JP6686086B2 - Controlled-release formulation and method for producing the same - Google Patents

Description

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

  The drug release control technique is a technique for spatially and temporally controlling the dissolution and release behavior of the drug. When broadly classified, a technique for gradually releasing the drug and a technique for controlling the release by coating the drug. There is. It aims to efficiently improve the effect of a drug by supplying a necessary minimum amount of drug to a necessary place at a necessary time. In order to achieve such an object, a number of controlled-release preparations have been proposed centering on the form and constituent components of the preparation containing such a drug (Patent Documents 1 and 2).

  US Pat. No. 6,968,086 discloses a core material and a shell wall material in which 1 to 75% by weight of glutaraldehyde crosslinked gelatin and 1 to 75% by weight of said core material is prohibited from migrating through said crosslinked gelatin. A microcapsule comprising a capsule shell wall that completely surrounds the core material, the water-soluble plasticizer being a water-soluble starch, a sugar, a cyclodextrin, a maltodextrin, a corn. The microcapsules described are selected from syrup solids and sorbitol. However, the above-mentioned 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 in which (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 dispersion polymer. And (b) at least a majority of the drug is amorphous; and (b) a substantially water-permeable coating around the core, wherein at least one delivery in the coating. A port is present and the coating controls the flow of water from the aqueous use environment into the core such that at least a portion of the core is extruded through the at least one delivery port into the aqueous use environment; and Said dosage form consisting of: said coating being insoluble and non-erodable during said drug release. However, the above-mentioned controlled-release dosage form has a problem that the delivery port needs to be prepared again after preparation of the preparation.

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

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

  In order to solve the above problems, as a result of intensive studies, the present inventors have used an outer film containing gelatin and a specific polysaccharide, particularly a water-swelling polysaccharide, in a formulation consisting of an outer film and contents. Alternatively, by using a content containing a drug, a polysaccharide, particularly a water-swellable polysaccharide and an oil or fat having a specific melting point, it has excellent production uniformity, handleability and productivity, and is excellent. The inventors have found that it is possible to provide a preparation having a controlled release property and a method for producing the same, and completed the present invention.

  That is, the present invention comprises an outer film containing gelatin and a polysaccharide, and a content containing the drug inside the outer film, the outer film releasing the drug by swelling of the polysaccharide The present invention relates to a formulation having a controlled release property, which is characterized in that the release of the drug is controlled.

  As another aspect of the present invention, a drug, a water-swellable polysaccharide and a content containing a fat and oil having a melting point of 37 ℃ or more, and a water-soluble or water-permeable outer coating for coating the content, There is a formulation having a release controlling ability, which is characterized in that the release of a drug is controlled by releasing the drug from an oil or fat having a melting point of 37 ° C. or higher due to the swelling of a water-swelling polysaccharide.

Furthermore, in order to preferably carry out the present invention,
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, ethyl cellulose, hydroxypropylmethyl cellulose and carboxymethyl cellulose;
The formulation is either a soft capsule or a seamless capsule;
Is desirable.

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

  According to the invention, in a formulation consisting of an outer coating and a content, by using an outer coating comprising gelatin and a specific polysaccharide, in particular a water-swellable polysaccharide, or alternatively a drug, a polysaccharide, especially a water-swellable one. Provided are a preparation having excellent production uniformity, handleability and productivity, and an excellent controlled release ability, and a method for producing the same, by using a content containing a polysaccharide and an oil or fat having a specific melting point. can do.

FIG. 3 is a schematic diagram illustrating a drug release mechanism of one embodiment of the formulation having controlled release ability of the present invention. FIG. 6 is a schematic view illustrating a drug release mechanism of another embodiment of the formulation having controlled release ability of the present invention. 1 is a seamless capsule of one embodiment of the preparation having controlled release ability of the present invention. FIG. 1 is a schematic vertical cross-sectional view showing one aspect of a nozzle portion of a production apparatus of one aspect (two-layer structure) in which the formulation having controlled release ability of the present invention is in the form of a seamless capsule. It is a graph figure which shows the release behavior of the chemical | medical agent (carbamazepine) in the soft capsule of Examples A-1-1 to A-1-4 of this invention. It is a graph which shows the release behavior of the chemical | medical agent (carbamazepine) in the soft capsule of Example A-1-5 to A-1-8 of this invention. It is a graph figure which shows the release behavior of the chemical | medical agent (carbamazepine) in the seamless capsule of Examples B-1-1 to B-1-4 of this invention. It is a graph which shows the release behavior of the chemical | medical agent (carbamazepine) in the seamless capsule of Examples B-1-5 to B-1-8 of this invention. FIG. 8 is a graph showing the release behavior of a drug (carbamazepine) in the soft capsule of Example C of the present invention as compared with the soft capsule of Comparative Example C. It is a graph figure which shows the release behavior of the chemical | medical agent (ibuprofen) in the seamless capsule of Example D of this invention compared with the seamless capsule of Comparative Example D.

As a formulation having a controlled release property of the present invention,
(A) An outer coating containing gelatin and a polysaccharide, and a content containing a drug inside the outer coating,
(B) Some include a content containing a drug, a water-swelling polysaccharide, and an oil or fat having a melting point of 37 ° C. or higher, and one including an outer film coating the content.

  Examples of the above-mentioned polysaccharides include, but are not limited to, agar, gellan gum, carrageenan, modified starch, dextrin, maltodextrin, pullulan, trehalose, gum arabic, arabinogalactan, farcelane, 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, lignin Which water-oil non-swellable polysaccharide, as well as one or more combinations thereof. In the present specification, the “low-substituted hydroxypropyl cellulose” is one in which a hydroxypropoxy group is introduced into the glucose ring at a molar substitution degree of 0.2 to 0.4.

  As an example of the above drug, in order not to feel unpleasant taste on the tongue, or to release the drug in sublingual absorption suppression or specific digestive organs, a drug having an unpleasant taste such as bitterness, a water-soluble drug, Examples include water-insoluble lipophilic drugs. The drug is not limited to the following examples, but includes acetaminophen, chlorpheniramine maleate, mequitazine, tipepidine hibenzate, diphenhydramine salicylate, meclizine hydrochloride, methylephedrine hydrochloride, guaifenesin, dihydrocodeine phosphate, ibuprofen, ticlopidine hydrochloride. , Berberine chloride, digitoxin, sulpirine, azelastine hydrochloride, etilefrine hydrochloride, diltiazem hydrochloride, propranolol hydrochloride, chloramphenicol, aminophylline, erythromycin, phenobarbital, calcium pantothenate, aminoguanidine hydrochloride, donepezil hydrochloride, meclizine hydrochloride, diphenhydramine hydrochloride, malein Chlorpheniramine acid, phenylpropanolamine hydrochloride, nicotinic acid amide, 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, halopredone acetate, indomethacin, aspirin, prostaglandin E1, acetohexamide, estradiol, phenytoin, phenobarbital, carbamazepine, valproic acid, ethosuximide, zonisamide, gabapentin, topiramate, lamotrigin, atropine. Thiamine, scopolamine hydrochloride, scopolamine hydrobromide, theophylline, lidocaine Mehibakain, such as dibucaine and the like.

Formulation with controlled release (a)
The above-mentioned 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, water supply from the external environment to the water-swelling polysaccharide by water-oil non-swelling polysaccharide is essential, and therefore, among the above examples, water-swelling polysaccharide and water A combination of non-swelling oily polysaccharides is preferred, and a combination of agar and crystalline cellulose, respectively, is more preferred. As shown in FIG. 1, the formulation (20) comprises an outer coating containing gelatin (24), a water-swelling polysaccharide (22) and a water-oil non-swelling polysaccharide (23), and an outer coating of the outer coating. When the formulation (20) is placed in water (25) by including the content containing the drug (21) inside and including the water-swellable polysaccharide (22) in the gelatin (24) base. A type of the water-swellable polysaccharide, in which the water-swellable polysaccharide (22) swells or dissolves to form a route (26) for eluting the drug (21) from the outer coat or disintegrates the outer coat. The drug release can be controlled within the range of 0.5 to 30 minutes by adjusting the content of the drug.

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

  As the contents of the formulation (a) of the present invention, the drug may be dissolved in a liquid oil (melting point less than 37 ° C) under the use environment of the formulation. Examples of the fats and oils include, but are not limited to, palm 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 oils, and carbon numbers. Substituted esters of saturated fatty acids of 4 to 10 with glycerol and the like can be mentioned. From the viewpoint 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 formulation (a) is 0.1 to 30% by mass, preferably 0.5 to 30% by mass, 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 above-mentioned preparation (a) of the present invention is
(I) providing a content containing a drug,
(Ii) a step of preparing a material for forming an outer film by mixing gelatin and a polysaccharide,
(Iii) a step of coating the above-mentioned contents with the above-mentioned outer film forming material to form a preparation containing the above-mentioned contents inside the outer film.

  The method of coating the content of the step (iii) with the material for forming an outer film is not particularly limited, but in consideration of manufacturing uniformity of the preparation, productivity, etc., a seamless capsule or a soft capsule described later is formed. The method of doing is desirable.

  The method for producing the above-mentioned preparation (a) of the present invention, in particular, the method for coating the above-mentioned contents with the above-mentioned outer film is not particularly limited, but in consideration of production uniformity, productivity, etc. of the preparation, a seamless capsule or A method of forming soft capsules is desirable.

Formulation with controlled release (b)
The above-mentioned preparation (b) of the present invention includes a content containing a drug, a water-swelling polysaccharide and an oil or fat having a melting point of 37 ° C or higher, and an outer film for coating the content. Among the above examples, the water-swelling polysaccharide is preferable as the polysaccharide used for the above-mentioned contents, and carrageenan is more preferable. As shown in FIG. 2, the formulation (30) comprises a drug (31), a water-swellable polysaccharide (32) and a fat (33) having a melting point of 37 ° C. or higher, and the above-mentioned contents. When the preparation (30) is placed in water (35) by including the outer film (34) for coating and including the water-swellable polysaccharide (32) in the content, the water-swellable polysaccharide The saccharide (32) swells or dissolves to form a path for the drug (31) to elute in the contents, and the release can be controlled by adjusting the type and content of the water-swellable polysaccharide.

  Examples of the oils and fats 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 formulation, but animal and vegetable oils such as palm oil, rapeseed oil, soybean oil, beef tallow, lard, and fish oil, Examples thereof include hydrogenated hydrogenated oil, beeswax, carnauba wax, and substituted esters of saturated fatty acids having 4 to 10 carbon atoms with glycerol. From the viewpoint of formulation, coconut oil, rapeseed oil, soybean oil, hydrogenated hydrogenated oils thereof and the like are preferable. The melting point of the fats and oils is preferably 40 ° C or higher, more preferably 40 to 90 ° C.

  The content of the drug in the content of the formulation (b) is 0.1 to 40% by mass, preferably 0.5 to 40% by mass, more preferably 1 to 35% 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 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. If the content of the above-mentioned polysaccharide is less than 0.01% by mass, the dissolution rate of the drug will be low or it will not be eluted, and if it exceeds 40% by mass, the dissolution rate of the drug will be too high.

  The content of the oil having a melting point of 37 ° C. or higher in the content of the formulation (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 content cannot be fixed, and if it exceeds 95% by mass, the content of the drug is reduced, so that the effective release amount cannot be maintained.

  As described above, since the above-mentioned preparation (b) can function as a preparation having a release-controlling ability only with the contents, only the contents may be molded into a preparation, but the handleability, productivity, etc. Considering this, it is desirable to coat the above contents with an outer coating using a conventional capsule coating material such as gelatin.

The method for producing the above-mentioned preparation (b) of the present invention is
(I) a step of forming a content by mixing a drug, a water-swelling polysaccharide and an oil or fat having a melting point of 37 ° C. or higher,
(Ii) a step of preparing a material for forming an outer film,
(Iii) a step of coating the above-mentioned contents with the above-mentioned outer film forming material to form a preparation containing the above-mentioned contents inside the outer film.

  The method of coating the content of the step (iii) with the material for forming an outer film is not particularly limited, but in consideration of manufacturing uniformity of the preparation, productivity, etc., a seamless capsule or a soft capsule described later is formed. The method of doing is desirable.

(Seamless capsule)
Hereinafter, a seamless capsule and a method for producing the same as one mode of the formulation having a controlled release function of the present invention will be described in detail. The seamless capsule of the present invention comprises a content and an outer coating containing the content. The seamless capsule can be formed with a diameter of 0.1 to 10 mm, preferably 0.3 to 8 mm.

