JPS615010A - Sustained release preparation of hydrogenated ergot-alkaloid and its preparation - Google Patents

Abstract

PURPOSE:The titled pharmaceutical preparation capable of keeping blood concentration without damaging biological utility, obtained by coating nucleated particles of water-soluble additional matter of drug with a water-soluble gel high polymer film containing a hydrogenated ergot-alkaloid and a film consisting of an enteric base. CONSTITUTION:The surface of nucleated particles obtained by granulating a water-soluble additional matter of drug (e.g., lactose, or mannitol) is sprayed with a solution of a hydrogenated ergot-alkaloid (e.g., dihydroergotoxine) and a water-soluble gel high polymer such as hydroxypropyl cellulose, hydroxypropylmethyl cellylose, etc. in a blending ratio (weight ratio) of the former to the latter of 1:1-20, preferably 1:2-10 in an organic solvent, and it is dried. The prepared film is coated with a film of coating consisting of an enteric base (e.g., hydroxypropylmethyl cellulose phthalate) and/or ethyl cellulose, or coated in the opposite order, to give the aimed sustained release preparation.

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. It is being

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, approximately 4 hours or less, and it is necessary to take them several times a day. . Moreover, many patients who require treatment with hydrogenated ergot alkaloids are elderly, and problems with medication compliance 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, Belgian Patent No. 882,913 describes a formulation that releases dihydroergotoxine gradually over a 12 hour period by coating with an enteric base.

However, the AUC (area under the blood concentration one-hour curve) of this preparation
is considerably smaller than the AUG of the immediate release formulation. In other words, hydrogenated ergot alkaloids are poorly absorbed from the gastrointestinal tract, and when attempting to achieve sustained release using conventional sustained release methods such as coating with wax hetrix, plastic matrix, or enteric base, it is difficult to maintain sufficient blood concentration. Not only is this not possible, but the bioavailability is significantly reduced.

In order to improve these drawbacks, Japanese Patent Application Laid-Open No. 55-87718
The publication describes a solid enteric coating composition containing an ergot alkaloid and a polyalkoxyalkylene sterol ether in the core, which does not delay 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, in order to improve the gastrointestinal absorption of ergot alkaloids, Japanese Patent Publication No. 5B-54122 discloses that ergot alkaloids and solid polymers such as polyethylene glycol and polyvinylpyrrolidone are dissolved in a solvent, and after the solvent is distilled off, the product is powdered. Formulations containing solid solutions have been described. However, ergot alkaloids, especially their salts, are soluble in water to some extent, and the absorption improvement effect is based on improved solubility by forming a solid solution with solid polymers such as polyethylene glycol and polyvinylpyrrolidone. Since it is explained that ergot alkaloid is not necessarily a solid solution, it does not necessarily lead to improved absorption.
Rather, it is thought that the use of a specific solid polymer brought about the absorption improvement effect.

On the other hand, it is known that ergot alkaloids are unstable in polyethylene glycol, and that polyvinylpyrrolidone is highly hygroscopic 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 is a sustained-release hydrogenated ergot alkaloid preparation comprising a base obtained by granulating a water-soluble pharmaceutical additive and a coating made of ethyl cellulose.

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 prepared 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 mixture.
It can be produced by applying MU of an enteric base and/or ethyl cellulose on the resulting coating, or 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 sulfuroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose, do not cause deterioration of hydrogenated ergot alkaloids, so that stable preparations can be provided. Furthermore, during production, an organic solvent solution of hydrogenated ergot alkaloids and water-soluble gel polymers can be directly sprayed onto core particles made of water-soluble pharmaceutical additives and dried, so it can be used in fluidized bed granulation coaching equipment, pan coaching equipment, etc. By using this, there are no GMP problems and production on an industrial scale is easy.

