JPH0761962B2 - Method for producing coated fine granules - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention provides a hardened oil and a water-soluble coating base of 4: 1.
The present invention relates to a method for producing coated fine granules, which comprises coating with a coating composition consisting of ˜9: 1 (weight ratio). An object of the present invention is to provide a coated fine granule having improved blendability of the fine granule and improved taste.

[Prior Art] Conventionally, in the combined administration of two or more kinds of pharmaceutical solid preparations having a small particle size, the interaction between pharmaceutical ingredients of different kinds causes a change in the color tone, and the efficacy decreases due to denaturation or decomposition. There were some things that weren't preferable. Therefore, in order to prevent their interaction, to make a stable and effective preparation, and to mask the unpleasant taste of various solid preparations, and to make it easier to take, in order to make them easier to take, it is possible to use various coating forming agents. It is being coated with a substance.

As a film-forming substance used as a coating base, it is known that water-soluble cellulose derivatives are generally used.

Hardened oil is also used as a coating material for pharmaceuticals (for example, JP-A-57-9713).

[Problems to be Solved by the Invention] Fine granules are compounded and dosed with other drugs due to their ease of handling, but when the efficacy decreases due to denaturation or decomposition due to interaction between different drugs during formulation. , The coating mentioned above is required.

However, when coating fine granules with a water-soluble cellulose derivative, these have a large surface area per unit weight, so compared to coating tablets,
It is necessary to increase the coating amount.

In addition, a coating pan, a fluidized bed coating device, a centrifugal fluidized coating device, etc. are usually used for these coatings, but in that case, the so-called agglomeration phenomenon, in which particles are bonded to each other and grow into large particles, is likely to occur.

Furthermore, this agglomeration phenomenon tends to occur as the coating amount increases and the particles become smaller.

As a method for suppressing this agglomeration phenomenon, it has been attempted to add a disintegrating agent for tablets such as talc, sugar and powder to the coating composition and spray the dispersed liquid agent. In fact, there are many obstacles such as the above, and the sufficient effect is not always recognized.

It is not preferable to use hardened oil alone as a coating base for coating fine granules, which causes pinholes, has a problem in safety, and tends to delay elution time.

[Means for Solving the Problems] In order to solve the above problems, the present inventors have considered that the coating amount of fine granules is as small as possible and does not cause granulation or agglomeration during the coating operation. The present inventors have earnestly conducted research on a coating method that brings about a coating effect, for example, a compounding with a contraindicated item, an improvement in taste and an improvement in moisture resistance.

The result is a 4: 1 ratio of hydrogenated oil and water soluble coating base.
By coating a fine granule with a coating composition consisting of ~ 9: 1 (weight ratio), it can be formulated into an excellent solid preparation with excellent moisture resistance, no pinholes, and no aggregation. And completed the present invention.

Hereinafter, the present invention will be described in detail.

The hydrogenated oil used in the present invention may be vegetable or animal as long as it is pharmaceutically acceptable. For example, paraffin wax, carnauba wax, spermaceti wax, beeswax, caster wax (Caster Wax) Hydrogenated beef oil, hydrogenated vegetable oil, such as hydrogenated castor oil, hydrogenated rapeseed oil, hydrogenated peanut oil, and the like.

Examples of the water-soluble coating base include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl cellulose and the like.

A preferred combination of hydrogenated oil and water-soluble coating base is a combination of hydrogenated rapeseed oil and hydroxypropyl methylcellulose.

The mixing ratio of hydrogenated oil and water-soluble coating base in the coating composition is 4: 1 to 9: 1 (weight ratio).

The coating amount is 1 to 20% by weight, preferably 3 to 10% by weight, based on the weight of the target powder coating agent.

The coating composition comprising the hardened oil and the water-soluble coating base used in the present invention is usually used by dissolving and dispersing (coating solution) in a suitable solvent, and in this case, the solvent is methylene chloride, chloroform or the like. Halogenated hydrocarbons; alcohols such as methanol and ethanol / halogenated hydrocarbons; acetone / halogenated hydrocarbons; water / alcohol / halogenated hydrocarbons and the like, single solvents or mixed solvents .
Moreover, it is preferable to dissolve at a suitable temperature as needed.

The concentration of the hardened oil and the water-soluble coating base in the coating liquid is 1 to 10% by weight, preferably 2 to 5% by weight, based on the total solid components.

The coating liquid thus obtained may contain various auxiliaries, for example, food dyes, food lakes, coloring agents such as titanium chloride, glycerin fatty acid esters, polyethylene glycols, propylene glycols, etc. Examples include plasticizers, silicone oils, surfactants, and fragrances.

A centrifugal fluidized coating apparatus is usually used in the method of the present invention, but a fluidized bed coating apparatus can also be used.

The spray gun may be a commonly used gun.

[Effects of the Invention] (1) Mixing Change Test 3: 2 of the formulations of Examples and Reference Examples and magnesium oxide
(Weight ratio), and allowed to stand under the conditions of 40 ° C.-75% relative humidity, and bis (2-trimethylammonioethyl = α-acetoxypropionate) -naphthalene-1,
5-disulfonate (generic name: aclatonium napadisylate, hereinafter referred to as aclatonium napadisylate)
The quantitative value of acratonium napadisylate in the compounded product after standing was calculated as a relative percentage with respect to the quantitative value of 1. The results are shown in Table-1.

In addition, the quantification of acratonium napadisylate is a bromcresol green colorimetric method, that is, by combining acratonium napadisylate and bromcresol green, this was extracted with chloroform, then sodium hydroxide solution was added, and the mixture was shaken and then mixed in the aqueous layer. The back-extracted bromcresol green was quantified by absorptiometry.