  Hereinafter, with reference to FIGS. 3 to 4, a seamless capsule as one form of the formulation having a controlled release function of the present invention and a method for producing the same will be described in more detail. FIG. 3 is a schematic cross-sectional view schematically showing one embodiment (two-layer structure) in which the formulation having a controlled release property of the present invention is in the form of a seamless capsule. The seamless capsule (10) comprises a drug-containing content (1) and an outer coating (2) containing the content. The simplest structure of the seamless capsule is a two-layer seamless capsule having one outer coat (2) as shown in FIG.

  The method for producing the seamless capsule is basically the content liquid from the inner nozzle of the multiple nozzles, the outer film preparation liquid as the outer film forming material from the outer nozzle, by simultaneously discharging into the carrier fluid, A two-layered seamless capsule in which the content liquid is wrapped with the above-mentioned outer film preparation liquid is formed to obtain a desired capsule.

  The viscosity of the above-mentioned outer film preparation liquid at 60 ° C. is preferably 30 to 350 mPa · s, more preferably 50 to 300 mPa · s, and further preferably 100 to 250 mPa · s. When the viscosity of the outer coating solution is in the above range, there is an advantage that the seamless capsule can be favorably prepared by the dropping method.

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

  As a method for producing a seamless capsule, which is one embodiment of the present invention, as shown in FIG. 4, a double nozzle is used to apply an outer coating solution to an inner first nozzle (120) and an outer content liquid to an outer first nozzle (120). Each is supplied to the second nozzle (110). Then, these liquids are simultaneously extruded from the tip of each annular hole, and the obtained two-phase composite jet is discharged into the flowing cooling liquid, whereby the seamless capsule (10) according to the present invention can be obtained. Here, the "jet" refers to an extrudate obtained by continuously extruding a fluid, and the "composite jet" refers to a jet having a plurality of phases (layers).

  The 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 (coconut oil, sunflower oil, safflower oil, sesame oil, rapeseed oil, grape seed oil, and mixtures thereof), liquid paraffin and mixtures thereof are used. be able to.

  In the above-mentioned manufacturing method, it is also possible to impart appropriate vibration to the composite jet flow using a vibrating means to improve the breakage of the composite jet, make the particle diameter uniform, and 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 substance that separates the content from the outer film include the above-mentioned lipophilic liquid substance. In the case of preparing a seamless capsule having a three-layer structure, the above-mentioned figure is used except that a concentric triple nozzle is newly provided inside the first nozzle (120) (inner nozzle) described in FIG. It can be manufactured using a method similar to the method shown in FIG. In addition, a seamless capsule having a four-layer structure can be produced by using the same method.

(Soft capsule)
Similar to the case of the seamless capsule, the soft capsule has a structure in which a non-aqueous solvent solution is used as a content liquid and the outer coating sheet surrounds the content liquid.

  The content liquid is prepared in the same manner as in the case of seamless capsules, and as the material of the outer film sheet, use the same material as the material for forming the outer film of the seamless capsules, which has been formed into a sheet according to a conventional method. You can In the production of soft capsules, the outer coating sheet and the content liquid are used, and a pair of the outer coating sheet is prepared by using a rotary die capsule filling machine (for example, "S-1" manufactured by Kamata Co., Ltd.). Is sent between the rotating cylindrical molds, and a soft capsule is formed by jetting the above-mentioned content liquid between the sheets by a pump which is interlocked with this.

  The soft capsule has a major axis of usually 3 to 16 mm and a minor axis of usually 2 to 10 mm, preferably a major axis of 5 to 7 mm and a minor axis of 2 to 3 mm.

1. Preparation of capsule content liquid (suspension) (content liquid 1-1)
Unishort K (high melting point oil and fat manufactured by Fuji Oil Co., Ltd .; 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 and stirred to suspend. A suspension was prepared.

(Contents liquid 1-2 to 1-4)
A suspension was prepared in the same manner as the content liquid 1-1, except that carrageenan was used in the blending amounts shown in Table 1 below.

(Content liquid 1-5 to 1-8)
Same as the content liquids 1-1 to 1-4 except that "UNISHORT K" is changed to "Melano H-3000" (high melting point oil and fat manufactured by Fuji Oil Co., Ltd .; mp: 42 to 44 ° C). To prepare a suspension.