Hydrogenated ergot alkaloids include dihydroergotamine, dihydroergocornine, dihydroergoherlistin, α- and β-dihydroergocributine, and the like. Although they can be used individually, it is preferred to use dihydroergotoxine and dihydroergotamine, which are isocompounds of dihydroergocornine, cyhydroergocristen, α- and β-dihydroergocributine. 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 are water-soluble pharmaceutical additives 1 such as lactose, sucrose, glucose, mannitol, and sorbitol, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone,
Add a solution of a binder such as polyvinyl alcohol, gelatin, or gum arabic dissolved in water and/or an organic solvent, and granulate using a commonly used method such as extrusion granulation, fluidized bed granulation, or transfer granulation. It can be manufactured by

The amount of the water-soluble pharmaceutical additive and the binder (4Vc) is not particularly limited and may be the same as in the case of ordinary granulation. Furthermore, a surfactant etc. can also be added.

Further, spherical fine particles (so-called non-barrel 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 particles, but 0.1 to 2 inches 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 (cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose can be used). Preferred. Hydroxypropyl.

Cellulose has a diurnal cycle of 10 ``Hydroxypropylcellulose'', and hydroxypropyl methylcellulose has a diurnal cycle of ``Hydroxypropyl methylcellulose 2208''.
．． 2906.2910'', and examples of methylcellulose include the same ``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 apply a coating of a water-soluble gel polymer containing hydrogenated ergot alkaloids to a core particle, a predetermined amount of each is dissolved in an organic solvent, and the solution is kept in a fluid or rotating state to coat the core particle or coating. The treated core particles may be uniformly sprayed and dried. As the organic solvent, those capable of dissolving the hydrogenated ergot alkaloid and the water-soluble gel polymer are used, such as methanol, ethanol, acetone, methylene chloride, trichloroethane, and mixtures thereof. 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, and crystalline ululose. Formulation aids such as silicic anhydride, magnesium silicate, and magnesium metasilicate aluminate may also be included. To blend these, they can be applied 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 pH 5.0 or higher, such as hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, carboxymethyl aethyl cellulose, methacrylic acid methyl methacrylate copolymer, shellac, etc. is used. Mixtures of these can also be used.

Hydroxypropyl methylcellulose phthalate has a diurnal frequency of 10 [Hydroxypropyl methylcellulose phthalate 200731.220824J], cellulose acetate phthalate has the same [cellulose acetate phthalate], and carboxymethyl ethyl cellulose has a diurnal frequency of 10
c@ (manufactured by Freund Sangyo Co., Ltd.), methacrylic acid methyl methacrylate copolymer with a non-local standard "Eudragid", shellac with a diurnal frequency of 10 "refined shellac,"
Examples include "white shellac". 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 includes an enteric coat made of an enteric base, an ethyl cellulose coat made of ethyl cellulose, an enteric base,! : Any mixed coating made of ethyl cellulose may be used, but enteric coatings and mixed coatings are particularly preferred. In the case of a mixed film, the blending ratio of the enteric base and ethyl cellulose is 1:0.02 to 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. This solution contains a suitable plasticizer such as diethyl phthalate,
It is preferable to include triacetin, acetylated monoglyceride, and the like.

When applying these films, auxiliary agents commonly used in coating may be added, such as anti-adhesion agents such as talc and silicic acid, waxes, and colorants. 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 coating equipment, a centrifugal fluid granulation coating equipment, a vacuum granulation/drying coating equipment, Examples include bread coaching equipment.

The preparation of the present invention may each have two or more layers of a water-soluble polymer coating containing hydrogenated ergot alkaloid and an enteric base and/or ethyl cellulose coating.

Further, the outermost layer of the preparation may be any of the above-mentioned coatings.

When applied to multiple layers of water-soluble gel polymer coatings containing hydrogenated ergot alkaloids, the compositions of the respective coatings do not need to 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 film is determined by the hydrogenated ergot alkaloid content,
Although it is not uniform because it varies depending on the coating composition, the number of times the coating is applied, etc., it is preferably 5 to 100 μm per coating. Further, the ergot alkaloid content in Preparation 19 is preferably 5 to 80 mg.

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 compressed to form tablets.

