JPH05163163A - Core-containing preparation - Google Patents

Abstract

PURPOSE:To obtain a core-containing preparation having masked undesirable taste such as bitterness and excellent releasability of active component. CONSTITUTION:The objective core-containing preparation is produced by using a spheroidized hydroxypropyl cellulose having low substitution degree as a core, coating the core with a main agent having undesirable taste and coating the outer surface of the main agent layer with a water-insoluble coating agent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention can mask unpleasant tastes such as bitterness, which are useful in dry-coated preparations, particularly in the field of pharmaceuticals.
The present invention also relates to a dry-coated preparation having excellent release of the active ingredient.

[0002]

2. Description of the Related Art Conventionally, in the field of pharmaceutical products, it has been an important matter to eliminate the unpleasant taste such as bitterness of the main drug. When even a drug having an excellent medicinal effect feels uncomfortable for the patient, the drug compliance may be lowered and a sufficient effect may not be obtained, and various methods have been considered as countermeasures.

In this method, 1) a method of adding a taste different from the taste such as saccharides to alleviate the taste of the drug, and 2) adding a taste of the drug to water such as ethyl cellulose or wax. It is roughly divided into a method of coating using an insoluble coating agent.

Since the method of 1) has a low taste-masking effect, it is mainly used for drugs having an unpleasant taste and low strength. In the method of 2), there are a drug coated with a water-insoluble coating agent and a drug dispersed in a water-insoluble coating agent to form a matrix. The former is a drug with a strong unpleasant taste. However, since the drug is exposed on the surface of the preparation, the latter cannot be applied to such drugs. The former is excellent in masking the unpleasant taste in the oral cavity of the patient, but has a drawback that the drug releasing property after transfer to the digestive tract is generally low.

On the other hand, in JP-A-63-258809, fine particles in which the inner core particles are coated with a water-soluble coating, which is further coated with an enteric coating agent such as carboxymethylethyl cellulose, are also disclosed. JP-A-63-188021 discloses a preparation coated with a gastric-soluble coating agent such as polyvinyl acetal diethylaminoacetate. However, in these formulations, the drug release after gastrointestinal transit is not
Since it depends on the solubility, the release property of the drug may change as the pH of the gastric juice or intestinal juice changes.

Therefore, research on a drug-coated preparation with a pH-independent water-insoluble film forming agent such as ethyl cellulose has been advanced. JP-A-57-58631 discloses a formulation in which bitterness is masked and an immediate release is obtained by coating a drug with a coating composition containing such a water-insoluble polymer and a water-soluble polymer. It is shown. However, it cannot be applied to drugs with an unpleasant taste.

In Japanese Patent Laid-Open No. 130214/1993, granules of a main ingredient and a water-swelling substance are used as cores, and the surroundings are covered with ethyl cellulose and a water-soluble polymer to mask unpleasant taste. Formulations with immediate release are shown.
However, since the core granules have a non-uniform size and a wide particle size distribution range as a whole and contain a large amount of irregularly shaped granules, if an attempt is made to coat them with a water-insoluble film-forming agent, a uniform film is difficult to form and an unpleasant taste is produced. It was necessary to use a large amount to conceal it.

[0008]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a dry-coated preparation in which unpleasant taste such as bitterness is masked and the release of the active ingredient is excellent.

[0009]

The dry-coated preparation according to the present invention has a spheroidized low-substituted hydroxypropylcellulose as a core, and an unpleasant-tasting main drug is coated around the core, and the outside is further coated. It is formed by coating with a water-insoluble coating agent.

The present invention will be described in detail below. The low-substituted hydroxypropyl cellulose (hereinafter referred to as L-HPC) used for producing the dry-coated formulation of the present invention is a substance having a large swelling property which is widely used as a disintegrating agent and a binder. The present invention has found that the water swelling property is not impaired even when the L-HPC is subjected to a spheroidizing treatment, and the drug releasing property is still excellent, and thus the present invention has been accomplished.

The degree of substitution of the hydroxypropoxyl group of L-HPC may be within the range of 5.0 to 16.0% described in the Japanese Pharmacopoeia. L- in the nuclear granule composition after spheroidization
The content of HPC is preferably 90% by weight or more,
As other components, other excipients such as lactose, starch and crystalline cellulose may be contained.

As the spheroidizing method of L-HPC,
1) Kneading and granulating L-HPC and water with a stirring granulator, followed by drying and sieving to obtain a product having a desired particle size distribution; 2)
After kneading L-HPC and water with a stirring granulator or a kneader, granulation is performed with a cylindrical extruder, and then malm treatment is performed with a marumerizer, and the obtained granules are dried and sieved. 3) A solution in which L-HPC is dispersed in water is wet pulverized, and the suspension is spray-dried to obtain a product.

The granules thus spheroidized are
Since the sphericity represented by the ratio of major axis / minor axis of the granule is 1.3 or less, the coating in the next step is performed uniformly and precisely, and the effect of masking unpleasant taste is excellent. .

Further, since the obtained granules can be selected and employed only in the desired particle size range by the above-mentioned sieving operation, the particle size distribution width can be narrowed. The particle size distribution width is, for example, 200 to 300 μm, 300 to 500 μm, 5
When separated into groups of 00 to 700 μm and 700 to 900 μm, it is desirable that the content of 300 to 500 μm is 80% by weight or more of the whole, and if it is less than 80% by weight, the particle size distribution width is wide. Precise coaching is difficult. If the final product is a fine granule, 200 to 300
It is preferable to use the one having a particle size distribution mainly of μm or 300 to 500 μm.

The ratio of the spheroidized L-HPC to the final product depends on the thickness of the water-insoluble coating.
It is preferably about 90% by weight. If it is less than 40% by weight, the drug release property will be reduced, and if it exceeds 90% by weight, the effect of masking unpleasant taste cannot be expected.

