JP2020152671A - Water insoluble substance containing particles - Google Patents

Abstract

To provide water insoluble substance containing particles having an excellent elution property of water insoluble substance and an excellent particle fluidity.SOLUTION: There is provided water insoluble substance containing particles that contains the following contents (A), (B) and (C): (A) gelatin, (B) water insoluble substance, (C) one or more selected from a group of (c1) monoglycerin fatty acid ester whose constituent fatty acids are saturated fatty acids having 8 to 14 carbon atoms, (c2) polyglycerin fatty acid ester, (c3) glycerin acetic acid fatty acid ester, (c4) propylene glycol fatty acid ester whose constituent fatty acids are saturated fatty acids having 8 to 14 carbon atoms, and (c5) sucrose fatty acid ester. The water insoluble substance containing particles have a successive phase containing the component (A) and a dispersion phase that is dispersed in the successive phase and contains the component (B).SELECTED DRAWING: Figure 1

Description

The present invention relates to particles containing a poorly soluble substance in water.

Most of the substances having physiological activity such as drugs, vitamins, and nutritional components are poorly soluble in water. When such a substance is used as a medicine or health food, even if it is orally administered or ingested as it is, it is difficult to elute into digestive juices, etc., so that it is poorly absorbed in the body and its effectiveness is high. Low. Therefore, various formulation methods have been proposed in order to improve the elution property of the poorly water-soluble substance and enhance its effectiveness.

For example, a method for producing a drug composition, which comprises dissolving a poorly water-soluble drug in a mixed solvent composed of water in which layered silicate is dispersed and a water-soluble organic solvent, and removing and / or drying the solvent (Patent Document). 1), a poorly soluble drug ultrafine particle-containing preparation (Patent Document 2) obtained by dry-grinding a poorly soluble drug, polyvinylpyrrolidone and sodium dodecyl sulfate in the absence of another grinding medium, and a poorly water-soluble drug (A). Among the granulated particles containing the excipient (B), the volume average particle diameter of the particles of the component (A) and the particles of the component (B) is 0.01 to 35 μm, and further, a water-soluble polymer compound and / Or Consists of granulated particles (Patent Document 3) containing a water-swellable polymer compound (C) and a surfactant (D), a poorly soluble drug, an elution-enhancing polymer, and an elution-suppressing polymer. Drug-encapsulating particles (Patent Document 4), which have a solid dispersion composition (Patent Document 4), an inner layer containing (A) a poorly water-soluble drug and (B) a solvent, and an outer layer containing (C) a coating substance. 5) etc. are known.

On the other hand, although the purpose is not to improve the elution of a poorly water-soluble substance, as a formulation method different from the above method, an aqueous oil type in water is obtained by emulsifying an aqueous solution containing ubidecalenone and gelatin that has been melted by heating. Production of ubidecalenone-containing microcapsules characterized in that an emulsified composition is then prepared, and then the emulsified composition is sprayed into a column filled with liquid nitrogen to collect and dry the obtained frozen fine particles. A method (Patent Document 6) is known. Since the microcapsules obtained by this production method have a high sphericity and a dense structure, if this production method is used for a water-insoluble substance other than ubidecalenone, the water-insoluble substance-containing particles that can be preferably used in pharmaceuticals, health foods, etc. Is expected to be obtained.

However, it was found that even if the above production method was used for a water-insoluble substance other than ubidecalenone, the water-insoluble substance-containing particles did not necessarily have sufficient elution of the water-insoluble substance. Further, when an attempt was made to use an emulsifier to improve the elution property, particles having low fluidity were sometimes obtained. Since many poorly water-soluble substances have an unpleasant taste, if the fluidity of the poorly water-soluble substance-containing particles is low, the particles are coated with a coating polymer or the like for the purpose of reducing the unpleasant taste. It becomes difficult to use it, and its use is restricted. Therefore, there has been a demand for particles containing a poorly water-soluble substance, which are excellent in both the elution property of the poorly water-soluble substance and the fluidity of the particles.

Japanese Unexamined Patent Publication No. 2001-278810 Japanese Unexamined Patent Publication No. 2004-099442 Japanese Unexamined Patent Publication No. 2007-314529 Japanese Unexamined Patent Publication No. 2013-103899 Japanese Unexamined Patent Publication No. 2015-000867 Japanese Unexamined Patent Publication No. 2006-089381

An object of the present invention is to provide particles containing a poorly water-soluble substance having excellent elution property of the poorly water-soluble substance and excellent fluidity of the particles.

As a result of diligent studies on the above problems, the present inventors have determined that a specific emulsifier is used in the poorly water-soluble substance-containing particles in which gelatin constitutes a continuous phase and the poorly water-soluble substance constitutes a dispersed phase. It has been found that the above problems can be solved, and the present invention has been made based on this finding.

That is, the present invention comprises the following (1) to (3).
(1) The following components (A), (B) and (C):
(A) Gelatin,
(B) Water-insoluble substance,
(C) Monoglycerin fatty acid ester in which the constituent fatty acid is a saturated fatty acid having 8 to 14 carbon atoms, (c2) polyglycerin fatty acid ester, (c3) glycerin acetic acid fatty acid ester, and (c4) constituent fatty acid has 8 to 14 carbon atoms. A poorly water-soluble substance-containing particle containing at least one selected from the group of propylene glycol fatty acid ester which is a saturated fatty acid of 14 and (c5) sucrose fatty acid ester, and a continuous phase containing the component (A). A poorly water-soluble substance-containing particle having a dispersed phase containing the component (B) dispersed in the continuous phase.
(2) The poorly water-soluble substance-containing particles according to (1) above, wherein the component (C) is contained in the dispersed phase.
(3) The poorly water-soluble substance-containing particles according to (1) above, wherein the component (C) is contained in the continuous phase.

