thereof, are used. In addition to nonionic and anionic surfactants that are acceptable for safety, this coating also contains organic acids such as tartaric acid and citric acid, sugars such as sucrose, glucose, lactose, and starch, crystalline cellulose, Formulation aids such as silicic anhydride, magnesium silicate, and magnesium metasilicate aluminate can also be blended. To blend these, they can be deposited in powder form when spraying an organic solvent solution of hydrogenated ergot alkaloid and water-soluble gel polymer, or they can be dissolved or suspended in the solution and then sprayed. good. The enteric base used in the present invention is preferably one that dissolves at a pH of 5.0 or higher, such as hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, methacrylic acid methyl methacrylate copolymer, and sierac. Mixtures of these can also be used. Hydroxypropyl methylcellulose phthalate is JP
10 "Hydroxypropyl methyl cellulose phthalate 200731, 220824", "Cellulose acetate phthalate" as cellulose acetate phthalate,
As carboxymethylethylcellulose
Examples include CMEC (manufactured by Freund Sangyo Co., Ltd.), methacrylic acid methyl methacrylate copolymer such as "Eudragid L", a non-regular product, and JP 10 "Refined Shellac, White Shellac" as a Sierra. Examples of ethyl cellulose include ``ethyl cellulose,'' which is a non-governmental drug. The enteric base and/or ethyl cellulose coating in the present invention may be any of an enteric coat made of an enteric base, an ethyl cellulose coat made of ethyl cellulose, and a mixed coat made of an enteric base and ethyl cellulose. Soluble coatings and mixed coatings are preferred. In the case of mixed coating, the blending ratio of enteric base and ethyl cellulose is 1:0.02
-10 (weight ratio), preferably 1:0.05-2. To apply this coating, a predetermined amount of enteric base and/or ethylcellulose is dissolved in an organic solvent, and this solution is kept in a fluid or rotating state to form a coating consisting of a hydrogenated ergot alkaloid and a water-soluble gel polymer. The treated core particles may be uniformly sprayed and dried. Examples of organic solvents used include methanol, ethanol, acetone, methylene chloride, trichloroethane, and mixtures thereof. Preferably, a suitable plasticizer such as diethyl phthalate, triacetin, acetylated monoglyceride, etc. is blended into this solution. When applying these coatings, auxiliary agents commonly used in coating may be added, such as anti-adhesion agents such as talc and silicic acid, waxes, and coloring agents. Further, the equipment for applying the coating may be any ordinary equipment used when applying a coating to tablets, granules, etc., such as a fluidized bed granulation coaching equipment, a centrifugal fluid granulation coaching equipment, a vacuum granulation/drying coating equipment,
Examples include bread coaching equipment. The preparation of the present invention comprises a water-soluble polymer coating containing a hydrogenated ergot alkaloid, an enteric base and/or
Alternatively, each layer may have two or more layers of ethyl cellulose. Further, the outermost layer of the preparation may be any of the above-mentioned coatings. When applying multiple layers of water-soluble gel polymer coatings containing hydrogenated ergot alkaloids, the compositions of each coating need not be the same. The type of water-soluble gel polymer may be different, and the blending ratio of hydrogenated ergot alkaloid and water-soluble gel polymer may be changed. The same holds true for enteric base and/or ethyl cellulose coatings. The thickness of each coating varies depending on the hydrogenated ergot alkaloid content, coating composition, number of coatings, etc., and is not uniform, but it is preferably 5 to 100 μm per coating. The ergot alkaloid content is preferably 5 to 80 mg per gram of the preparation. The preparation of the present invention may be administered directly as fine granules or granules, but the granules may also be filled into capsules to form capsules or tablets may be compressed. Example 1 5 kg of lactose was put into a fluidized bed granulation coaching device,
Add 75g of hydroxypropylcellulose to this and add water.
A solution dissolved in 3000 ml was sprayed, granulated, dried, and sized to obtain core particles of 32 to 42 meshes. 450 g of the core particles were placed in a centrifugal flow granulation coating device, and 10 g of dihydroergotamine mesylate was added.
and hydroxypropyl methylcellulose 2910
40g of ethanol/methylene chloride (3:2) mixture
A coating liquid dissolved in 1500 ml was sprayed at a spray rate of 10 ml/min and dried. Next, a coating solution prepared by dissolving 100 g of hydroxypropyl methylcellulose phthalate 200731 and acetylated monoglyceride (Myverset 9-40T) as a plasticizer in 1200 ml of an ethanol/methylene chloride (3:7) mixture was sprayed.
Formulation A was obtained by drying. In addition, talc was added as an anti-adhesion agent at a ratio of 2 g to 100 ml of the coating solution. Example 2 870 g of the core particles obtained in Example 1 were placed in a centrifugal fluid coating device, and a coating solution having the following composition was sprayed in the order of A to B in the same manner as in Example 1, followed by drying to obtain Preparation B.

