WO2015060313A1

WO2015060313A1 - Preparation having controlled release ability and method for producing same

Info

Publication number: WO2015060313A1
Application number: PCT/JP2014/077992
Authority: WO
Inventors: 卓彦足立; 賀津俊石井
Original assignee: 森下仁丹株式会社
Priority date: 2013-10-22
Filing date: 2014-10-21
Publication date: 2015-04-30
Also published as: JPWO2015060313A1; JP6404826B2; JP2019014725A; JP6686086B2

Abstract

　The invention provides a preparation having controlled release ability with excellent production uniformity, handling properties, and productivity; and a method for producing the same. The invention pertains to a preparation having controlled release ability, characterized by comprising an outer coating containing gelatin and polysaccharides, and contents including a drug inside this outer coating; or characterized by comprising contents including a drug, water-swellable polysaccharides, and fats or oils having a melting point of 37°C or higher, and an outer coating covering these contents.

Description

Formulation having controlled release ability and production method thereof

The present invention relates to a preparation having a controlled release ability and a method for producing the same.

The drug release control technology is a technology for controlling the dissolution and release behavior of a drug in terms of space and time, and is roughly divided into a technology for slow release of the drug and a technology for controlling release by coating the drug. There is. By supplying the minimum required amount of drug to the required place at the time required, the effect of the drug is efficiently improved. In order to achieve such an object, a number of controlled-release preparations have been proposed (

Patent Documents

1 and 2, etc.) centering on the form and components of the preparation containing such a drug.

Patent Document 1 discloses that a core material and a shell wall material are gelatin cross-linked with glutaraldehyde, and 1 to 75% by weight of at least one type that inhibits movement of the core material through the cross-linked gelatin. A microcapsule comprising a capsule shell wall that completely surrounds the core material, wherein the water-soluble plasticizer is a water-soluble starch, saccharide, cyclodextrin, maltodextrin, corn Said microcapsules are described which are selected from syrup solids and sorbitol. However, the above microcapsules have a problem that the dissolution time of the film for releasing the core substance cannot be adjusted.

Patent Document 2 discloses a controlled-release dosage form comprising: (a) a core composed of a penetrant and a low-solubility drug, wherein the drug is in the form of a solid dispersion of the drug in a dispersed polymer. And at least a majority of the drug is amorphous; and (b) a substantially water permeable coating around the core, wherein at least one delivery is in the coating. There is a port, the coating controls the inflow of water from the aqueous use environment to the core, and at least a portion of the core is extruded through the at least one delivery port to the aqueous use environment; and The dosage form is described wherein the coating consists of: non-dissolving and non-erodible during the drug release. However, the above-mentioned controlled release dosage form has a problem that a delivery port needs to be prepared again after preparation preparation.

Japanese Patent Laid-Open No. 6-40807 JP 2000-229846 A

The present invention solves the problems of the conventional controlled release preparations as described above, and provides a preparation having excellent release control ability without impairing manufacturing uniformity, handleability and productivity, and a method for producing the same. The purpose is to do.

In order to solve the problems as described above, the present inventors have intensively researched and used an outer film containing gelatin and a specific polysaccharide, particularly a water-swellable polysaccharide, in a preparation comprising the outer film and the contents. Or by using a content containing a drug, a polysaccharide, particularly a water-swellable polysaccharide, and an oil having a specific melting point, and having excellent production uniformity, handleability and productivity, and The present inventors have found that a preparation having a controlled release ability and a method for producing the same can be provided, and the present invention has been completed.

That is, the present invention includes an outer film containing gelatin and a polysaccharide and a content containing the drug inside the outer film, and the outer film releases the drug by swelling of the polysaccharide. The present invention relates to a preparation having a controlled release characteristic, characterized in that the release of is controlled.

Another embodiment of the present invention includes a content comprising a drug, a water-swellable polysaccharide, and an oil having a melting point of 37 ° C. or higher, and a water-soluble or water-permeable outer film covering the content. There is a preparation having a release-controlling ability, wherein the release of the drug is controlled by releasing the drug from an oil having a melting point of 37 ° C. or higher by swelling of the water-swellable polysaccharide.