The poorly water-soluble substance-containing particles of the present invention are excellent in elution of the poorly water-soluble substance and fluidity of the particles.

FIG. 1 is a schematic view showing the structure of the poorly water-soluble substance-containing particles of the present invention.

[Component (A)]
The poorly water-soluble substance-containing particles of the present invention contain gelatin as a component (A). As the gelatin, gelatin produced by heat-extracting crude collagen obtained by treating the skin, bones, tendons of cows, pigs, chickens, etc. with acid or alkali with water is usually used. Further, fish gelatin made from the skin and bone of fish such as tuna, salmon and tilapia can also be used. The gelatin jelly strength can be in the range of 0 to 285 g, preferably the jelly strength is 85 g or more, and more preferably the jelly strength is 85 to 135 g. The jelly strength is measured according to the jelly strength test specified in "Gelatin and gelatin" of Japanese Industrial Standards (JIS) K6503-1996.

[Component (B)]
The poorly water-soluble substance-containing particles of the present invention contain a poorly water-soluble substance as the component (B). Here, in the present invention, the "water-insoluble substance" means a drug, vitamins, nutritional components and other physiologically active substances that are difficult to dissolve in water, and more specifically, it is stipulated in the 17th revised general rules of the Japanese Pharmacy. Depending on the method of measuring solubility, it is "extremely insoluble" (the amount of solvent required to dissolve 1 g or 1 mL of solute is 1000 mL or more and less than 10000 mL: the solute corresponds to a water-difficult substance and the solvent corresponds to water), "almost. It refers to a physiologically active substance classified as "insoluble" (the amount of the same solvent is 10,000 mL or more). Further, from the viewpoint of improving the elution of the poorly water-soluble substance, the poorly water-soluble substance used in the present invention preferably has a melting point or a decomposition point of 75 ° C. or higher. Hereinafter, specific examples of poorly water-soluble substances are shown together with their solubility and melting point or decomposition point.

Examples of poorly water-soluble substances include astaxanthin (almost insoluble / melting point: 182 to 183 ° C), amcinonide (almost insoluble / decomposition point: about 252 ° C), and ibuprofen (almost insoluble / melting point: 75 to 77.5 ° C). , Indomethacin (almost insoluble / melting point: 155 ° C or 162 ° C), etenzamid (almost insoluble / melting point: 132.22 to 133.89 ° C), erythromycin (extremely insoluble / melting point: 191 ° C), omeprazole (almost soluble) No / decomposition point: 155 ° C), capsantin (almost insoluble / melting point: 176 ° C), carbamatepine (extremely insoluble / melting point: 189 to 193 ° C), prednisolone valerate acetate (almost insoluble / decomposition point: about 186 ° C) ), Diflucortron valerate (almost insoluble / melting point: 200-204 ° C), dexametazone valerate (almost insoluble / melting point: 179-184 ° C), betamaison valerate (almost insoluble / decomposition point: about 190 ° C) ), Clarislomycin (almost insoluble / melting point: 220-227 ° C), glyceofrubin (almost insoluble / melting point: 220 ° C), curcumin (almost insoluble / melting point: 183 ° C), chronazepam (almost insoluble / decomposition point) : Approximately 240 ° C), chlorpropamide (melting point: almost insoluble / 127-131 ° C), cortisone acetate (almost insoluble / melting point: 222 ° C), diflorazone acetate (almost insoluble / decomposition point: 222 ° C), acetate Dexametazone (almost insoluble / melting point: 240 ° C), triamcinolone acetate (almost insoluble / melting point: 270 ° C), parameterzone acetate (almost insoluble / melting point: 228-241 ° C), hydrocortisone acetate (almost insoluble / decomposition point:) 220 ° C), fludrocortisone acetate (almost insoluble / decomposition point: 220 ° C), diazepam (almost insoluble / melting point: 125-126 ° C), digitoxin (almost insoluble / melting point: 255.5 ° C), digoxin (almost insoluble / melting point: 255.5 ° C) Almost insoluble / melting point: about 235 ° C), diflupredonato (almost insoluble / decomposition point: about 190 ° C), bechrometazone dipropionate (almost insoluble / decomposition point: about 208 ° C), betamethasone dipropionate (almost) Insoluble / melting point: 176-180 ° C), sulfiride (almost insoluble / decomposition point: about 178 ° C), sulfatiazole (almost insoluble / melting point: 175 ° C or 202 ° C), zeaxanthin ( Almost insoluble / melting point: 215.5 ° C), dexamethasone (almost insoluble / decomposition point: about 245 ° C), triamsinolone (almost insoluble / decomposition point: about 264 ° C), triamsinolone acetonide (almost insoluble / decomposition point) : Approximately 290 ° C), tolbutamide (almost insoluble / melting point: 126-132 ° C), droperidol (almost insoluble / melting point: 145 to 146.5 ° C), naproxene (almost insoluble / melting point: 154 to 158 ° C), Nicaldipine (almost insoluble / melting point: 136-138 ° C), nifedipine (almost insoluble / melting point: 172-175 ° C), nilvazipine (almost insoluble / melting point: 167-171 ° C), noscapin (almost insoluble / melting point:) 174 to 177 ° C), halcinonide (almost insoluble / melting point: 276 to 277 ° C), hydrocortisone (extremely insoluble / decomposition point: 212 to 220 ° C), flumethasone pivalate (almost insoluble / decomposition point: 269 to 273 ° C) ), Phenacetin (extremely insoluble / melting point: 134-135 ° C), phenitoin (almost insoluble / decomposition point: about 296 ° C), budesonide (almost insoluble / decomposition point: about 240 ° C), placepam (almost insoluble / almost insoluble / Melting point: 145-146 ° C.), Fluoronide (almost insoluble / melting point: 309 ° C.), Fluosinolone acetonide (almost insoluble / decomposition point: 266-274 ° C.), Fluorometron (almost insoluble / melting point: 292-) 303 ° C), fludroxycortide (almost insoluble / decomposition point: 247-255 ° C), prednisolone (extremely insoluble / decomposition point: about 235 ° C), alcoholone propionate (almost insoluble / decomposition point: 190 ° C) ~ 216 ° C), clobetazole propionate (almost insoluble / decomposition point: about 196 ° C), dexamethasone propionate (almost insoluble / melting point: 200-206 ° C), deprodon propionate (almost insoluble / melting point: 225-230 ° C) ℃), β-carotene (almost insoluble / melting point: 176 to 184 ° C), β-cryptoxanthin (almost insoluble / melting point: 172 to 173 ° C), hesperetin (extremely insoluble / melting point: 227.5 ° C), Betamethasone (almost insoluble / decomposition point: about 240 ° C), myconazole (almost insoluble / melting point: 84-87 ° C), mylicetin (almost insoluble / melting point: 357 ° C), methiclan (almost insoluble) / Decomposition point: Approximately 234 ° C), Methylprednisolone (almost insoluble / Decomposition point: 232-240 ° C), Mephenamic acid (Almost insoluble / Decomposition point: Approximately 225 ° C), Clobetazone butyrate (Almost insoluble / Melting point: Approximate 178 ° C), hydrocortisone butyrate (almost insoluble / decomposition point: about 200 ° C), hydrocortisone propionate butyrate (almost insoluble / melting point: 117-124 ° C), riboflavin butyrate (almost insoluble / melting point: 146-150 ° C) , Lansoprazole (almost insoluble / decomposition point: about 166 ° C), riboflavin (almost insoluble / decomposition point: about 290 ° C), lutein (almost insoluble / melting point: 196 ° C) and the like.

[Component (C)]
The poorly water-soluble substance-containing particles of the present invention have (c1) monoglycerin fatty acid ester, (c2) polyglycerin fatty acid ester, and (c3) glycerin acetic acid in which the constituent fatty acids are saturated fatty acids having 8 to 14 carbon atoms. It contains one or more emulsifiers selected from the group of fatty acid esters, propylene glycol fatty acid esters in which (c4) constituent fatty acids are saturated fatty acids having 8 to 14 carbon atoms, and (c5) sucrose fatty acid esters. Among these emulsifiers, in the water-soluble substance-containing particles (type A) described later, (c1) monoglycerin fatty acid ester in which the constituent fatty acid is a saturated fatty acid having 8 to 14 carbon atoms, (c2) polyglycerin fatty acid ester, and (c3). The glycerin acetic acid fatty acid ester and the (c4) constituent fatty acid are preferably at least one selected from the group of propylene glycol fatty acid esters which are saturated fatty acids having 8 to 14 carbon atoms, and are poorly water-soluble substance-containing particles (type B) described later. ), It is preferably (c5) sucrose fatty acid ester.

The monoglycerin fatty acid ester in which the constituent fatty acid (c1) used as the component (C) in the present invention is a saturated fatty acid having 8 to 14 carbon atoms is an esterification product of glycerin and a saturated fatty acid having 8 to 14 carbon atoms. ..

The fatty acid constituting the monoglycerin fatty acid ester is not particularly limited as long as it is a saturated fatty acid derived from edible animal and vegetable fats and oils and has 8 to 14 carbon atoms. For example, caprylic acid (saturated fatty acid having 8 carbon atoms) ), Capric acid (saturated fatty acid having 10 carbon atoms), lauric acid (saturated fatty acid having 12 carbon atoms), myristic acid (saturated fatty acid having 14 carbon atoms) and the like, and caprylic acid or lauric acid is preferable. Only one type of these fatty acids may be used alone, or two or more types may be used in any combination.

Examples of the monoglycerin fatty acid ester include Poem M-100 [trade name; monoglycerin monofatty acid ester; constituent fatty acids: capriclic acid; manufactured by RIKEN Vitamin Co., Ltd.], Poem M-300 [trade name; monoglycerin monofatty acid ester; Fatty acid: lauric acid; manufactured by RIKEN Vitamin Co., Ltd.] and the like are commercially manufactured and sold, and these can be used in the present invention.

The (c2) polyglycerin fatty acid ester used as the component (C) in the present invention is an esterification product of polyglycerin and a fatty acid.

The average degree of polymerization of polyglycerin is not particularly limited, but for example, those having an average degree of polymerization of 2 to 10, specifically diglycerin (average degree of polymerization 2), triglycerin (average degree of polymerization 3), tetraglycerin (average degree of polymerization 3). Degree of polymerization 4), pentaglycerin (average degree of polymerization 5), hexaglycerin (average degree of polymerization 6), octaglycerin (average degree of polymerization 8), decaglycerin (average degree of polymerization 10) and the like, preferably diglycerin or Decaglycerin, more preferably decaglycerin. When the polyglycerin is triglycerin or diglycerin, the polyglycerin fatty acid ester is preferably a monoester, and if it is a mixture, it is preferable to contain 50% or more, preferably 80% or more of the monoester.

The fatty acid constituting the polyglycerin fatty acid ester is not particularly limited as long as it is a fatty acid derived from edible animal and vegetable fats and oils, and is, for example, a linear saturated fatty acid having 6 to 24 carbon atoms (for example, caproic acid, capric acid, etc.). Capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoseric acid, etc.) or unsaturated fatty acids (eg, palmitooleic acid, oleic acid, elaidic acid, rinoleic acid, γ-linolenic acid) , Α-linolenic acid, arachidonic acid, ricinoleic acid, condensed ricinoleic acid, etc.). Among these, linear saturated fatty acids having 8 to 12 carbon atoms (for example, caprylic acid, capric acid, lauric acid, etc.) or unsaturated fatty acids having 16 to 22 carbon atoms (for example, palmitooleic acid, oleic acid, elaidic acid, etc.) Acids, linoleic acid, γ-linolenic acid, α-linolenic acid, arachidonic acid, ricinoleic acid, condensed ricinoleic acid, etc.) are preferable, lauric acid or oleic acid is more preferable, and oleic acid is particularly preferable. Only one type of these fatty acids may be used alone, or two or more types may be used in any combination.

Examples of the polyglycerin fatty acid ester include Poem DL-100 (trade name; diglycerin monofatty acid ester; constituent fatty acid: lauric acid; manufactured by RIKEN Vitamin Co., Ltd.) and Poem DO-100V (trade name; diglycerin monofatty acid ester; constituent fatty acid). : Oleic acid; manufactured by RIKEN Vitamin Co., Ltd.), Poem J-0021 (trade name; decaglycerin fatty acid ester; constituent fatty acid: lauric acid; manufactured by RIKEN Vitamin Co., Ltd.), Poem J-0381V (trade name; decaglycerin fatty acid ester; constituent fatty acid) : Oleic acid; manufactured by RIKEN Vitamin Co., Ltd.) and the like are commercially manufactured and sold, and these can be used in the present invention.

The (c3) glycerin acetic acid fatty acid ester used as the component (C) in the present invention is an esterification product of glycerin, acetic acid and fatty acid, for example, a reaction between glycerin monofatty acid ester and anhydrous acetic acid or fat and triacetin. It can be obtained by a transesterification reaction or the like.

The fatty acid constituting the glycerin acetic acid fatty acid ester is not particularly limited as long as it is a saturated fatty acid derived from edible animal and vegetable fats and oils, and is, for example, a linear saturated fatty acid having 6 to 24 carbon atoms (for example, caproic acid and capric acid). , Capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoseric acid, etc.) or unsaturated fatty acids (eg, palmitooleic acid, oleic acid, eleic acid, rinoleic acid, γ-linolenic acid) Acids, α-linolenic acid, arachidonic acid, ricinoleic acid, condensed ricinoleic acid, etc.) can be mentioned. Among these, saturated fatty acids having 14 to 22 carbon atoms (for example, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, etc.) or unsaturated fatty acids having 18 to 22 carbon atoms (for example, oleic acid, linoleic acid, linolenic acid, etc.) Acid, erucic acid, etc.) are generally used.

As the glycerin acetic acid fatty acid ester, for example, Poem G-002 (trade name; manufactured by RIKEN Vitamin) and the like are commercially manufactured and sold, and this can be used in the present invention.

The propylene glycol fatty acid ester in which the constituent fatty acid (c4) used as the component (C) in the present invention is a saturated fatty acid having 8 to 14 carbon atoms is an esterification product of propylene glycol and a saturated fatty acid having 8 to 14 carbon atoms. is there. The ester is preferably a monoester, and if it is a mixture, it is preferable to contain 50% or more, preferably 80% or more, more preferably 90% or more of the monoester.

The fatty acid constituting the propylene glycol fatty acid ester is not particularly limited as long as it is a saturated fatty acid derived from edible animal and vegetable fats and oils and has 8 to 14 carbon atoms. For example, capric acid (saturated with 8 carbon atoms). Fatty acid), capric acid (saturated fatty acid having 10 carbon atoms), lauric acid (saturated fatty acid having 12 carbon atoms), myristic acid (saturated fatty acid having 14 carbon atoms) and the like, and lauric acid is preferable. Only one type of these fatty acids may be used alone, or two or more types may be used in any combination.

As the propylene glycol fatty acid ester, for example, Type-BP (trade name; propylene glycol monofatty acid ester; constituent fatty acid: lauric acid; manufactured by RIKEN Vitamin) and the like are commercially manufactured and sold, and in the present invention, this is used. Can be used.

The (c5) sucrose fatty acid ester used as the component (C) in the present invention is an esterification product of sucrose and fatty acid.

The fatty acid constituting the sucrose fatty acid ester is not particularly limited as long as it is a fatty acid derived from edible animal and vegetable fats and oils, and is, for example, a linear saturated fatty acid having 6 to 24 carbon atoms (for example, caproic acid, capric acid, etc.). Capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoseric acid, etc.) or unsaturated fatty acids (eg, palmitooleic acid, oleic acid, eleic acid, rinoleic acid, γ-linolenic acid) , Α-linolenic acid, arachidonic acid, ricinoleic acid, condensed ricinoleic acid, etc.). Among these, linear saturated fatty acids having 8 to 22 carbon atoms (for example, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, bechenic acid, etc.) are preferable, and lauric acid and palmitic acid are preferable. Acid or stearic acid is more preferred, and lauric acid is particularly preferred. Only one type of these fatty acids may be used alone, or two or more types may be used in any combination.

[Structure of particles containing poorly soluble substances in water]
The poorly water-soluble substance-containing particles of the present invention have a continuous phase containing the component (A) and a dispersed phase containing the component (B) dispersed in the continuous phase.

The component (C) is divided into a case where it is contained in the dispersed phase and a case where it is contained in the continuous phase. Hereinafter, the water-insoluble substance-containing particles of the present invention in which the component (C) is contained in the dispersed phase are referred to as "type A", and the water-insoluble substance-containing particles of the present invention in which the component (C) is contained in the continuous phase are referred to as "type B". ".

[Manufacturing method of poorly water-soluble substance-containing particles (type A)]
In the method for producing poorly water-soluble substance-containing particles (type A) of the present invention, for example, particles having a structure in which a dispersed phase containing a component (B) and a component (C) are dispersed in a continuous phase containing the component (A) can be obtained. The method is not particularly limited, but specifically, a dispersion phase containing the component (B) and the component (C) is dispersed in the aqueous phase containing the component (A) to prepare a water-insoluble substance dispersion. Examples thereof include a method of preparing and cooling and solidifying the poorly water-soluble substance dispersion liquid into droplets. More specifically, it can be produced, for example, by carrying out the following steps (1) to (5).

Step (1): The component (A) is added to water and heated to 40 to 75 ° C. to dissolve it, and this is used as an aqueous phase.
Step (2): The component (B) and the component (C) are heated to a temperature equal to or higher than the melting point of the component (C) (for example, 60 ° C. or higher) to be melted, stirred and mixed, and this is used as a dispersed phase.
Step (3): The dispersed phase prepared in (2) is added to the aqueous phase prepared in (1) and stirred, and the dispersed phase of solid and / or liquid is uniformly dispersed in the aqueous phase to disperse a poorly water-soluble substance. Get the liquid.
Step (4): The poorly water-soluble substance dispersion prepared in (3) is made into droplets by a method known per se, such as a dropping method, a spraying method, and a dispersion method, and cooled to obtain fine particles in a frozen state.
Step (5): Collect the fine particles produced in (4), and use a shelf-type ventilation dryer, fluidized bed dryer, vacuum freeze dryer, vibration vacuum dryer, etc. to collect the desired moisture content. Dry to obtain a poorly water-soluble substance-containing particle (type A) having a structure in which the dispersed phase containing the component (B) and the component (C) is dispersed in the continuous phase containing the component (A).

The composition of the poorly water-soluble substance dispersion prepared in the step (3) is, for example, the content of the component (A) of 30 to 70 parts by mass, the content of water of 130 to 400 parts by mass, and the content of the component (B). Is 0.01 to 40 parts by mass, and the content of the component (C) is 1 to 70 parts by mass.

The ratio of the aqueous phase to the dispersed phase in the water-insoluble substance dispersion prepared in the step (3) is 2/1 to 500/1, preferably 3/1 to 12/1 in the aqueous phase / dispersed phase. When the poorly water-soluble substance dispersion is prepared in such a ratio, the ratio of the continuous phase to the dispersed phase in the poorly water-soluble substance-containing particles (type A) after drying in the step (5) is 3 for the continuous phase / dispersed phase. It will be about / 7 to 99/1.

A high-speed rotary disperser / emulsifier such as Homomixer MARK II (manufactured by Primix Corporation) or Clairemix (manufactured by M Technique) is used for stirring the steps (2) and (3). As the stirring conditions, it is preferable that the rotation speed is 3000 to 10000 rpm and the stirring time is 1 to 60 minutes.

From the viewpoint of productivity, the fine particle formation in the step (4) is preferably carried out by spraying droplets into a column filled with liquid nitrogen by a spray method. For spraying, for example, a pressurized spray nozzle, a rotary spray nozzle, a rotary disk, or the like is used, and a rotary spray nozzle is preferable. When a rotary spray nozzle is used, a preferred rotation speed of 200 to 2000 rpm can be exemplified. The cooling temperature is preferably -196 to −15 ° C., more preferably −120 to −20 ° C.

The drying in the step (5) is preferably performed using a fluidized bed dryer because it can be dried in a short time. Further, drying is carried out until the water content is usually 10% by mass or less, preferably 5% by mass or less. After drying, the obtained water-insoluble substance-containing particles (type A) may be mixed by adding a fluidizing agent in order to prevent the particles from adhering to each other or solidifying due to static electricity or the like. Examples of the fluidizing agent include calcium silicate, light anhydrous silicic acid, silicon dioxide, titanium oxide, talc and the like. The amount of the fluidizing agent added is usually 0.1 to 4% by mass with respect to 100% by mass of the poorly water-soluble substance-containing particles (type A).

The average particle size of the poorly water-soluble substance-containing particles (type A) obtained through each of the above steps is preferably 150 to 1000 μm, more preferably 150 to 400 μm. Examples of the method for measuring the average particle size include a laser diffraction method, a wet image analysis method, a centrifugal sedimentation method, an electrical detection band method, and a sieving method. Examples of the average particle size measuring device include a laser diffraction type particle size distribution measuring device, a laser diffraction type particle size distribution measuring device, a spray particle size distribution measuring device, an image analysis type particle size distribution measuring device, and a sonic vibration type sieving measuring device. Examples thereof include a centrifugal sedimentation type particle size distribution measuring device, a high-precision particle size distribution measuring device, and a precision particle size distribution measuring device.

