JP2006089461A - Layered granule containing raw material for stimulant - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a preparation containing a raw material for a stimulant, capable of keeping a concentration of the raw material for the stimulant at 10% or less in all of production processes, and to provide small-sized layered granules containing the raw material for the stimulant. <P>SOLUTION: The layered granules containing the raw material for the stimulant in an amount of 10 mass% or less are characterized so that a pharmaceutical-containing layer is 0.1-5 pts.wt. based on 1 pt.wt. of nuclear particles and a concentration of the raw material for the stimulant in the pharmaceutical-containing layer is 12-100 mass%. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a laying granule containing a stimulant raw material such as pseudoephedrine.

  Since pseudoephedrine hydrochloride is a stimulant raw material, the concentration in the preparation must be 10% by mass or less (hereinafter, abbreviated as “%” where appropriate) as pseudoephedrine (see Non-Patent Document 1). . In consideration of convenience such as storage during the production, it is necessary to maintain this 10% or less in the whole production process, and such a prescription design and production method are preferable. If it does so, there will be no problem if pseudoephedrine hydrochloride is mixed with other main ingredient ingredients, excipients, and the like in the first production process so that the pseudoephedrine is 10% or less.

  However, if pseudoephedrine, which cannot be said to be a small amount due to the compounding amount in the preparation, is added to 10% or less in the first stage of the manufacturing process, the preparation may be large depending on the amount of additives added thereafter. There is a concern that this may lead to deterioration of the feeling of administration.

  In particular, in the case of a laying granule in which sugar or crystalline cellulose is used as a core and a drug-containing powder is coated on this, an increase in size as a preparation is an important issue. This leads to an increase in the size or the number of small capsules taken, and has a great influence on the merchantability through the doseability, the size of the packaging container, and the like.

  Therefore, how to mix pseudoephedrine hydrochloride in the preparation, or the method of layering granulation, is a problem.

  In addition, it is considered that the higher the content of pseudoephedrine in the drug layer, the faster the release, and it is preferable for the quick-release layering granule.

Edited by Yoshio Hirai et al., “Shoroku Law”, Stimulant Control Law, Article 2, Paragraph 5, Appendix, Yukaku

  An object of the present invention is to provide a method for producing a stimulant raw material-containing preparation in which the concentration of a stimulant raw material such as pseudoephedrine is 10% or less in all production steps, and a small stimulant raw material-containing laying granule.

  As a result of intensive studies to solve such problems, the present inventors have added a portion of pseudoephedrine hydrochloride to the binding solution so as to have a concentration of 10% or less as pseudoephedrine. It has been found that the final preparation can be made smaller than before while achieving a concentration of 10% or less. In particular, the effect is enormous in the case of layering granulation, leading to the development of small capsules filled with pseudoephedrine-containing layering granules.

  In addition, it was found that pseudoephedrine hydrochloride has an action as a binder, and in reducing the size of the preparation, it is caused by the combination of the binder by reducing the amount of the binder rather than simply reducing the amount of the excipient. It came to prevent the disintegration and dissolution delay of the preparation.

  The aspect of the present invention completed based on such knowledge is that the drug-containing layer is 0.1 to 5 parts by mass with respect to 1 part by mass of the core particles, and the concentration of the stimulant raw material in the drug-containing layer is 12 to 100% by mass. A layering granule containing 10% by mass or less of a stimulant raw material characterized by

  In another aspect of the present invention, the drug-containing layer is 0.5 to 3 parts by mass with respect to 1 part by mass of the core particle, and the concentration of the stimulant raw material in the drug-containing layer is 13 to 30% by mass. A layering granule containing 10% by mass or less of the characteristic stimulant raw material.

  Another aspect of the present invention is characterized in that a binding solution containing 10% by mass or less of a stimulant raw material is sprayed, and a granulating powder containing 0 to 10% by mass of the stimulant raw material is attached to the surface of the core particle. The layering granule.

  Another aspect of the present invention is the above-mentioned layering granule in which the stimulant raw material is pseudoephedrine.

  Another aspect of the present invention is characterized in that a binding solution containing 10% by mass or less of a stimulant raw material is sprayed, and a granulating powder containing 0 to 10% by mass of the stimulant raw material is attached to the surface of the core particle. A stimulant raw material characterized in that the drug-containing layer is 0.1 to 5 parts by mass with respect to 1 part by mass of the core particles, and the concentration of the stimulant raw material in the drug-containing layer is 12 to 100% by mass. It is a manufacturing method of the layouting granule containing 10 mass% or less.

  According to the present invention, it has become possible to provide a small stimulant raw material-containing laying granule while maintaining the content of the stimulant raw material less than 10% in the entire production process.

  “Nucleic particles” are substances that serve as nuclei for the preparation of laying granules. For example, spheres having an average particle size of 40 to 1800 μm, sugar having substantially uniform particle size distribution, crystalline cellulose, etc. are used. ing. Usually, these core particles do not contain a drug as an active ingredient, but even if they are contained, there is no problem in using them as the core particles of the present invention.

  The “drug-containing layer” refers to a layered portion formed of excipients such as a stimulant raw material, a drug as an active ingredient, and a disintegrant and coated on the surface of the core particle. This layered portion is preferably a single layer from the viewpoint of miniaturization of the preparation, but it may be composed of two or more layers. The drug-containing layer may be further coated with a general coating layer.

  The ratio of the drug-containing layer in the laying granules varies depending on the ratio of the core particles, and the standard is 0.1 to 5 parts by weight, preferably 0.25 to 4 parts by weight with respect to 1 part by weight of the core particles. Yes, more preferably 0.5 to 3 parts by mass.

  The “stimulant raw material” in the present invention includes a stimulant and the like, and is of course 10% or less in the final preparation as a free body, and in consideration of convenience such as storage in each production process, a mixed powder It must be 10% or less even in the medium or in the binding solution. Examples of the stimulant raw material include pseudoephedrine and methylephedrine, and these may be salts and hydrates. Examples of the salt include hydrochloride, sulfate, phosphate and the like.

  The concentration of the stimulant raw material in the drug-containing layer varies depending on the ratio between the core particles and the drug-containing layer, and is 12 to 100% as a free body, preferably 12.5 to 50%, more preferably 13 to 30%. It is. It is 10% or less in the entire laying granule.

  Among the stimulant raw materials, pseudoephedrine has an action as a binder, and when reducing the size of the preparation, it can reduce the amount of the binder, especially from excipients. Suitable for preparation.

  The “laying granule” is a particle having an average particle diameter of 50 to 2000 μm, which is covered with one or more drug-containing layers, coating layers, etc. around the core particles. The laying granules are prepared by a granulation method such as rolling granulation, rolling fluidized bed granulation, coating granulation or the like.

  A “binding solution” is a solution in which a stimulant raw material is dissolved in water, an organic solvent (ethanol, 2-propanol, etc.) or a mixture of water and an organic solvent. A liquid that adheres to the surroundings and contributes to the formation of a drug-containing layer. The concentration of the stimulant raw material in this binding solution is 10% or less, and 2.5 to 10% is preferable in view of production efficiency and the like. In the binding solution, a binder, a dispersant and the like may be further dissolved or suspended. The binding solution includes a granulating solution.

  “Granulation powder” refers to a powder composed of excipients such as drugs and disintegrants as active ingredients, and adheres to the surface of core particles to form a layered portion of laying granules. When the stimulant raw material is contained in this granulating powder, the content (formulation) is 10% or less, but when all of the stimulant raw material is dissolved in the “binding solution”, it is used for granulation. The content of the stimulant raw material in the powder is 0%. Therefore, the content of the stimulant raw material in the granulating powder is 0 to 10%.

  As the “laying granule production method”, for example, core particles are rolled in a tumbling granulator, and a granulating powder containing 10% or less of a stimulant raw material in addition to a main ingredient and excipients. In addition to the binder, spraying a binding solution containing 10% or less of the stimulant raw material in addition to the binder, the granulating powder is attached to the surface of the core particles, dried and classified to prepare granules. The method is adopted.

  The method for reducing the size of the preparation of the present invention contributes to a certain size reduction even when used for tablets, powders, etc., but the effect is greatest in the laying granules for attaching the drug to the core particles.