Furthermore, in order to implement this invention suitably,
The drug is water-soluble and / or water-insoluble;
The water-swellable polysaccharide is one or more selected from agar, gellan gum, carrageenan, starch, modified starch, dextrin, maltodextrin, cellulose, acetylated cellulose, ethylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose;
The formulation is either a soft capsule or a seamless capsule;
It is desirable.

As yet another aspect of the present invention, (i) a step of mixing a drug, a water-swellable polysaccharide and an oil having a melting point of 37 ° C. or higher to form a content,
(Ii) a step of preparing an outer film forming material;
(Iii) There is a method for producing a preparation, which includes a step of coating the contents with the material for forming an outer film and forming a preparation containing the contents inside the outer film.

According to the present invention, in a formulation comprising an outer film and a content, by using an outer film containing gelatin and a specific polysaccharide, in particular a water-swellable polysaccharide, or a drug, a polysaccharide, in particular a water-swellable By using a content containing polysaccharides and fats and oils having a specific melting point, a preparation having excellent production uniformity, handleability and productivity, and having excellent release control ability, and a method for producing the same are provided. can do.

It is the schematic explaining the chemical | medical agent release mechanism of one aspect | mode of the formulation which has the release control ability of this invention. It is the schematic explaining the drug release mechanism of the other aspect of the formulation which has the release control ability of this invention. It is a seamless capsule of one embodiment of the preparation having controlled release ability of the present invention. The typical longitudinal cross-sectional view which shows one aspect | mode of the nozzle part of the manufacturing apparatus of one aspect (2 layer structure) which made the formulation which has the release control ability of this invention into the form of a seamless capsule is shown. FIG. 3 is a graph showing the release behavior of a drug (carbamazepine) in soft capsules of Examples A-1-1 to A-1-4 of the present invention. FIG. 3 is a graph showing the release behavior of a drug (carbamazepine) in soft capsules of Examples A-1-5 to A-1-8 of the present invention. FIG. 3 is a graph showing the release behavior of a drug (carbamazepine) in seamless capsules of Examples B-1-1 to B-1-4 of the present invention. FIG. 6 is a graph showing the release behavior of a drug (carbamazepine) in seamless capsules of Examples B-1-5 to B-1-8 of the present invention. It is a graph which shows the release | release behavior of the chemical | medical agent (carbamazepine) in the soft capsule of Example C of this invention compared with the soft capsule of Comparative Example C. It is a graph which shows the discharge | release behavior of the chemical | medical agent (ibuprofen) in the seamless capsule of Example D of this invention compared with the seamless capsule of the comparative example D.

As a preparation having release controlling ability of the present invention,
(A) including an outer film containing gelatin and polysaccharide, and a content containing a drug in the outer film;
(B) Some include a content including a drug, a water-swellable polysaccharide, and an oil having a melting point of 37 ° C. or higher, and an outer film covering the content.

Examples of such polysaccharides include, but are not limited to, agar, gellan gum, carrageenan, modified starch, dextrin, maltodextrin, pullulan, trehalose, gum arabic, arabinogalactan, farseleran, pectin, curdlan, psyllium seed gum, xanthan gum , Locust bean gum, guar gum, alginic acid, glucomannan, inulin, fucoidan, glucan, chondroitin sulfate, chitin, chitosan, hydroxypropylmethylcellulose phthalate, acetylated cellulose, ethylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose, acetic acid Water-swellable polysaccharides such as cellulose phthalate, and starch, cellulose, hemicellulose, ligni Water-oil non-swellable polysaccharides such, as well as one or more combinations thereof. In the present specification, “low-substituted hydroxypropyl cellulose” is a product obtained by introducing a hydroxypropoxy group into a glucose ring with a molar substitution degree of 0.2 to 0.4.

Examples of the above-mentioned drugs include drugs that have an unpleasant taste such as bitterness, water-soluble drugs, so as not to feel an unpleasant taste on the tongue, or to suppress sublingual absorption or release a drug in a specific digestive organ. Examples include water-insoluble lipophilic drugs. Examples of the drug include, but are not limited to, acetaminophen, chlorpheniramine maleate, mequitazine, tipepidine hibenzate, diphenhydramine salicylate, meclizine hydrochloride, methylephedrine hydrochloride, guaifenesin, dihydrocodeine phosphate, ibuprofen hydrochloride, ticlopidine hydrochloride , Berberine chloride, digitoxin, sulpyrine, azelastine hydrochloride, ethylephrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride, chloramphenicol, aminophylline, erythromycin, phenobarbital, calcium pantothenate, aminoguanidine hydrochloride, donepezil hydrochloride, meclizine hydrochloride, diphenhydramine hydrochloride, malein Acid chlorpheniramine, phenylpropanolamine hydrochloride, nicotinamide, anhydrous caffeine Vitamin B1 (VB1), vitamin B2 (VB2), vitamin B6 (VB6), vitamin B12 (VB12); ivermectin, spiramycin, ceftiofur, amoxicillin, erythromycin, oxytetracycline, lincomycin, dexamethasone, phenylbutazone, levothyroxine, Dexamethasone palmitate, triamcinolone acetonide, halopredon acetate, indomethacin, aspirin, prostaglandin E1, acetohexamide, estradiol, phenytoin, phenobarbital, carbamazepine, valproic acid, ethosuximide, zonisamide, gabapentin, topiramate, lamotrigine, atropine Thiamine, scopolamine hydrochloride, scopolamine hydrobromide, theophylline, lidocaine Mehibakain, such as dibucaine and the like.

Formulation having controlled release ability (a)
The preparation (a) of the present invention includes an outer film containing gelatin and a polysaccharide and a content containing a drug inside the outer film. As the polysaccharide used in the outer coating, since water supply from the external environment to the water-swellable polysaccharide by the water oil non-swellable polysaccharide is essential, among the above examples, the water-swellable polysaccharide and water A combination of non-oil swellable polysaccharides is preferred, with a combination of agar and crystalline cellulose being more preferred. As shown in FIG. 1, the preparation (20) comprises an outer film containing gelatin (24), a water-swellable polysaccharide (22) and a water-oil non-swellable polysaccharide (23), When the formulation (20) is placed in water (25) by including the contents containing the drug (21) inside and including the water-swellable polysaccharide (22) in the gelatin (24) base. The water-swellable polysaccharide (22) swells or dissolves to form a path (26) through which the drug (21) is eluted from the outer film, or the outer film is disrupted, and the type of the water-swellable polysaccharide is The drug release can be controlled within a range of 0.5 to 30 minutes by adjusting the content.

The dry content of the water-swellable polysaccharide in the outer film is 0.01 to 30% by mass, preferably 0.05 to 25% by mass, more preferably 0.1 to 20% by mass. desirable. When the content of the water-swellable polysaccharide is less than 0.01% by mass, the drug elution rate becomes too high, and when it exceeds 30% by mass, the drug elution rate is low or not eluted. The dry content of the water-oil non-swelling polysaccharide in the outer film is 0.01 to 30% by mass, preferably 0.05 to 25% by mass, more preferably 0.1 to 20% by mass. It is desirable that If the content of the non-swelling polysaccharide is less than 0.01% by mass, the amount of water supplied from the outside and the rate of supply to the outer film will decrease, and no dissolution or disintegration of the film will be seen. Release is not observed, and if it exceeds 30% by mass, the dissolution rate of the drug becomes too high.

As the contents of the preparation (a) of the present invention, the drug may be dissolved in liquid oil (melting point less than 37 ° C.) under the use environment of the preparation. Examples of the fats and oils include, but are not limited to, coconut oil, rapeseed oil, palm oil, olive oil, jojoba oil, corn oil, rice oil, rice germ oil, soybean oil, fish oil and other animal and vegetable oils, silicone oil, carbon number Examples thereof include substituted esters of saturated fatty acids of 4 to 10 and glycerol. In terms of formulation, rapeseed oil, coconut oil, palm oil, soybean oil and the like are preferable.

The content of the drug in the content of the preparation (a) is desirably 0.1 to 30% by mass, preferably 0.5 to 30% by mass, and more preferably 1 to 30% by mass. If the content of the drug is less than 0.1% by mass, the effect of the drug is small, and if it exceeds 30% by mass, it is not desirable in terms of formulation.