Example 1 5 kg of lactose was placed in a fluidized bed granulation coating device, and 75 g of hydroxypropyl cellulose was added to it in water.
A solution dissolved in 100 ml was sprayed, granulated, dried, and then sized to obtain core particles of 62 to 42 meshes.

450 g of these core particles were placed in a centrifugal flow granulation coating device, and 10 g of dihydroergotamine mesylate and 2910040 g of hydroxypropyl methyl cellulose were added to a mixture of ethanol and methylene chloride (3:2) at 1500 rrt.
Spray the coating liquid dissolved in 10ml at a spray rate of 10rnl/min,
Dry. Then 100.9 of hydroxyglobil methylcellulose phthalate 200731 and acetylated monoglyceride (Myversera) 9-40 as a plasticizer.
T■) into a mixture of ethanol and methylene chloride (5nia) 12
00mA! Formulation A is obtained by spraying and drying the coating liquid dissolved in
I got it. It was added as a talc anti-adhesion agent at a rate of 2 g per 1.0 ml of 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 liquid having the following composition was prepared in the same manner as in Example 1.
Formulation B was obtained by spraying and drying in this order.

Example 3 810 g of the core particles obtained in Example 1 were placed in a centrifugal flow 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 obtain Formulation C. .

Example 4 910 g of 101 g of 77 particles was placed in a centrifugal fluid granulation coating device, and a coating liquid having the following composition was sprayed in the same order as in Example 1, followed by drying to obtain a formulation.

Comparative Example 1 20 g of dihydroergotamine mesylate, 610 g of lactose
, 200 g of wheat starch, 100 g of microcrystalline cellulose and 50 g of carboxymethyl cellulose were mixed, kneaded by adding 400 ml of 5% hydroxypropylcellulose aqueous solution, granulated using an extrusion granulator, and then made into spherical granules using a marmerizer. Core particles of 20-30 meshes were obtained.

500 g of this core particle was placed in a centrifugal fluid granulation coating device, and hydroxypropyl methylcellulose phthalate)2
Comparative formulation P was obtained by spraying and drying a coating solution in which 100 g of 007310 and acetylated monoglyceride (Myversera) 9-40T''3 as a plasticizer were dissolved in 1200 m/+ of a mixed solution of ethanol and methylene chloride (5N).

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 according to the diurnal cycle 10 "Dissolution test method, method 1 (rotating basket method)", and the test solution was the diurnal cycle 10 first solution up to 2 hours, and the diurnal cycle 10 second solution thereafter, and the liquid volume was 900 ml. And so. A sample in an amount corresponding to dihydroergotamine mesylate 9rn9 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. It is known that in comparison preparation P, dissolution after dissolution of the enteric coat is slow, whereas in preparation A of the present invention, dissolution after dissolution of the enteric coat 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 The core particles 20 obtained in Example 1 were each coated with a coating liquid having the following composition.
It was sprayed onto 0 g and dried, stored at 40'C, 175% RH for 60 days, and examined for changes in appearance (coloration).

The test results are shown in the following table.At 1°K, the color was pale yellow, whereas at 1°K, no change was observed and it was stable.

[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)

[Scope of Claims] 1. A coating made of a water-soluble gel polymer containing hydrogenated ergot alkaloid, an enteric base and/or ethyl cellulose on core particles obtained by granulating a water-soluble pharmaceutical additive. A hydrogenated ergot alkaloid sustained release preparation having a coating consisting of. 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) The formulation according to item 1. 3. The formulation according to claim 1, wherein the enteric base is hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methacrylic acid methyl methacrylate copolymer and/or shellac. 4. Core particles obtained by granulating water-soluble pharmaceutical additives,
An organic solvent solution containing a hydrogenated ergot alkaloid and a water-soluble gel polymer is sprayed and then dried, and a coating made of an enteric base and/or ethyl cellulose is applied on the resulting coating, or a coating is applied in the reverse order. A method for producing a hydrogenated ergot alkaloid sustained-release preparation, the method comprising: