JP5141115B2 - Drug-containing preparation particles exhibiting an unpleasant taste - Google Patents

Description

  The present invention relates to a solid preparation containing a drug exhibiting an unpleasant taste.

  When a drug having an irritating bitter taste such as ibuprofen is blended in a preparation having a small particle size and a large specific surface area such as a powder or granule, the bitter taste of the drug is felt stronger than in the case of a tablet. Therefore, from the viewpoint of improving the dosage of these preparations, for example, in JP-A-9-208458, a composition containing 30% by weight or more of a water-swellable substance in a drug and a composition is wet with water or hydrous alcohol. An oral preparation in which the unpleasant taste of a drug is masked by granulation is described (see Patent Document 1).

  Also, Japanese Patent Publication No. 2003-504324 discloses an unpleasant taste by spraying a granule containing an active ingredient having an unpleasant taste and a granule disintegrating agent by spraying a suspension containing a coating agent and a membrane disintegrating agent. A masked granule is described (see Patent Document 2). However, this technique cannot sufficiently mask the unpleasant taste if it is intended to improve the dissolution property, but if it is intended to sufficiently mask the unpleasant taste, it is necessary to increase the thickness of the coating layer, resulting in a slow dissolution. There was a problem.

Japanese Patent Laid-Open No. 9-208458 Special table 2003-504324 gazette

  Therefore, in order to obtain a preparation satisfying both drug dissolution and masking of unpleasant taste, selection of components to be blended in the coating agent is important. For example, unpleasant taste masking can be realized by adding a water-insoluble polymer to the coating agent, and elution can be ensured by adding a water-soluble polymer. In film coating, the primary coating (undercoat layer) directly coated on the core particles and the coating (overcoat layer) coated on the undercoat layer for the purpose of reducing the coating amount and increasing the coating efficiency. ) May be applied in two layers.

  However, increasing the amount of water-insoluble polymer in the coating agent of the overcoat layer enhances the masking effect of unpleasant taste but slows the elution of the drug, while increasing the amount of water-soluble polymer increases the drug content. There was a problem that elution was faster but masking of unpleasant taste was insufficient.

  Accordingly, an object of the present invention is to provide a preparation particle containing a drug exhibiting an unpleasant taste such as ibuprofen, sufficiently masking the unpleasant taste of the drug and having improved dissolution property.

  In order to solve the above-mentioned problems, the present inventors have conducted intensive studies and prepared core particles containing a bitter drug, and a water-soluble polymer and a substance that promotes drug elution with a small amount (hereinafter, elution). By applying an undercoat using a coating agent blended with an accelerator), and further applying an overcoat using a coating agent blended with a water-soluble polymer, a water-insoluble polymer, and an elution accelerator, It has been found that pharmaceutical particles can be obtained in which masking of the unpleasant taste of the drug and dissolution are improved at the same time. Furthermore, as a result of earnest examination of the selection of dissolution enhancers, substances that have the property of enhancing the dissolution properties of drugs by increasing the disintegration properties of these preparations when incorporated in powders, granules, tablets, etc. as dissolution enhancers It was found that by using this, it is possible to obtain formulation particles that are sufficiently masked of unpleasant taste and that are rapidly eluted, thereby completing the present invention.

  That is, the present invention comprises (1) core particles containing a drug exhibiting an unpleasant taste, (2) an undercoat layer containing a water-soluble polymer and an elution accelerator, and (3) a water-soluble polymer, Formulation particles having an overcoat layer containing molecules and an elution promoter.

  ADVANTAGE OF THE INVENTION According to this invention, it became possible to provide the formulation particle | grains which contain the drug which exhibits an unpleasant taste, the unpleasant taste of the drug was masked, and the elution property was improved.

  The “formulation particles” of the present invention include (1) core particles containing a drug exhibiting an unpleasant taste, and (2) an undercoat that coats the core particles using a coating agent containing a water-soluble polymer and an elution accelerator. And (3) an overcoat layer coated on the undercoat layer using a coating agent containing a water-soluble polymer, a water-insoluble polymer and an elution accelerator.

  “A drug exhibiting an unpleasant taste” means a drug having an unpleasant taste by blending several kinds of drugs in addition to a drug having a bitter taste, an astringent taste, etc. It is also included when the amount of is increased as a whole. Examples of the compound having a large amount per day include ibuprofen, etenzamide, and acetaminophen. Examples of drugs having an unpleasant taste, although not much in themselves, include, for example, herbal extracts such as fennel oil, licorice extract, fennel extract, cinnamon oil, clove oil, belladonna extract, funnel extract, d -Chlorpheniramine maleate, L-aspartic acid, potassium L-aspartate, magnesium L-aspartate, L-isoleucine, L-glutamine, L-phenylalanine, L-methionine, L-histidine hydrochloride, ascorbic acid, aspirin, Sodium azulenesulfonate, aminoethylsulfonic acid, aldioxa, isopropylantipyrine, ursodeoxycholic acid, ergocalciferol, octothiamine, caffeine, guaifenesin, potassium guaiacolsulfonate, dipotassium glycyrrhizinate , Magnesium aluminate, Tocopherol succinate, Cholecalciferol, Sodium chondroitin sulfate, Salicylamide, Cyanocobalamin, Dibrofilin, Sucralfate, Semi-alkaline proteinase, Albumin tannate, Berberine tannate, Thiamine disulfide, Theophylline, Dehydrocholic acid, Tranexam Acid, nicotinamide, noscapine, retinol palmitate, calcium pantothenate, biotin, sodium picosulfate, bisacodyl, bisbutiamine, bisbenchamine, tipepidine hibenzate, dextromethorphan of phenolphthalate, cloperastine fendizoate, fumarate Cremastine acid, ferrous fumarate, fursultiamine, bromvalerylurea, hesperidin Hepronicart, benfotiamine, carbinoxamine maleate, chlorpheniramine maleate, pheniramine maleate, mequitazine, magnesium aluminate metasilicate, methylmethionine sulfonium chloride (VU), isopropamide iodide, riboflavin, codeine phosphate, dihydrocodeine phosphate, Dimemorphan phosphate, pyridoxal phosphate, sodium riboflavin phosphate, calcium hydrogen phosphate, sodium benzoate caffeine, carnitine chloride, berberine chloride, arginine hydrochloride, istipendyl hydrochloride, cloperastine hydrochloride, chlorhexidine hydrochloride, dicyclomine hydrochloride, dicetiamine hydrochloride, diphenidol hydrochloride Diphenylpyraline hydrochloride, diphenhydramine hydrochloride, cetraxate hydrochloride, thiamine hydrochloride, Riprolysine, Trimethoquinol hydrochloride, Noscapine hydrochloride, Papaverine hydrochloride, Hydroxocobalamin hydrochloride, Pyridoxine hydrochloride, Phenylpropanolamine hydrochloride, Phenylephrine hydrochloride, Fursulfiamine hydrochloride, Bromhexine hydrochloride, Meclizine hydrochloride, Methoxyphenamine hydrochloride, Lanitidine hydrochloride, Lysine hydrochloride, Loperamide hydrochloride, dry aluminum hydroxide gel, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, bismuth subgallate, alimemazine tartrate, butyl scopolamine bromide, methyl atropine bromide, methyl octatropine bromide, methyl bena bromide Cutidium, scopolamine hydrobromide, dextromethorphan hydrobromide, thiamine nitrate, tocopherol acetate, hydroxocobalamin acetate, aluminum hydroxide and hydrogen carbonate Thorium coprecipitate, magnesium hydroxide, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, sodium copper chlorophyllin, calcium lactate, anhydrous caffeine, folic acid, and a riboflavin butyrate. From the viewpoint of necessity of masking of unpleasant taste, the effect of the present invention is greater in the case of a drug incorporated in a large amount in a preparation typified by ibuprofen. Moreover, even if it is a trace amount, the case where the compounding quantity of the drug which exhibits an unpleasant taste increases as a whole is also included by mix | blending several types. In addition, the compounding amount of the drug exhibiting an unpleasant taste in the present invention is, for example, 30% by mass or more with respect to the mass of the core particles containing the drug exhibiting the unpleasant taste, when the drug exhibiting the unpleasant taste is ibuprofen. If it is 35% by weight or more, it is meaningful to use the present invention.