The method for producing the preparation (a) of the present invention comprises:
(I) providing a content containing a drug;
(Ii) a step of preparing a material for forming an outer film by mixing gelatin and polysaccharide;
(Iii) covering the contents with the material for forming an outer film, and forming a preparation containing the contents inside the outer film.

The method of coating the contents of the step (iii) with the outer film-forming material is not particularly limited, but in consideration of the production uniformity and productivity of the preparation, the below-mentioned seamless capsules and soft capsules are formed. The method to do is desirable.

The method for producing the preparation (a) of the present invention, particularly the method for coating the contents with the outer film, is not particularly limited. However, in consideration of the production uniformity and productivity of the preparation, A method of forming soft capsules is desirable.

Formulation having controlled release ability (b)
The said formulation (b) of this invention includes the content containing the chemical | medical agent, water-swellable polysaccharide, and the fats and oils which have melting | fusing point of 37 degreeC or more, and the outer membrane | film | coat which coat | covers the said content. Among the above examples, the water-swellable polysaccharide is preferable and the carrageenan is more preferable as the polysaccharide used for the content. As shown in FIG. 2, the preparation (30) comprises a drug (31), a water-swellable polysaccharide (32), and a content containing an oil (33) having a melting point of 37 ° C. or higher, and the content. The water-swellable polysaccharide (32) is contained in the contents, so that when the preparation (30) is placed in water (35), the water-swellable The saccharide (32) swells or dissolves to form a path through which the drug (31) elutes in the contents, and the release can be controlled by adjusting the type and content of the water-swellable polysaccharide.

Examples of fats and oils having a melting point of 37 ° C. or higher are not particularly limited as long as they are solid under the use environment of the above preparation, but animal and vegetable oils such as coconut oil, rapeseed oil, soybean oil, beef tallow, lard, fish oil, Examples include hydrogenated hydrogenated oil, beeswax, carnauba wax, substituted esters of saturated fatty acids having 4 to 10 carbon atoms and glycerol. From the viewpoint of formulation, coconut oil, rapeseed oil, soybean oil, or hydrogenated hydrogenated oil thereof is preferable. The melting point of the fat is preferably 40 ° C. or higher, more preferably 40 to 90 ° C.

The content of the drug in the content of the preparation (b) is 0.1 to 40% by mass, preferably 0.5 to 40% by mass, more preferably 1 to 35% by mass. When the content of the drug is less than 0.1% by mass, the effect of the drug is small, and when the content exceeds 40% by mass, it is not preferable in terms of formulation.

The content of the polysaccharide in the content of the preparation (b) is 0.01 to 40% by mass, preferably 0.1 to 40% by mass, more preferably 0.5 to 35% by mass. Is desirable. When the polysaccharide content is less than 0.01% by mass, the drug elution rate is low or not eluted, and when it exceeds 40% by mass, the drug elution rate becomes too high.

The content of the oil having a melting point of 37 ° C. or higher in the content of the preparation (b) is 5 to 95% by mass, preferably 10 to 90% by mass, more preferably 20 to 80% by mass. Is desirable. If the content of the oil or fat is less than 5% by mass, the contents cannot be immobilized, and if it exceeds 95% by mass, the content of the drug is reduced, so that an effective release amount cannot be maintained.

In the preparation (b), as described above, it can function as a preparation having a release control ability only with the contents, so that only the contents may be molded into a preparation, but handling properties, productivity, etc. are improved. Considering this, it is desirable to coat the above contents with an outer film using a normal capsule film material such as gelatin.

The method for producing the preparation (b) of the present invention comprises:
(I) a step of mixing a drug, a water-swellable polysaccharide, and an oil having a melting point of 37 ° C. or higher to form a content;
(Ii) a step of preparing an outer film forming material;
(Iii) covering the contents with the material for forming an outer film, and forming a preparation containing the contents inside the outer film.

(Seamless capsule)
Hereinafter, a seamless capsule as one form of a preparation having a release controlling ability of the present invention and a production method thereof will be described in detail. The seamless capsule of the present invention comprises a content and an outer film including the content. The seamless capsule can be formed with a diameter of 0.1 to 10 mm, preferably within a range of 0.3 to 8 mm.