[Table] Example 3 810 g of the core particles obtained in Example 1 were placed in a centrifugal fluid granulation coating device, and a coating liquid having the following composition was sprayed in the order of A to E in the same manner as in Example 1, and dried to form Formulation C. I got it.

[Table] Example 4 910 g of Nonpareil-101 was placed in a centrifugal granulation coating device, and a coating liquid having the following composition was sprayed in the order of A to D in the same manner as in Example 1, followed by drying to obtain Formulation D.

[Table] Comparative example 1 Dihydroergotamine mesylate 20g, lactose
610g, wheat starch 200g, microcrystalline cellulose 100g
and 50g of carboxymethyl cellulose,
5% hydroxypropylcellulose aqueous solution 400ml
was added, kneaded, and granulated using an extrusion granulator, and then made into spherical granules using a marmerizer to obtain core particles of 20 to 30 meshes. 500 g of these core particles were placed in a centrifugal flow granulation coating device, and 100 g of hydroxypropyl methylcellulose phthalate 200731 and acetylated monoglyceride (Myverset 9-
40T) to ethanol/methylene chloride (3:7)
A comparative preparation P was obtained by spraying and drying the coating liquid dissolved in 1200 ml of the mixed liquid. Test Example 1 A dissolution test was conducted on the formulation A of the present invention obtained in Example 1 and the comparative formulation P obtained in Comparative Example 1. The test was conducted in accordance with JP10 ``Dissolution Test Method - Method 1 (Rotating Basket Method)'', and the test solution was tested under JP10 for up to 2 hours.
1st liquid, then JP 10 2nd liquid, the amount of liquid is
The volume was 900ml. A sample in an amount equivalent to 9 mg of dihydroergotamine mesylate was added, and the eluate was sampled every hour and quantified using a fluorometer to determine the elution rate. The test results are shown in Figure 1. Comparative formulation P shows slow dissolution after dissolution of the enteric coating, whereas inventive formulation A
It is known that the dissolution of the enteric coating is rapid. In addition, FIG. 2 shows the dissolution test results of the present invention formulations B, C, and D obtained in Examples 2 to 4. It is known that dissolution is controlled in these preparations. Test Example 2 Coating liquids with the following compositions were each sprayed onto 200 g of the core particles obtained in Example 1, dried, and heated to 40°C and 75% RH.
After storage for 30 days, changes in appearance (coloration) were examined.

【table】

[Table] The test results are shown in the table below. K was colored pale yellow, whereas I and J were stable with no change observed.

【table】 [Brief explanation of the drawing]

FIG. 1 is a graph showing the results of the dissolution test for the formulations obtained in Example 1 and Comparative Example 1, and FIG. 2 is a graph showing the results of the dissolution test for the formulations obtained in Examples 2 to 4. , A to D are the formulations of the present invention, and P is the comparative formulation.

Claims (1)

[Claims] 1. A coating made of a water-soluble gel polymer containing hydrogenated ergot alkaloid, an enteric base and/or a core particle obtained by granulating a water-soluble pharmaceutical additive.
A hydrogenated ergot alkaloid sustained release preparation having a coating made of or ethyl cellulose. 2. A patent claim in which the water-soluble gel polymer is hydroxypropylcellulose, hydroxypropylmethylcellulose, and/or methylcellulose, and the blending ratio of hydrogenated ergot alkaloid and water-soluble gel polymer is 1:1 to 20 (weight ratio). Range 1
Preparations described in section. 3. The formulation according to claim 1, wherein the enteric base is hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, methacrylic acid methyl methacrylate copolymer and/or silica. 4 An organic solvent solution containing a hydrogenated ergot alkaloid and a water-soluble gel polymer is sprayed onto core particles obtained by granulating a water-soluble pharmaceutical additive, and then dried, and an enteric base is applied onto the resulting coating. A method for producing a sustained-release hydrogenated ergot alkaloid preparation, characterized by applying a coating consisting of and/or ethyl cellulose, or applying the coating in the reverse order.