  The core particles containing a drug exhibiting an unpleasant taste are, for example, a drug exhibiting an unpleasant taste mixed with an additive component, and a water-soluble polymer such as hydroxypropylcellulose is dissolved in a solvent (water or a mixture of water and ethanol). It is obtained by granulating using the prepared solution. Examples of the granulation method include stirring granulation method, fluidized bed granulation method, rolling fluid granulation method, kneading granulation method, extrusion granulation method, dry granulation method, spray granulation method, and the like. Examples thereof include a granulation method, a lamination granulation method, and a rolling granulation method. Furthermore, the average particle diameter of the core particles containing the bitter drug is preferably in the range of 100 to 500 μm. Here, the “mean particle diameter” in the present invention is a mass average diameter. Specifically, the sampled particles (for example, 5 g) are 30M (500 μm), 42M (355 μm), 60M (250 μm), 80M (180 μm), 100M (150 μm), 150M (106 μm), 200M (75 μm), and 270M. (53 μm) placed on a sieve stacked in order, classified by applying vibration for a certain time (for example, 3 minutes), 30M sieve residue, 42M sieve residue, 60M sieve residue, 80M sieve residue, 100M sieve residue, 150M sieve residue , 200M sieve residue, 270M sieve residue and 270M passage mass is measured. Multiply each mass by the median value of the particle size classification between each sieve that has been calculated in advance, and obtain the mass average diameter obtained by dividing the sum by the total mass (5 g), that is, the average particle size in the present invention. is there. For example, it can be automatically measured by using a robot shifter (seishin corporation). M represents a mesh. The average particle size depends on “Modern Chemical Engineering I” (1988, Asakura Shoten, p.239-p.245) edited by the Chemical Society of Japan.

  Furthermore, you may mix | blend another well-known additive with the core particle containing the medicine which exhibits the said unpleasant taste. Known additives include, for example, light anhydrous silicic acid, hydrous silicon dioxide, crystalline cellulose, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropylcellulose, croscarmellose, croscarmellose sodium, candy powder (Maltose Syrup Powder), powdered sugar, erythritol, xylitol, sorbitol, maltitol, lactitol, sucrose, anhydrous maltose and hydrous maltose.

  The “undercoat layer” in the present invention is a layer that directly covers the core particles, and the “overcoat layer” is a layer that covers the undercoat layer.

  The “dissolution enhancer” of the present invention is a substance having a property of enhancing the dissolution property of a drug by enhancing the disintegration property of these preparations when blended in powders, granules, tablets, etc. Sugar alcohol having a solubility in water of 15% by mass or more. Examples of the disintegrant include carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, carmellose, carmellose sodium, starch, and partially pregelatinized. Examples thereof include starch, sodium carboxymethyl starch, and pullulan. Examples of sugar alcohols having a solubility in water of 15% or more include mannitol, erythritol, xylitol, sorbitol, maltitol, and lactitol. Among these, from the viewpoint of stabilizing the drug in the preparation, for example, when the drug exhibiting an unpleasant taste is ibuprofen, a substance that is not reactive with the drug such as carmellose calcium or mannitol is preferable. The blending amount of the elution accelerator is preferably in the range of 1 to 20% by mass with respect to the total mass of the coating agent from the viewpoint of improving the drug elution and the size of the preparation.

  The water-soluble polymer blended in the coating agent of the present invention may be any one that is usually used as a coating agent for various solid preparations. For example, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose Can be mentioned. Among these water-soluble polymers, hydroxypropylmethylcellulose is preferred from the viewpoint of unpleasant taste masking of drugs and drug elution. Furthermore, the blending amount of the water-soluble polymer is preferably in the range of 40 to 80% by mass with respect to the total mass of the coating agent from the viewpoint of drug unpleasant taste masking and drug elution.

  The water-insoluble polymer to be blended in the coating agent of the present invention is not limited as long as it is usually used as a coating agent for various solid preparations, and examples thereof include ethyl cellulose, aminoalkyl methacrylate, and polyvinyl acetal diethylaminoacetate. it can. Among these water-insoluble polymers, ethyl cellulose is preferable from the viewpoint of unpleasant taste masking of drugs and drug elution. Furthermore, the blending amount of the water-soluble polymer is preferably in the range of 10 to 59% by mass with respect to the total mass of the coating agent from the viewpoint of drug unpleasant taste masking and drug dissolution.