[0016] On the other hand, as an active ingredient having an unpleasant taste suitable for the dry-coated preparation of the present invention which coats the granules as cores, for example, anti-ulcer agents such as propantheline bromide and cimetidine, macromolecules such as erythromycin, etc. Ride antibiotics, β-lactam antibiotics such as penicillin derivatives and cephalosporin derivatives, psychotropic agents such as chlorpromazine, cardiotonic agents such as digoxin, and antipyretics such as sulpiline. Depending on the effective amount of the drug and the degree of bitterness, the content of these main drugs is 30% by weight based on the final product.
The following is preferable.

Coating of spheroidized L-HPC with active ingredient,
Granulation is performed according to a conventional method using a fluidized bed coating device or a centrifugal fluidized granulation device. At that time, other excipients such as a water-soluble polymer, lactose, corn starch, and crystalline cellulose may be added.

The water-insoluble film forming agent used for forming the outermost layer in the production of the dry-coated preparation of the present invention includes water-insoluble polymers such as ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, waxes and the like. Among them, ethyl cellulose is preferable among them.

Although the amount used varies depending on the kind, it is preferably 1 to 15% by weight based on the final product. This is 1%
If it is less than the above range, the unpleasant taste cannot be masked, and if it is more than 15% by weight, the release of the active ingredient is lowered.

As the coating method, a conventional method using a fluidized bed coating device or a centrifugal fluidized granulation device is used. Further, in the coating liquid at this time, triethyl citrate, a plasticizer such as polyethylene glycol, an anti-adhesive agent such as talc, sugars for controlling the membrane permeability, salts,
A water-soluble component such as a water-soluble polymer may be added in an appropriate amount. The dry-coated granules according to the present invention thus produced usually take the form of granules or fine granules.

[0021]

When the oral preparation of the present invention, the water-insoluble coating on the outermost layer masks the unpleasant taste of the main drug when orally administered, and after the granules are transferred to the digestive tract, water permeates through the water-insoluble coating. The spheroidized L-HPC in the nucleus of the swelling swells and destroys the water-insoluble film, so that the drug is rapidly released to the outside to bring about a drug effect.

[0022]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the description of these Examples. Example 1 500 g of L-HPC having a sphericity of 1.0 and a particle size of 200 to 300 μm.
Was placed in a small fluidized bed coating apparatus MODEL STREA-1 (manufactured by Paulec Co., Ltd., trade name), and 500 g of a liquid having the following composition was coated at a spray rate of 17 g / min to obtain fine particles with nuclei.・ Hydroxypropyl methylcellulose TC-5R (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) ‥‥‥ 4.0% by weight ・ Propantheline bromide ‥‥‥‥‥‥ 〃 ・ Methylene chloride 47.0 〃 ・ Ethanol ‥‥‥ 47.0% by weight

Next, 300 g of the fine granules with nuclei were put into the above-mentioned small fluidized bed coating apparatus, and 150 g of a liquid having the following composition was coated at a spraying rate of 15 g / min to obtain a desired nucleated preparation.・ Ethyl cellulose N-10 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.2 〃 ・ Ethanol ‥‥‥‥ 95.8 〃

Example 2 A target dry preparation was prepared in the same manner as in Example 1 except that the coating amount of ethyl cellulose N-10 was 5% by weight of the final product.

Example 3 A target dry preparation was prepared in the same manner as in Example 1 except that the coating amount of ethyl cellulose N-10 was 10% by weight of the final product.

Comparative Example 1 L-HPC (1 kg) and propantheline bromide (20 g) were placed in a stirring granulator vertical granulator (trade name, manufactured by Paulec Co.), and hydroxypropylmethyl cellulose was added.
Granulation was performed while adding a 4 wt% aqueous solution of TC-5R (previously described), and the granulated product was dried and then sieved with a 30 mesh (500 μm) sieve to produce fine particles. The fine granules were coated with ethyl cellulose N-10 in the same amount as in Example 2 in an amount of 5% by weight of the final product to prepare a dry-coated formulation.

The dry-coated preparations obtained in each example were evaluated by the following methods, and the results are shown in Table 1. 1) Sensory test (masking effect of unpleasant taste) A fine drug equivalent to 15 mg was contained in the mouth as a drug amount, and the time until the start of feeling bitterness was measured. It was evaluated that the unpleasant taste was masked when the masking time was 60 seconds or more. 2) Dissolution test (D10 minutes, D30 minutes) Japanese Pharmacopoeia 12, paddle method 50 rpm Eluent: 0.2% sodium chloride aqueous solution 500 ml, 37 ° C. D 10 minutes: Elution rate after 10 minutes. D 30 minutes: Elution rate after 30 minutes.

[0028]

From the above results, it is understood that Examples 1 to 3 are preparations in which the bitterness of the drug is masked and the drug release property is excellent. Further, comparing Example 3 with Comparative Example 1, Example 3 in which the spheroidized L-HPC was used as the core and the main drug was coated around the core had a core in which the drug was dispersed in L-HPC. It can be seen that, as compared with Comparative Example 1 used, both the effect of masking unpleasant taste and the drug release property are superior.

[0030]

The dry-coated preparation of the present invention masks the unpleasant taste of a drug and is excellent in drug release.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yasuaki Muto No. 28 Nishi-Fukushima, Chugoku Village, Nakakubiki-gun, Niigata Prefecture 1 Shin-Etsu Chemical Co., Ltd.

Claims (1)

[Claims] 1. A nucleated preparation comprising a spheroidized low-substituted hydroxypropylcellulose as a core, a core drug having an unpleasant taste is coated around the core, and the outside thereof is coated with a water-insoluble film-forming agent. .