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

(Content liquid 3-1 to 3-8)
A suspension was prepared in the same manner as the content liquids 1-1 to 1-8, except that the carrageenan was changed to crystalline cellulose.

(Content liquid 4-1 to 4-8)
Suspensions were prepared in the same manner as the content liquids 1-1 to 1-8 except that carrageenan was changed to sodium carboxymethyl cellulose.

(1) Unishort: High melting point oil / fat commercially available from Fuji Oil Co., Ltd. under the product name “Unishort K” (mp: 56.5 to 60.5 ° C.)
(2) Melano: High melting point oil / fat (mp: 42 to 44 ° C.) under the trade name “Melano H-3000” from Fuji Oil Co., Ltd.
(3) Carrageenan: "MV101" made of MRC polysaccharide
(4) Agar: "Ina Agar Max" manufactured by Ina Food Industry Co., Ltd.
(5) Crystalline cellulose: "Theolus UF-F702" manufactured by Asahi Kasei Corporation
(6) CMC: carboxymethyl cellulose sodium (“Kickolate F-120” manufactured by Nichirin Chemical Co., Ltd.)
(7) CBZ: carbamazepine (Carbamazepine; “Japan Bureau Carbamazepine” manufactured by Yamamoto Chemical Co., Ltd.)
(8) Ibuprofen; (Ibuprofen; Yonezawahama Pharmaceutical Co., Ltd. "Japan Bureau Ibuprofen"

(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 liquid.

2. Preparation of Soft Capsule (1) Examples A-1-1 to A-4-8
80 parts by mass of gelatin and 20 parts by mass of glycerin were dissolved in 25 parts by mass of warm water to prepare a film for film, which was respectively subjected to a rotary die capsule filling machine (“S-1” manufactured by Kamata Co., Ltd.). Using the content liquids 1-1 to 1-8 as the capsule contents obtained as described above, soft capsules having a major axis of 4 mm and a minor axis of 3 mm were produced.

(2) Example C
1 part by mass of carrageenan was dissolved in 20 parts by mass of water at 100 ° C. 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 dies, and the contents 5 are jetted between the sheets by a pump which works in conjunction with the rotating die to obtain a long diameter A soft capsule having a diameter of 4 mm and a short diameter of 3 mm was 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 sheet.

3. Preparation of Seamless Capsule (1) Examples B-1-1 to B-4-8
80 parts by mass of gelatin and 20 parts by mass of glycerin were dissolved in 300 parts by mass of warm water to prepare an outer film solution, and using the above content liquids 1-1 to 4-8, seamless capsule production as shown in FIG. A seamless capsule having a diameter of 4 mm was produced by using a device ("Making machine KC-1" manufactured by Morishita Jintan Co., Ltd.).

(2) Example D
2 parts by mass of agar were 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 were dissolved in 250 parts by mass of warm water of 60 ° C., crystalline cellulose 5 parts by mass. Part was suspended in 70 parts by mass of warm water at 60 ° C. to prepare an outer coating solution for a seamless capsule, and the content liquid 5 was used to produce a diameter by using the seamless capsule manufacturing apparatus. A 4 mm seamless capsule was prepared.

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

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

(Test method)
(1) Dissolution test of carbamazepine (CBZ) Evaluation was carried out under the following conditions by a dissolution test method described in the United States Pharmacopeia (USP).
Rotating basket method (100 rpm)
Dissolution test liquid (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 were subjected to USP Carbamazepine Extended-Release Tablets dissolution test method. The test was conducted. 5 mL of the dissolution test solution was weighed out at a predetermined time 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 condition Wavelength: 240 nm
Column: 4.6 mm x 15 mm ODS column (GL Sciences: Inertsil ODS-3)
Column temperature: 40 ° C
Mobile phase: 7 mM acetate buffer (pH 7) mixed with acetonitrile (7: 3)
Injection volume: 20 μL
Flow rate: 1.0 mL / minute (carbamazepine retention time 9 minutes)

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

(2) Ibuprofen dissolution test Evaluation was carried out under the following conditions by the dissolution test method described in the United States Pharmacopeia (USP).
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 Eleven capsules containing 9 mg of ibuprofen per capsule, USP ibuprofen tablet dissolution test The test was conducted according to the law. 4 mL of the dissolution test solution was weighed out at a predetermined time and used as a sample solution. The concentration of the sample solution was measured under the following high performance liquid chromatogram conditions.