[Manufacturing method of poorly water-soluble substance-containing particles (type B)]
In the method for producing poorly water-soluble substance-containing particles (type B) of the present invention, for example, particles having a structure in which a dispersed phase containing the component (B) is dispersed in a continuous phase containing the component (A) and the component (C) can be obtained. The method is not particularly limited, but specifically, the component (B) is dispersed as a dispersed phase in the aqueous phase containing the component (A) and the component (C) to prepare a poorly water-soluble substance dispersion. A method of cooling and solidifying the water-insoluble substance dispersion liquid into droplets can be mentioned. More specifically, it can be produced, for example, by carrying out the following steps (1) to (5).

Step (1): The component (A) and the component (C) are added to water and heated to 40 to 75 ° C. to mix and dissolve, and this is used as an aqueous phase.
Step (2): Add component (B) as a dispersed phase to the aqueous phase prepared in (1) and stir to obtain a poorly water-soluble substance dispersion by uniformly dispersing the solid or liquid dispersed phase in the aqueous phase. ..
Step (3): The poorly water-soluble substance dispersion prepared in (2) is made into droplets by a method known per se, such as a dropping method, a spraying method, and a dispersion method, and cooled to obtain fine particles in a frozen state.
Step (4): Collect the fine particles produced in (3), and use a shelf-type ventilation dryer, fluidized bed dryer, vacuum freeze dryer, vibration vacuum dryer, etc. to collect the desired moisture content. Dry to obtain water-insoluble substance-containing particles (type B) having a structure in which a dispersed phase containing the component (B) is dispersed in a continuous phase containing the component (A) and the component (C).

The composition of the poorly water-soluble substance dispersion prepared in the step (2) is, for example, the content of the component (A) is 30 to 70 parts by mass, the content of the component (C) is 1 to 70 parts by mass, and the content of water. Is 130 to 700 parts by mass, and the content of the component (B) is 0.01 to 40 parts by mass.

The ratio of the aqueous phase to the dispersed phase in the water-insoluble substance dispersion prepared in the step (2) is 19/4 to 80000/1, preferably 8/1 to 800/1 in the aqueous phase / dispersed phase. When the poorly water-soluble substance dispersion is prepared in such a ratio, the ratio of the continuous phase to the dispersed phase in the poorly water-soluble substance-containing particles (type B) after drying in the step (4) is 3 for the continuous phase / dispersed phase. It will be about / 2 to 10000/1.

Specific methods for stirring in step (2), microparticulation in step (3), and drying in step (4) (including use of a fluidizing agent after drying), obtained through each of the steps. The average particle size of the poorly water-soluble substance-containing particles (type B) is the same as that of the above-mentioned poorly water-soluble substance-containing particles (type A).

[Other ingredients]
The poorly water-soluble substance-containing particles of the present invention (common to types A and B; the same shall apply hereinafter) are arbitrary other than the above-mentioned component (A), component (B) and component (C) as long as the object of the present invention is not impaired. May contain the components of. Examples of such components include excipients, antioxidants, pH regulators, sweeteners, flavors and the like. These components may be added to either the aqueous phase or the dispersed phase depending on their properties.

Examples of the excipient include celluloses such as crystalline cellulose, saccharides such as lactose and purified sucrose, sugar alcohols such as D-sorbitol, D-mannitol, erythritol and trehalose, cornstarch, potato starch, partially pregelatinized starch and the like. Examples thereof include starches, calcium phosphate, anhydrous calcium hydrogen phosphate, aluminum silicate, magnesium aluminometasilicate and other inorganic substances. Examples of the antioxidant include vitamin Es, ascorbic acids, catechins, rosemary extract, sunflower extract, enzyme-treated rutin, ferulic acid, quercetin and the like. Examples of the pH adjuster include sodium hydroxide, sodium hydrogencarbonate and the like. Examples of the sweetener include acesulfame potassium, aspartame, neotame and the like. Examples of fragrances include citrus essential oils such as orange, lemon, lime and grapefruit, flower essential oils, peppermint oil, sparemint oil, plant essential oils such as spice oil, cola nut extract, coffee extract, crocodile extract and cocoa extract. , Tea extracts, oily extracts such as spices extracts and their oleoledins, synthetic fragrance compounds (eg L-menthol, etc.), oily blended fragrance compositions and any mixture thereof, oily fragrances and Examples thereof include powdered spices dried together with excipients.

The poorly water-soluble substance-containing particles of the present invention have excellent fluidity, and in order to reduce (mask) the unpleasant taste in the oral cavity when taken, the particle surface is coated (forming a coating layer) according to a conventional method. ) Suitable for. As the coating method, for example, the method disclosed in Japanese Patent Application Laid-Open No. 2012-153665 can be carried out.

Here, the angle of repose is used as an index indicating the fluidity of the particles. The angle of repose refers to the angle formed by the free surface of the deposited powder layer and the horizontal plane. The smaller the angle of repose, the higher the fluidity and the more suitable for coating the particle surface.

The method for measuring the angle of repose is roughly classified into three methods: an injection method, a discharge method, and an inclination method. The angle of repose in the present invention is preferably a value measured by the injection method. In the injection method, particles are discharged from above on a horizontal plane and deposited in a conical shape, and the inclination angle of the surface is measured.

The angle of repose of the poorly water-soluble substance-containing particles of the present invention is preferably less than 45 °, more preferably less than 30 °.

The poorly water-soluble substance-containing particles of the present invention can be preferably used by blending them in foods, health foods, pharmaceuticals and the like. Further, the poorly water-soluble drug-containing particles of the present invention may be used as they are as pharmaceuticals, foods, health foods and the like.

When the poorly water-soluble substance-containing particles of the present invention are used in combination with a pharmaceutical product, the form of the pharmaceutical product is not particularly limited, and pharmaceutical additives, food additives, food materials, etc. are appropriately added together with the poorly water-soluble substance-containing particles of the present invention. It can be blended and produced as a preparation in the form of, for example, powders, granules, tablets, microcapsules, soft capsules, hard capsules, etc. according to a conventional method.