  In addition, the preparation particles of the present invention need to contain a lubricant and / or a fluidizing agent in the coating agent in order to prevent aggregation of the preparation particles. Examples of the lubricant and the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide, magnesium stearate, calcium stearate, magnesium aluminate metasilicate, and talc. Among these, talc is preferable from the viewpoint of contraindication of other components such as ibuprofen and a highly reactive drug. Furthermore, the blending amount of the lubricant and / or the fluidizing agent is 10 to 50% by mass, preferably 15 to 45% by mass, based on the total mass of the coating agent when talc is used as the lubricant. If it is less than 10% by mass, the expected aggregation prevention and lubrication effects cannot be obtained, and if it exceeds 50% by mass, the moldability of the film is affected and a sufficient bitterness masking effect cannot be obtained.

  The coating layer of the present invention contains the elution accelerator and the water-soluble polymer and covers the core particle, the elution accelerator, the water-soluble polymer, and the water-insoluble polymer. It is a layer composed of two layers of an overcoat layer covering the undercoat layer. The ratio of the coating layer to the mass of the preparation particles is preferably in the range of 6 to 30% by mass from the viewpoint of unpleasant taste masking, drug dissolution, drug stability, and the like.

  In the preparation particles of the present invention, by coating the undercoat layer on the core particles, the overcoat layer thereon can be thinly and uniformly coated, so that the coating amount can be reduced as compared with the conventional film coating. Can do. Thereby, masking of an unpleasant taste can be ensured, without enlarging a particle diameter compared with the conventional coating formulation. The ratio of the undercoat layer and the overcoat layer to the core particles is 1 to 10% by mass for the undercoat layer and 5 to 20% by mass for the overcoat layer with respect to the mass of the core particles.

  In addition, as a method of coating the core particles with the coating layer, a general method can be used, for example, a fluidized bed coating method, a rolling fluidized bed coating method, a rolling fluidized coating method, a pan coating method, or the like. Is mentioned.

  The preparation particles of the present invention can be prepared into various solid preparations by a conventional method after further mixing with an excipient or other components. Examples of various solid preparations include granules, powders, pills, tablets, and capsules.

  Hereinafter, the present invention will be described in more detail with reference examples, examples, comparative examples and test examples. An example is an example which shows an embodiment of the invention concretely, and a test example is an example of a test which evaluated an example. The present invention is not limited to these examples.

Reference example 1
Production method of core particles 27000 g of ibuprofen, 240 g of riboflavin, 3000 g of light anhydrous silicic acid, 12000 g of crystalline cellulose, 21000 g of candy powder, weighed, mixed and pulverized, dissolved 5400 g of hydroxypropylcellulose (HPC-L) in 54600 g of purified water The obtained solution was used as a binding liquid, and granulated using a rolling fluidized bed granulator (MP: manufactured by POWREC) to produce core particles. The average particle diameter of the core particles was 306 μm, and the bulk density was 421.7 kg / m ³ . (Measurement method of bulk density: Add a powder sample to a container with a known volume (for example, a cylindrical container with a diameter of 30 mm, 100 mL), scrape the surface of the powder, weigh it, and measure the mass of the powder sample at this time. The value divided by the inner volume of the container, where the container is not tapped, which is also referred to as apparent specific gravity. (A measuring instrument was used.)

Reference example 2
Production method of core particles 27000g of ibuprofen, 240g of riboflavin, 3000g of light anhydrous silicic acid, 12000g of crystalline cellulose, 21000g of candy powder, weighed, mixed and pulverized, dissolved 5400g of hydroxypropyl cellulose (HPC-L) in 48600g of purified water The obtained solution was used as a binding liquid, and granulated using a rolling fluidized bed granulator (MP: manufactured by POWREC) to produce core particles. The average particle diameter of the core particles was 281 μm, and the bulk density was 429.0 kg / m ³ .

Example 1
The core particle obtained in Reference Example 1 is a coating agent obtained by dissolving and dispersing 34.2 g of hydroxypropylmethylcellulose, 22.8 g of talc and 5.7 g of carmellose calcium in 575 g of purified water, and a spouted bed with a draft tube (GPCG: After coating and drying, 46.2 g of ethylcellulose, 27.6 g of hydroxypropylmethylcellulose and 49.2 g of talc and 12.3 g of carmellose calcium were dissolved and dispersed in a mixture of 1131 g of ethanol and 283 g of purified water. The obtained coating agent was coated using a spouted bed with a draft tube (GPCG: manufactured by Paulek) to produce granules.