(2) Dissolution test Japanese Pharmacopoeia (10th revision) Dissolution test method (paddle method, 100rp)
m, the first solution 800 ml used in the disintegration test method is used), and the elution amount of acratonium napadisylate is measured by the absorptiometric method, and the time until the elution rate reaches 75% (T ₇₅ ).
Was calculated. The results are shown in Table-2.

From the above results, the fine granules produced by the coating method of the present invention did not generate pinholes (see FIG. 1 and FIG.
It can be understood that the composition change can be effectively prevented with a small coating amount without agglomeration and the coating agent thus obtained exhibits a good dissolution. Furthermore, the unpleasant feeling of the tongue felt with the fine granules coated with hydrogenated oil alone is eliminated, and the taste of the drug inside is hidden.

EXAMPLES Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited to these.

In the examples and reference examples, granulated sugar, centrifugal fluidized coating machine, 5% hydroxypropylmethylcellulose, lactose, hydrogenated rapeseed oil, hydroxypropylmethylcellulose, mannitol, corn starch, ethylene oxide / propylene oxide copolymer are respectively I used one.

Granulated sugar [60-80 mesh; Shimizu Port Sugar Co., Ltd.
Made] Centrifugal fluid coating machine [CF-360; made by Freund Sangyo Co., Ltd.] 5% Hydroxypropyl methylcellulose [HPC-L;
Made by Nippon Soda Co., Ltd.] Lactose [Nicrotose; made by Megre Co., Ltd.] Hardened rapeseed oil [Labrywax 102; made by Freund Sangyo Co., Ltd.] Hydroxypropyl methylcellulose [TC-5RW; made by Shin-Etsu Chemical Co., Ltd.] Mannit [ Towa Kasei Co., Ltd.] Constarch [Hokuriku Sugar Co., Ltd.] Ethylene chloride / propylene chloride copolymer [PEP-101;
Freund Sangyo Co., Ltd.] Example 1 (1) 1400 g of granulated sugar was charged into a centrifugal fluidized coating machine, and a 5% hydroxypropylmethylcellulose hydrous ethanol solution [water: ethanol = 1: 3.25 (weight ratio)]
Accratonium napadisylate 302.4 while spraying 1040 g
Powder coat a mixture of g and lactose 625.6 g.
Subsequently, 420 g of lactose is powder-coated in a continuous operation. The particles produced are dried overnight at 40 ° C. to give 2752 g of fine granules for coating.

(2) A solution prepared by charging 500 g of the coating fine particles obtained in (1) in a centrifugal fluidized coating machine and dissolving 48.6 g of hydrogenated rapeseed oil and 5.4 g of hydroxypropylmethylcellulose in a mixed solution of 1674 g of methylene chloride and 432 g of ethanol (hereinafter , Coating liquid A) is sprayed and coated. If the generated particles are dried at 40 ° C overnight,
545 g of fine granules are obtained.

Example 2 To 500 g of the fine granules for coating of Example 1 (1), 30.1 g of hydrogenated rapeseed oil and 7.5 g of hydroxypropylmethylcellulose were added, 1164.8 g of methylene chloride and 30 parts of ethanol.
A solution (hereinafter referred to as coating solution B) dissolved in 0.6 g of a mixed solution is sprayed and coated. The produced particles are dried at 40 ° C. overnight to obtain 533 g of fine granules.

Example 3 (1) 1400 g of granulated sugar was charged into a centrifugal fluidized coating machine, and a 5% hydroxypropylmethylcellulose-containing ethanol solution [water: ethanol = 1: 7.5 (weight ratio)] 8
Powder coating a mixture of 280 g acratonium napadisylate and 420 g mannite while spraying 23 g. Continuously, in continuous operation, 280 g of Mannit and 42 of Constarch
Powder coating 0 g of the mixture. 40 particles generated
After drying at ℃ overnight, 2784g of fine granules for coating are obtained.

(2) The coating liquid A1247g is sprayed on 600 g of the coating fine particles obtained in (1) to perform coating. If the generated particles are dried at 40 ℃ overnight, 620g of fine granules
To get

Example 4 406 g of the coating fine particles obtained in Example 3 (1) is sprayed with 886 g of the coating liquid B for coating. If the generated particles are dried at 40 ° C overnight, 422g of fine granules
To get

Reference Example 1 To 500 g of the coating fine particles obtained in Example 3 (1), a solution prepared by dissolving 34.3 g of hardened rapeseed oil in a mixture of 1131.9 g of methylene chloride and 205.8 g of ethanol is sprayed and coated. If the generated particles are dried at 40 ° C overnight,
524 g of fine granules are obtained.

Reference Example 2 To 500 g of the fine particles for coating obtained in Example 3 (1), 19.8 g of hydroxypropylmethyl cellulose and 2.0 g of ethylene oxide / propylene oxide copolymer were added, 612.8 g of methylene chloride, 158.1 g of ethanol and 10.3 of water. Spray the solution dissolved in g mixture to coat. The produced particles are dried at 40 ° C. overnight to obtain 509 g of fine granules.

[Brief description of drawings]

1 and 2 are photographs (scanning electron microscope, magnification: 70 times) showing the shapes of particles of the fine granules of Reference Example 1 and Example 1, respectively.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-57-21314 (JP, A) JP-A-55-149211 (JP, A)

Claims (1)

[Claims] 1. A hydrogenated oil and a water-soluble coating base are 4:
A method for producing a coated fine granule, which comprises coating using a coating composition consisting of 1 to 9: 1 (weight ratio).