When the poorly water-soluble substance-containing particles of the present invention are used in a food or health food, the form of the food or health food is not particularly limited, and for example, confectioneries such as baked confectionery, chocolate, chewing gum, candy, and gummies. , Yogurt, ice cream, desserts such as pudding, tablet confectionery (including supplements) produced by tableting together with powders such as excipients, and the like.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

[Preparation of particles containing poorly soluble substances in water]
(1) Raw materials 1) Water 2) Gelatin (trade name: RGB; jelly strength: 100 g; manufactured by Nitta Gelatin)
3) Nifedipine (trade name: NIFEDIPINE MICRONIZED JP; manufactured by Sicor Societa Italiana Corticosteroid)
4) Monoglycerin fatty acid ester 1 (trade name: Poem M-100; constituent fatty acids: caprylic acid; manufactured by RIKEN Vitamin Co., Ltd.)
5) Monoglycerin fatty acid ester 2 (trade name: Poem M-300; constituent fatty acids: lauric acid; manufactured by RIKEN Vitamin Co., Ltd.)
6) Monoglycerin fatty acid ester 3 (trade name: Emalgie MS powder; constituent fatty acids: palmitic acid and stearic acid; manufactured by RIKEN Vitamin Co., Ltd.)
7) Polyglycerin fatty acid ester 1 (trade name: Poem DL-100; diglycerin monofatty acid ester; constituent fatty acids: lauric acid; manufactured by RIKEN Vitamin Co., Ltd.)
8) Polyglycerin fatty acid ester 2 (trade name: Poem DO-100V; diglycerin monofatty acid ester; constituent fatty acids: oleic acid; manufactured by RIKEN Vitamin Co., Ltd.)
9) Polyglycerin fatty acid ester 3 (trade name: Poem J-0021; decaglycerin fatty acid ester; constituent fatty acids: lauric acid; manufactured by RIKEN Vitamin)
10) Polyglycerin fatty acid ester 4 (trade name: Poem J-0381V; decaglycerin fatty acid ester; constituent fatty acids: oleic acid; manufactured by RIKEN Vitamin)
11) Monoglycerin acetate fatty acid ester (trade name: Poem G-002; manufactured by RIKEN Vitamin Co., Ltd.)
12) Propylene glycol fatty acid ester 1 (trade name: Type BP; propylene glycol monofatty acid ester; constituent fatty acids: lauric acid; manufactured by RIKEN Vitamin)
13) Propylene glycol fatty acid ester 2 (trade name: Rikemar PP-100; propylene glycol monofatty acid ester; constituent fatty acids: palmitic acid; manufactured by RIKEN Vitamin)
14) Propylene glycol fatty acid ester 3 (trade name: Rikemar PO-100V; propylene glycol monofatty acid ester; constituent fatty acids: oleic acid; manufactured by RIKEN Vitamin)
15) Sucrose fatty acid ester 1 (trade name: Ryoto sugar ester L-1695; constituent fatty acids: lauric acid; manufactured by Mitsubishi Chemical Foods Co., Ltd.)
16) Sucrose fatty acid ester 2 (trade name: Ryoto Sugar Ester P-1670; constituent fatty acids: palmitic acid; manufactured by Mitsubishi Chemical Foods Co., Ltd.)
17) Sucrose fatty acid ester 3 (trade name: Ryoto Sugar Ester S-770; constituent fatty acids: stearic acid; manufactured by Mitsubishi Chemical Foods Co., Ltd.)
18) Diacetyl tartrate glycerin fatty acid ester (trade name: Poem W-60; manufactured by RIKEN Vitamin Co., Ltd.)
19) Sorbitan fatty acid ester 1 (trade name: L-300; manufactured by RIKEN Vitamin Co., Ltd.)
20) Sorbitan fatty acid ester 2 (trade name: Poem S-60V; manufactured by RIKEN Vitamin Co., Ltd.)
21) Polyoxyethylene sorbitan fatty acid ester (trade name: polysorbate 20; manufactured by Kao Corporation)

(2) Formulation of poorly water-soluble substance-containing particles Tables 1 to 3 show the composition of the poorly water-soluble substance-containing particles 1 to 18 prepared using the above raw materials. Of these, the poorly water-soluble substance-containing particles 1 to 11 shown in Tables 1 and 2 are examples according to the present invention, and the poorly water-soluble substance-containing particles 12 to 18 shown in Table 3 are comparative examples thereof.

(3) Method for preparing particles containing poorly water-soluble substances (3-1) Particles containing poorly water-soluble substances 1 to 8 and 12 to 18 In a glass beaker having a capacity of 1000 mL, according to 525 g of water and the blending amounts shown in Tables 1 to 3. The raw material of the continuous phase was added, heated to 75 ° C., mixed and dissolved uniformly, and this was used as the aqueous phase.
On the other hand, in a glass beaker having a capacity of 300 mL, the raw materials of the dispersed phase were added according to the blending amounts shown in Tables 1 to 3, and this was heated to 80 ° C. to dissolve it, and Homomixer MARK II (model: 2.5 type; Primix). The mixture was stirred at 10000 rpm for 2 minutes and uniformly dispersed, and this was used as a dispersed phase.
While maintaining the aqueous phase at 75 ° C., a dispersed phase is added thereto, and the mixture is stirred with the same homomixer MARK II at 10000 rpm for 2 minutes to uniformly disperse the dispersed phase in the aqueous phase to obtain a water-insoluble substance dispersion liquid. It was.
Next, the poorly water-soluble substance dispersion was sent to a spray cooling device (testing machine) whose lower part of the column was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotation speed of 1500 rpm to spray spherically. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
500 g of each of the collected particles was dried using a fluidized bed dryer (model: LAB-1; manufactured by Paulec) in the order of 20 ° C. for 1 hour and 40 ° C. for 1 hour, and 110 g of each of the poorly water-soluble substance-containing particles 1 -8 and 12-18 were obtained. The obtained poorly water-soluble substance-containing particles 1 to 8 and 12 to 18 had an average particle diameter of about 180 μm and a water content of about 5% by mass.