Hereinafter, with reference to FIGS. 3 to 4, the seamless capsule as one form of the preparation having the release controlling ability of the present invention and the production method thereof will be described in more detail. FIG. 3 is a schematic cross-sectional view schematically showing one embodiment (two-layer structure) in which the preparation having release controlling ability of the present invention is formed into a seamless capsule form. The seamless capsule (10) comprises a content (1) containing a drug and an outer coating (2) containing the content. As shown in FIG. 3, the simplest structure of the seamless capsule is a two-layered seamless capsule having a single-layer outer coating (2).

The above-described seamless capsule manufacturing method basically includes discharging the content liquid from the inner nozzle of the multi-nozzle and the outer film preparation liquid as the outer film forming material from the outer nozzle into the carrier fluid at the same time. A seamless capsule having a two-layer structure in which the content liquid is wrapped with the outer film preparation liquid is formed to obtain a desired capsule.

The viscosity of the outer film preparation solution is preferably 30 to 350 mPa · s at 60 ° C., more preferably 50 to 300 mPa · s, and still more preferably 100 to 250 mPa · s. When the viscosity of the outer film preparation liquid is within the above range, there is an advantage that seamless capsule preparation by the dropping method can be performed satisfactorily.

The viscosity of the content liquid is preferably 20 to 350 mPa · s at 60 ° C., more preferably 50 to 300 mPa · s, and still more preferably 100 to 250 mPa · s.

As shown in FIG. 4, the method for producing a seamless capsule which is one aspect of the present invention uses a double nozzle to feed the outer film preparation liquid to the inner first nozzle (120) and the contents liquid to the outer side. Each is supplied to the second nozzle (110). Then, these liquids are simultaneously extruded from the tips of the respective annular holes, and the obtained two-phase composite jet is discharged into the cooling liquid flowing down, whereby the seamless capsule (10) according to the present invention can be obtained. Here, “jet” refers to an extrudate obtained by continuously extruding a fluid, and “composite jet” refers to a jet having a plurality of phases (layers).

This cooling liquid is typically 35 ° C. or lower, preferably 0 to 30 ° C. The temperature of each liquid extruded from the nozzle is not particularly limited, but is typically 15 to 90 ° C., preferably 20 to 85 ° C.

As the cooling liquid, for example, medium chain fatty acid triglyceride (MCT), vegetable oil (such as coconut oil, sunflower oil, safflower oil, sesame oil, rapeseed oil, grape seed oil, and a mixture thereof), liquid paraffin and a mixture thereof are used. be able to.

In the above manufacturing method, it is also possible to impart proper vibration to the composite jet flow using the vibrating means to improve the cutting of the composite jet, to make the particle diameter uniform, and to facilitate encapsulation. It is more preferable to use a concentric multiple nozzle as the multiple nozzle.

Furthermore, in order to perform precise release control, a seamless capsule having a three-layer structure or a four-layer structure can be used. When the seamless capsule has a three-layer structure, examples of the liquid material that separates the contents from the outer film include the above-described lipophilic liquid materials. When preparing a seamless capsule having a three-layer structure, the above diagram is used except that a concentric triple nozzle having a new nozzle is provided further inside the first nozzle (120) (inner nozzle) shown in FIG. 4 can be produced using a method similar to the method shown in FIG. A seamless capsule having a four-layer structure can also be produced using the same method.

(Soft capsule)
As in the case of seamless capsules, soft capsules have a structure in which a non-aqueous solvent solution is used as a content liquid and is surrounded by an outer film sheet.

The content liquid is prepared in the same manner as in the case of the seamless capsule, and as the material for the outer film sheet, the same material as the material for forming the outer film of the seamless capsule described above is used and the sheet is used in accordance with a conventional method. Can do. In the production of soft capsules, the outer film sheet and the contents liquid are used, and a rotary die type capsule filling machine (for example, “S-1” manufactured by Kamata Co., Ltd.) is used. A soft capsule is formed by ejecting the content liquid between the sheets with a pump that is fed between the rotating cylindrical molds and interlocked therewith.