Example 2
The core particle obtained in Reference Example 2 is a coating agent obtained by dissolving and dispersing 34.2 g of hydroxypropylmethylcellulose, 22.8 g of talc and 5.7 g of mannitol in 575 g of purified water, and a spouted bed with a draft tube (GPCG: Paulec) Can be dissolved and dispersed in a mixed solution of 1131 g of ethanol and 283 g of purified water. 46.2 g of ethylcellulose, 27.6 g of hydroxypropylmethylcellulose, 49.2 g of talc and 12.3 g of carmellose calcium The resulting coating agent was coated using a spouted bed with a draft tube (GPCG: manufactured by Paulek) to produce granules.

Comparative Example 1
A coating agent obtained by dissolving and dispersing 34.2 g of hydroxypropylmethylcellulose and 22.8 g of talc in 575 g of purified water from the core particles obtained in Reference Example 1, and using a spouted bed with a draft tube (GPCG: manufactured by Paulec) After coating and drying, a spouted bed with a draft tube is a coating agent obtained by dissolving and dispersing 46.2 g of ethylcellulose, 27.6 g of hydroxypropylmethylcellulose and 49.2 g of talc in a mixed solution of 1131 g of ethanol and 283 g of purified water. Granules were produced by coating using GPCG (manufactured by Paulek).

Comparative Example 2
Coating obtained by dissolving and dispersing 46.2 g of ethyl cellulose, 27.6 g of hydroxypropylmethylcellulose, 49.2 g of talc and 12.3 g of carmellose calcium in a mixed solution of 1131 g of ethanol and 283 g of purified water. Using an agent, a spouted bed with a draft tube (GPCG: manufactured by Paulek) was applied to produce granules.

Test Example The coated granules prepared in Examples 1 and 2 and Comparative Examples 1 and 2, and drugs and excipients are weighed, mixed and pulverized, and granulated at high speed using a 95% alcohol solution as a solvent (vertical granulator: POWREC A test sample was prepared by mixing granules containing a drug obtained by performing a test. The test sample was subjected to a dissolution test using water as a test solution by the Japanese Pharmacopoeia General Test Method Dissolution Test Method Paddle Method. The test results are shown in FIG.

  The test sample was filled in a transparent bottle, sealed, and stored at 5 ° C. and 65 ° C. for 1 week, and then ibuprofen in the sample was quantified by HPLC method to evaluate the residual rate. The test results are shown in Table 1.

  The flavor evaluation of the test sample was performed by three testers, and a sample in which one or more felt bitterness was indicated by Δ. The results are shown in Table 2.

In Comparative Example 1, masking of unpleasant taste was sufficient, but a tendency of elution to be delayed was confirmed. In Comparative Example 2, dissolution was rapid, but masking of unpleasant taste was insufficient. On the other hand, in Examples 1 and 2, the dissolution property was good and the masking of unpleasant taste was sufficient. Moreover, the stability of the drug was comparable in the examples and comparative examples.
From the above results, it was possible to provide a preparation particle containing a drug exhibiting an unpleasant taste such as ibuprofen, sufficiently masking the unpleasant taste of the drug and improving the dissolution property.

FIG. 1 shows the dissolution rate of ibuprofen.

  According to the present invention, it can be expected to provide granules, powders and the like that are excellent in unpleasant taste masking properties and rapidly dissolve while containing a drug having an unpleasant taste such as ibuprofen at a high concentration.

Claims (3)

(1) Core particles containing ibuprofen , (2) Undercoat layer containing hydroxypropylmethylcellulose and carmellose calcium or mannitol , and (3) Overcoat layer containing hydroxypropylmethylcellulose , ethylcellulose and carmellose calcium Formulation particles. The formulation particle according to claim 1, wherein the content of ibuprofen in the core particle containing ibuprofen is 30% by mass or more. The core particle containing ibuprofen is undercoated with a coating solution containing hydroxypropylmethylcellulose and carmellose calcium or mannitol , dried, and then dried, and then a film coating solution containing hydroxypropylmethylcellulose , ethylcellulose and carmellose calcium A method for producing pharmaceutical particles, characterized in that an overcoat is applied using

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