(3-2) Water-soluble substance-containing particles 9 and 10 To a glass beaker having a capacity of 1000 mL, add 525 g of water and raw materials of continuous phase according to the blending amounts shown in Table 2, heat to 75 ° C., and mix uniformly. It was dissolved and used as an aqueous phase.
While keeping the aqueous phase at 75 ° C., the raw materials for the dispersed phase are added thereto according to the blending amounts shown in Table 2, and the mixture is stirred with the same homomixer MARK II at 10000 rpm for 2 minutes to make the dispersed phase uniform in the aqueous phase. It was dispersed to obtain a water-insoluble substance dispersion.
Next, the poorly water-soluble substance dispersion was sent to a spray cooling device (testing machine) whose lower part of the column was cooled with liquid nitrogen, and the rotary spray nozzle was rotated at a rotation speed of 1500 rpm to spray spherically. The sprayed composition was cooled and dropped to the bottom of the tower and collected as frozen particles.
500 g of each of the collected particles was dried using a fluidized bed dryer (model: LAB-1; manufactured by Paulec) in the order of 20 ° C. for 1 hour and 40 ° C. for 1 hour, and 110 g of each of the poorly water-soluble substance-containing particles 9 And 10 were obtained. The obtained poorly water-soluble substance-containing particles 9 and 10 had an average particle diameter of about 180 μm and a water content of about 5% by mass.

(3-3) Water-insoluble substance-containing particles 11 In preparing the aqueous phase, 900 g of water was used instead of 525 g of water, and the collected particles were charged at 20 ° C. for 1 hour and then at 40 ° C. for 1 hour. The same procedure as in (3-2) above was carried out except that the particles were dried at 20 ° C. for 2 hours and then at 40 ° C. for 1.5 hours instead of being dried to obtain 110 g of poorly water-soluble substance-containing particles 11. .. The obtained poorly water-soluble substance-containing particles 11 had an average particle diameter of about 180 μm and a water content of about 5% by mass.

[Evaluation test of particles containing poorly soluble substances in water]
(1) Dissolution Evaluation Test In order to simulate the elution of water-insoluble substances in the digestive tract when particles 1 to 18 containing water-insoluble substances were taken, an evaluation test by the paddle method shown below was carried out. .. The results are shown in Table 4.
<Test method>
According to the 17th revised Japanese Pharmacopoeia dissolution test (second method: paddle method), the test is carried out using purified water at 37 ° C. at a paddle rotation speed of 50 rpm. A sample is weighed so that the amount of nifedipine is 10 mg, sampling is performed 4 hours after the start of the test, and the nifedipine concentration is determined by measuring the maximum absorption wavelength near 350 nm of the sampled test solution by visible ultraviolet spectroscopy. Based on the determined nifedipine concentration, the elution amount with respect to the amount of nifedipine used in the test is evaluated as a percentage. The evaluation results are symbolized according to the following evaluation criteria.
⊚: Very good Elution rate after 4 hours is 85% or more ○: Good Elution rate after 4 hours is 60% or more and less than 85% ×: Bad Elution rate after 4 hours is less than 60

(2) Fluidity Evaluation Test Calcium silicate (manufactured by Tomita Pharmaceutical Co., Ltd.) as a fluidizing agent was added to particles 1 to 18 containing a poorly soluble substance in 1% by mass and mixed by an injection method. The angle of repose was measured and the fluidity was evaluated. The evaluation results are symbolized according to the following evaluation criteria. The results are shown in Table 4.
◎: Very good angle of repose less than 30 ° ○: Good angle of repose 30 ° or more, less than 45 ° ×: Bad angle of repose 45 ° or more

As is clear from the results in Table 4, the poorly water-soluble substance-containing particles 1 to 11 according to the examples of the present invention were excellent in both elution and fluidity of "○" or higher. On the other hand, the poorly water-soluble substance-containing particles 12 to 18 of the comparative example were inferior to those of the present invention because either the elution property or the fluidity was a result of "x".

1 continuous phase 2 dispersed phase

Claims (3)

The following components (A), (B) and (C):
(A) Gelatin,
(B) Water-insoluble substance,
(C) Monoglycerin fatty acid ester in which the constituent fatty acid is a saturated fatty acid having 8 to 14 carbon atoms, (c2) polyglycerin fatty acid ester, (c3) glycerin acetic acid fatty acid ester, and (c4) constituent fatty acid has 8 to 14 carbon atoms. A poorly water-soluble substance-containing particle containing at least one selected from the group of propylene glycol fatty acid ester which is a saturated fatty acid of 14 and (c5) sucrose fatty acid ester, and a continuous phase containing the component (A). A poorly water-soluble substance-containing particle having a dispersed phase containing the component (B) dispersed in the continuous phase. The poorly water-soluble substance-containing particles according to claim 1, wherein the component (C) is contained in the dispersed phase. The poorly water-soluble substance-containing particles according to claim 1, wherein the component (C) is contained in the continuous phase.

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