The long diameter of the soft capsule is usually 3 to 16 mm, and the short diameter is usually 2 to 10 mm, preferably the long diameter is 5 to 7 mm and the short diameter is 2 to 3 mm.

1. Preparation of capsule content liquid (suspension) (content liquid 1-1)
Unishort K (Fuji Oil Co., Ltd. high melting point oil and fat; mp: 56.5 to 60.5 ° C.) 250 parts by mass, carrageenan 30 parts by mass and carbamazepine 20 parts by mass are heated to 100 ° C., stirred and suspended. A turbid liquid was prepared.

(Content liquid 1-2 to 1-4)
A suspension was prepared in the same manner as the contents liquid 1-1 except that the carrageenan was used in the amount shown in Table 1 below.

(Content liquids 1-5 to 1-8)
Except that “Unishort K” is “Melano H-3000” (Fuji Oil Co., Ltd., high melting point oil; mp: 42-44 ° C.), the same as the contents liquid 1-1-1-4, respectively. A suspension was prepared.

(Content liquid 2-1 to 2-8)
Suspensions were prepared in the same manner as the contents liquids 1-1 to 1-8, except that the carrageenan was changed to agar.

(Content liquid 3-1 to 3-8)
Suspensions were prepared in the same manner as the contents liquids 1-1 to 1-8, except that the carrageenan was crystalline cellulose.

(Content liquids 4-1 to 4-8)
Suspensions were prepared in the same manner as the contents liquids 1-1 to 1-8, except that the carrageenan was sodium carboxymethylcellulose.

(1) Unishort: A high melting point oil and fat commercially available from Fuji Oil Co., Ltd. under the trade name “Unishort K” (mp: 56.5 to 60.5 ° C.)
(2) Melano: a high melting point oil and fat commercially available from Fuji Oil Co., Ltd. under the trade name “Melano H-3000” (mp: 42-44 ° C.)
(3) Carrageenan: “MV101” made by MRC polysaccharides
(4) Agar: “Ina Agar Max” manufactured by Ina Food Industry Co., Ltd.
(5) Crystalline cellulose: “Theolas UF-F702” manufactured by Asahi Kasei Corporation
(6) CMC: Sodium carboxymethyl cellulose (“Kickolate F-120” manufactured by Nichirin Chemical Industries, Ltd.)
(7) CBZ: Carbamazepine (Carbamazepine; “Nippon Carbamazepine” manufactured by Yamamoto Chemical Co., Ltd.)
(8) Ibuprofen; (Ibuprofen; “Nippon Ibuprofen” manufactured by Yonezawa Hamari Pharmaceutical Co., Ltd.)

(Content liquid 5)
30 parts by mass of ibuprofen was dissolved in 70 parts by mass of rapeseed oil at 80 ° C. to prepare a capsule content solution.

2. Preparation of soft capsule (1) Examples A-1-1 to A-4-8
A film for film was prepared by dissolving 80 parts by mass of gelatin and 20 parts by mass of glycerin in 25 parts by mass of hot water, and using a rotary die type capsule filling machine (“S-1” manufactured by Kamata Co., Ltd.) Soft capsules having a major axis of 4 mm and a minor axis of 3 mm were prepared using the contents liquids 1-1 to 1-8 as the capsule contents obtained as described above.

(2) Example C
1 part by mass of carrageenan was dissolved at 100 ° C. by 20 parts by mass of water. 23 parts by mass of water was added to 85 parts by mass of gelatin and 10 parts by mass of glycerin and dissolved at 60 ° C., 4 parts by mass of starch were mixed, and after sufficient stirring, a film sheet was prepared. By using the rotary die type capsule filling machine, the obtained sheet is sent between a pair of rotating cylindrical molds, and the content 5 is ejected between the sheets by a pump interlocking with the die. Soft capsules having a diameter of 4 mm and a minor axis of 3 mm were obtained.

(3) Comparative Example C
A soft capsule of Comparative Example C was obtained in the same manner as in Example C, except that 90 parts by mass of gelatin and 10 parts by mass of glycerin were dissolved and stirred in 25 parts by mass of warm water to prepare a film for coating.