  In addition, other active ingredients and additives can be added to the drug-containing layer or the like as long as the effects of the present invention are not impaired. For example, herbal extracts such as 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 azulene sulfonate, acetaminophen, aminoethyl sulfonic acid, aldioxa, isopropylantipyrine, ibuprofen, ursodeoxycholic acid, etenzamide, ergocalciferol, octothiamine, cafe In, guaifenesin, potassium guaiacolsulfonate, dipotassium glycyrrhizinate, magnesium aluminate silicate, tocopherol succinate, cholecalciferol, co Sodium droitin sulfate, salicylamide, cyanocobalamin, dibrofilin, sucralfate, semi-alkaline proteinase, albumin tannate, berberine tannate, thiamine disulfide, theophylline, dehydrocholic acid, tranexamic acid, nicotinamide, noscapine, retinol palmitate, calcium pantothenate , Biotin, sodium picosulfate, bisacodyl, bisibutamine, bisbenchamine, tipepidine hibenzate, dextromethorphan phenolphthalate, cloperastine fendizoate, clemastine fumarate, ferrous fumarate, fursultiamine, bromvalerylurea , Hesperidin, hepronicart, benfotiamine, carbinoxamine maleate, chlorf maleate Niramine, phenylamine maleate, mequitazine, magnesium aluminate metasilicate, methylmethionine sulfonium chloride (VU), isopropamide iodide, riboflavin, codeine phosphate, dihydrocodeine phosphate, dimemorphan phosphate, pyridoxal phosphate, riboflavin sodium phosphate, phosphorus Calcium oxyhydrogen, sodium benzoate caffeine, carnitine chloride, berberine chloride, arginine hydrochloride, isothipentyl hydrochloride, cloperastine hydrochloride, chlorhexidine hydrochloride, dicyclomine hydrochloride, dicetiamine hydrochloride, diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, cetraxate hydrochloride, thiamine hydrochloride, Triprolidine hydrochloride, Trimethquinol hydrochloride, Noscapine hydrochloride, Papaverine hydrochloride, Hydroxo hydrochloride Cobalamin, pyridoxine hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, fursulfiamine hydrochloride, bromhexine hydrochloride, meclizine hydrochloride, methoxyphenamine hydrochloride, ranitidine hydrochloride, lysine hydrochloride, loperamide hydrochloride, dry aluminum hydroxide gel, synthetic aluminum silicate, synthesis Hydrotalcite, magnesium oxide, bismuth subgallate, alimemazine tartrate, butyl scopolamine bromide, methyl atropine bromide, methyl octatropine bromide, methylbenactidium bromide, scopolamine hydrobromide, dextrohydrobromide Turfan, thiamine nitrate, tocopherol acetate, hydroxocobalamin acetate, aluminum hydroxide / sodium bicarbonate coprecipitate, magnesium hydroxide, magnesium carbonate, sodium bicarbonate, precipitated coal Western medicine ingredients such as calcium, copper chlorophyllin sodium, calcium lactate, anhydrous caffeine, folic acid and riboflavin butyrate, excipients such as lactose, sucrose, mannitol, starch, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, polyvinylpyrrolidone Binders such as low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, lubricants such as magnesium stearate, calcium stearate, talc, fragrances, pigments and flavoring agents.

  Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.

Example 1
(1) Preparation of powder for granulation 9.6 g carbinoxamine maleate
Pseudoephedrine hydrochloride 140.0g
Lysozyme chloride 60.0g
Anhydrous caffeine 200.0g
8.8 g of magnesium aluminate metasilicate
1145.6g corn starch
After weighing the above components, they were mixed and pulverized to prepare a granulating powder.

(2) Preparation of binding solution pseudoephedrine hydrochloride 100.0 g
Hydroxypropylcellulose 36.0g
The above components were weighed and dissolved in a mixed solution of 80.0 g of purified water and 634.0 g of IPA (2-propanol) to prepare a binding solution.

(3) Preparation of laying granules Non-parrel (trade name) 800.0 g is rolled in a CF-granulator (Freund Sangyo Co., Ltd.), and the granulating powder is supplied at a rate of 40 to 80 g / min. However, the binding solution was sprayed at a rate of 40 g / min. Extruded with purified water so that all of the binding solution was sprayed, dried and classified with a 1200 μm sieve to prepare laying granules (1250 mg as a daily prescription).

Comparative Example 1
(1) Preparation of powder for granulation 9.6 g carbinoxamine maleate
Pseudoephedrine hydrochloride 240.0g
Lysozyme chloride 60.0g
Anhydrous caffeine 200.0g
8.8 g magnesium aluminate metasilicate
Corn starch 1991.6g
After weighing the above components, they were mixed and pulverized to prepare a granulating powder.

(2) Preparation of binding solution 90.0 g of hydroxypropylcellulose was dissolved in a mixed solution of 120.0 g of purified water and 930.0 g of IPA to prepare a binding solution.

(3) Preparation of laying granule 1000.0 g of non-parrel was rolled in a CF-granulator, and while supplying the granulating powder at a rate of 40 to 80 g / min, the binding solution was 40 g / min. Sprayed at a rate of Extruded with purified water so that all of the binding solution was sprayed, dried and classified with a 1200 μm sieve to prepare laying granules (1800 mg as the daily dosage).

Example 2
(1) Preparation of granulation solution Carbinoxamine maleate 9.6 g
Pseudoephedrine hydrochloride 240.0g
Magnesium aluminate metasilicate 5.0g
Hydroxypropylcellulose 30.0g
853.8 g of purified water
After weighing the above components, it was dispersed and dissolved in purified water to prepare a granulation solution.

(2) Preparation of laying granule Spray granulation was carried out in a draft tube type spouted bed using SELFIA (trade name) 2200.0 g. The granulation solution spray rate was 20-50 g / min. After drying, the mixture was classified with a 850 μm sieve to prepare laying granules (daily prescription amount: 1242.3 mg).

Test Example 1 Apparent specific gravity and capsule filling of laying granules Capsule filling was performed using the laying granules prepared in Example 1, Example 2 and Comparative Example 1. Table 1 shows the daily prescription amount, the apparent specific gravity, and the number of capsules that can be filled.

  In Examples 1 and 2, part or all of pseudoephedrine hydrochloride is added to the binding solution (granulation solution), and the amount of pseudoephedrine hydrochloride added to the granulated powder at a concentration of 10% or less is small. The daily prescription is reduced. Further, in Example 2 in which the total amount of pseudoephedrine hydrochloride was added to the liquid, the apparent specific gravity was increased, so that further miniaturization (reduction in the number of capsules) became possible.

Test Example 2 Comparison of dissolution behavior The dissolution behavior of the laying granules prepared in Example 1 and Comparative Example 1 was examined using the paddle method described in the Japanese Pharmacopoeia. In addition, Japanese Pharmacopoeia purified water (37 ± 0.5 ° C.) was used as the eluate. The results are shown in FIG.

  As can be seen from FIG. 1, the laying granule of Example 1 has a faster elution rise than the laying granule of Comparative Example 1, and exhibits excellent elution behavior.

  According to the present invention, it is possible to prepare pseudoephedrine-containing laying granules that are small and have good dissolution properties, and development of an excellent preparation for rhinitis is expected.

It is a graph which shows the elution behavior of pseudoephedrine hydrochloride in the laying granules prepared in Example 1 and Comparative Example 1.

Claims (5)

  10 parts by mass of the stimulant material, wherein the drug-containing layer is 0.1 to 5 parts by mass with respect to 1 part by mass of the core particles, and the concentration of the stimulant material in the drug-containing layer is 12 to 100% by mass Laying granules containing up to 5%.   10 parts by mass of the stimulant material, wherein the drug-containing layer is 0.5 to 3 parts by mass with respect to 1 part by mass of the core particles, and the concentration of the stimulant material in the drug-containing layer is 13 to 30% by mass Laying granules containing up to 5%.   2. The layering according to claim 1, wherein a binding solution containing 10% by mass or less of the stimulant raw material is sprayed, and a granulating powder containing 0-10% by mass of the stimulant raw material is adhered to the surface of the core particle. Granules.   The layering granule according to any one of claims 1 to 3, wherein the stimulant raw material is pseudoephedrine. To 1 part by mass of core particles, characterized in that a binding solution containing 10% by mass or less of a stimulant raw material is sprayed, and a granulating powder containing 0 to 10% by mass of the stimulant raw material is adhered to the surface of the core particle. In contrast, the layer containing 0.1 to 5 parts by mass of the drug-containing layer and the concentration of the stimulant raw material in the drug-containing layer is 12 to 100% by mass. Granule manufacturing method.

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