HPLC condition 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 reagent solution (pH 2.6) and acetonitrile mixed solution (2: 3)
Injection volume: 50 μL
Flow rate: 0.85 mL / min (Ibuprofen retention time 6 min)

  The results are shown in FIG. 10 as the elution behavior of ibuprofen.

(Test results)
(1) Examples A-1-1 to A-1-8
In Examples A-1-1 to A-1-4 (high melting point oils and fats "Unishort K") and Examples A-1-5 to A-1-8 (high melting point oils and fats "Melano H-3000"), Elution behaviors as shown in FIGS. 5 and 6 were 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 hydrogenated oil.

(2) Examples B-1-1 to B-1-8
In Examples B-1-1 to B-1-4 (high melting point fats and oils "Unishort K") and Examples B-1-5 to B-1-8 (high melting point fats and oils "Melano H-3000"), The elution behaviors shown in FIGS. 7 and 8 were observed, respectively, and the release property can be controlled by the concentration of the water-swellable polysaccharide as the disintegrant, regardless of the type of 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 behavior of each of Examples A-2-1 to A-4-8 and B-2-1 to B-4-8 was 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 mixed amount of various polysaccharides.

(4) Example C and Comparative Example C
In the soft capsule as the preparation of the present invention, from the dissolution 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 delay time of 5 minutes. Release of the product was seen, indicating that the release rate can be controlled. Furthermore, after 60 minutes, the elution of all the ibuprofen according to the theory was confirmed.

(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 sample of Comparative Example D showed the release of the content after 2 minutes, but in Example D, the delay time of 5 minutes elapsed. Release of the contents was later seen, indicating that the release rate could be controlled. Furthermore, after 60 minutes, the elution of all the ibuprofen according to the theory was confirmed.

  The formulation with controlled release of the present invention has excellent production uniformity, handleability and productivity, and also has excellent controlled release. Therefore, it has a controlled release form such as a soft capsule or a seamless capsule. It can be used for formulation purposes.

1, 12 ... Contents 2, 11, 34 ... Outer coating 10 ... Seamless capsule 20, 30 ... Formulation having release controlling ability 21, 31 ... Drug 22, 32 ... Water-swelling polysaccharide 23 ... Water-oil non-swelling poly Sugar 24 ... Gelatin 26 ... Drug elution route 33 ... Oil / fat having melting point of 37 ° C. or higher 25, 35 ... Water 110 ... Second nozzle (outer nozzle)
120 ... No. 1 nozzle (inner nozzle)

Claims (5)

It contains a drug, a water-swelling polysaccharide that is agar or carrageenan, and a content containing an oil or fat having a melting point of 37 ° C. or higher, and a water-soluble or water-permeable outer film that coats the content. The release of the drug is controlled by the release of the drug from the oil or fat having a melting point of 37 ° C. or higher due to the swelling of the polysaccharide , and the content of the water-swellable polysaccharide in the content is 4 to 8% by mass. characterized in that, formulations with controlled release ability.   The controlled release formulation according to claim 1, wherein the drug is water-soluble and / or water-insoluble. The formulation having a controlled release function according to claim 1 or 2, wherein the formulation is a seamless capsule . It contains a drug, a water-swelling polysaccharide that is agar or carrageenan, and a content containing an oil or fat having a melting point of 37 ° C. or higher, and a water-soluble or water-permeable outer film that coats the content. The release of the drug is controlled by releasing the drug from an oil or fat having a melting point of 37 ° C. or higher due to swelling of the polysaccharide , the drug is water-soluble and / or water-insoluble, and the formulation is a seamless capsule, Content of the water-swellable polysaccharide in the content is 4 to 8% by mass, and a formulation having a controlled release property . (I) mixing a drug, a water-swelling polysaccharide that is agar or carrageenan, and an oil or fat having a melting point of 37 ° C. or higher to form a content,
(Ii) a step of preparing a material for forming an outer film,
And (iii) covering the contents of said external film forming material, in the interior of the outer film comprises a step of forming a formulation containing the contents, according to any one of claims 1-4 Manufacturing method of pharmaceuticals.

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