3. Production of seamless capsule (1) Examples B-1-1 to B-4-8
An outer film solution is prepared by dissolving 80 parts by weight of gelatin and 20 parts by weight of glycerin in 300 parts by weight of warm water, and using the above contents liquids 1-1 to 4-8, seamless capsule production as shown in FIG. A seamless capsule having a diameter of 4 mm was produced using an apparatus (“Manufacturing Machine KC-1” manufactured by Morishita Nitan Corporation).

(2) Example D
2 parts by mass of agar dissolved in 80 parts by mass of water at 100 ° C., allowed to cool to 60 ° C., 88 parts by mass of gelatin and 10 parts by mass of glycerin dissolved in 250 parts by mass of hot water at 60 ° C., 5 parts by weight of crystalline cellulose A suspension of the suspension in 70 parts by mass of warm water at 60 ° C. to prepare an outer film solution for seamless capsules, using the above-described content liquid 5 and using the seamless capsule production apparatus, A 4 mm seamless capsule was produced.

(3) Comparative Example D
A soft capsule of Comparative Example D was obtained in the same manner as Example D, except that the coating was prepared by dissolving 90 parts by mass of gelatin and 10 parts by mass of glycerin in 355 parts by mass of hot water to prepare the above coating solution.

4). Capsule Performance Evaluation The obtained soft capsules and seamless capsules were subjected to a United States Pharmacopoeia (USP) dissolution test. The test method was as follows.

(Test method)
(1) Dissolution test of carbamazepine (CBZ) The dissolution test method described in the United States Pharmacopeia (USP) was evaluated under the following conditions.
Rotating basket method (100 rpm)
Dissolution test solution (distilled water 900mL, 37 ° C)
Test equipment: “NTR-6100A” manufactured by Toyama Sangyo Co., Ltd.
Sampling time: 1, 2, 3, 4.5, 6, 9, 12, 15, 18, 21, and 24 hours 100 capsules containing 2 mg of carbamazepine per capsule according to USP Carbamapine Extended-Release Tables dissolution test method A test was conducted. At a predetermined time, 5 mL of the dissolution test solution was weighed and used as a sample solution. The concentration of the sample solution was measured under the conditions of the following high performance liquid chromatogram.

HPLC conditions Wavelength: 240 nm
Column: 4.6 mm × 15 mm ODS column (manufactured by GL Sciences: Inertsil ODS-3)
Column temperature: 40 ° C
Mobile phase: 7 mM acetate buffer (pH 7) and acetonitrile mixture (7: 3)
Injection volume: 20 μL
Flow rate: 1.0 mL / min (Carbamazepine retention time 9 minutes)

The results are shown in FIG. 9 as CBZ elution behavior.

(2) Dissolution test of ibuprofen The dissolution test method described in the United States Pharmacopeia (USP) was evaluated under the following conditions.
Paddle method (50 rpm)
Dissolution test solution (pH 7.2 phosphate buffer 900 mL, 37 ° C.)
Test equipment: “NTR-6100A” manufactured by Toyama Sangyo Co., Ltd.
Sampling time: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 60 minutes 11 capsules containing 9 mg of ibuprofen per tablet were dissolved in USP ibuprofen tablet dissolution test The test was conducted according to the law. In a predetermined time, 4 mL of the dissolution test solution was weighed and used as a sample solution. The concentration of the sample solution was measured under the following high performance liquid chromatogram conditions.

HPLC conditions Wavelength: 264 nm
Column: 4.6 mm × 150 mm ODS column (TSK-gel ODS-100S manufactured by Tosoh Corporation)
Column temperature: 40 ° C
Mobile phase: 0.05 mol / L sodium dihydrogen phosphate test solution (pH 2.6) and acetonitrile (2: 3)
Injection volume: 50 μL
Flow rate: 0.85 mL / min (Ibuprofen retention time 6 minutes)

The result is shown as elution behavior of ibuprofen in FIG.

(Test results)
(1) Examples A-1-1 to A-1-8
In Examples A-1-1 to A-1-4 (high melting point oil “Unishort K”) and Examples A-1-5 to A-1-8 (high melting point oil “Melano H-3000”) The elution behavior as shown in FIG. 5 and FIG. 6 was observed, respectively, and it was found that the release property can be controlled by the concentration of the water-swellable polysaccharide as the disintegrant regardless of the type of the hardened oil.

(2) Examples B-1-1 to B-1-8
In Examples B-1-1 to B-1-4 (high melting point oil “Unishort K”) and Examples B-1-5 to B-1-8 (high melting point oil “Melano H-3000”) Elution behavior as shown in FIG. 7 and FIG. 8 is observed, respectively, and the release property can be controlled by the concentration of the water-swellable polysaccharide as a disintegrant, regardless of the type of the hardened oil, as in the case of the soft capsule. I understood.

(3) Examples A-2-1 to A-4-8 and B-2-1 to B-4-8
The behaviors of Examples A-2-1 to A-4-8 and B-2-1 to B-4-8 were observed, and the dissolution rate (drug release concentration) after 12 hours was as follows. It was. The results are shown in Table 2 below.

From this, it was found that the release behavior can be controlled by the mixing amount of various polysaccharides.

(4) Example C and Comparative Example C
In the soft capsule as the preparation of the present invention, from the elution behavior of ibuprofen shown in FIG. 9, the release of the content was observed after 2 minutes in Comparative Example C, but in Example C, the content was released after the lapse of 5 minutes. The release of objects was seen, indicating that the release rate can be controlled. Furthermore, elution of all ibuprofen as expected was confirmed after 60 minutes.

(5) Example D and Comparative Example D
In the seamless capsule as the preparation of the present invention, from the elution behavior of ibuprofen shown in FIG. 10, the content of the sample of Comparative Example D was released after 2 minutes, but in Example D, the delay time of 5 minutes passed. Later, the release of the contents was seen, indicating that the release rate could be controlled. Furthermore, elution of all ibuprofen as expected was confirmed after 60 minutes.

The preparation with release controlling ability of the present invention has excellent production uniformity, handleability and productivity, and has excellent release controlling ability. Therefore, it has a form of soft capsule or seamless capsule having release controlling ability. It can be used for pharmaceutical applications.

DESCRIPTION OF

SYMBOLS

1, 12 ...

Contents

2, 11, 34 ... Outer membrane | film | coat 10 ...

Seamless capsule

20, 30 ... Formulation which has

release control ability

21, 31 ...

Drug

22, 32 ... Water-swellable polysaccharide 23 ... Water oil non-swellable Sugar 24 ... Gelatin 26 ... Drug elution route 33 ... Oil and fat having a melting point of 37 ° C or higher 25, 35 ... Water 110 ... Second nozzle (outer nozzle)
120 ... 1st nozzle (inner nozzle)

Claims

The outer skin containing gelatin and polysaccharide and the content containing the medicine covered by the outer skin, and the release of the medicine by the outer skin releasing the medicine by the swelling of the polysaccharide. A preparation having a controlled release ability.
The preparation having release controlling ability according to claim 1, wherein the polysaccharide is one or more selected from agar, gellan gum, carrageenan, modified starch, cellulose and low-substituted hydroxypropylcellulose.
A content comprising a drug, a water-swellable polysaccharide and an oil having a melting point of 37 ° C. or higher, and a water-soluble or water-permeable outer film covering the content, and by swelling the water-swellable polysaccharide A drug product having controlled release, wherein the drug release is controlled by releasing the drug from an oil having a melting point of 37 ° C or higher.
The preparation having release controlling ability according to claim 3, wherein the water-swellable polysaccharide is at least one selected from agar, gellan gum, carrageenan, modified starch and low-substituted hydroxypropylcellulose.
The preparation having release controlling ability according to any one of claims 1 to 4, wherein the drug is water-soluble and / or water-insoluble.
6. The preparation having release controlling ability according to any one of claims 1 to 5, wherein the preparation is either a soft capsule or a seamless capsule.
(I) a step of mixing a drug, a water-swellable polysaccharide, and an oil having a melting point of 37 ° C. or higher to form a content;
(Ii) a step of preparing an outer film forming material;
(Iii) A method for producing a preparation, comprising a step of coating the contents with the outer film-forming material and forming a preparation containing the contents inside the outer film.