JPH06256170A - Coated pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain a solid pharmaceutical preparation for internal use, capable of effectively masking taste or odor of a medicinally active substance and thereby readily administrable and excellent in releasability of the medicinally active substance and the pharmaceutical stability. CONSTITUTION:This coated pharmaceutical preparation is characterized by forming a coating layer composed of an aminoalkyl methacrylate and copolymer RS on the surface of an inner core containing a medicinally active substance and further forming a coating layer composed only of a hydrophobic substance and a water-insoluble inorganic substance on the outer layer of the coating layer.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a solid preparation for internal use, and more particularly to a coated preparation in which the unpleasant taste and odor of a pharmaceutically active substance are masked.

[0002]

2. Description of the Related Art Conventionally, when a pharmaceutically active substance has an unpleasant taste or odor, a gastric-soluble substance such as aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate or the like is formed on the surface of the inner core containing the pharmaceutically active substance. The material was coated with a material that dissolves in the acidic solution. However, since the gastric-soluble material is likely to change the compounding with the pharmaceutically active substance, the coloration change of the coated preparation with time may be accelerated. In addition, since the pH of the gastrointestinal tract solution of a patient in the coated preparation using a gastric-soluble material varies greatly depending on before and after meals, age, etc., the release of the pharmaceutically active substance is not constant and the pharmacological effect varies. It is easy to occur.

As a study for improving the drawbacks of the gastric-soluble material, one of the proposals is a coated preparation in which a hydrophobic substance (wax, higher fatty acid, etc.) is added to a water-soluble material (Japanese Patent Application Laid-Open No. 2000-242242). 53-139717). On the other hand, a coating preparation using a heat-meltable material as a material and a water-insoluble acrylic polymer (aminoalkylmethacrylate copolymer RS) has been proposed (JP-A-4-217913, JP-A-4-217913). JP-A-2-42967, JP-A-63-27423, JP-A-2-497.
21). However, it is difficult to say that any of the disclosed coated preparations is easy to take and is excellent in the release of the pharmaceutically active substance and the pharmaceutical stability.

[0004]

The object of the present invention is to effectively mask the taste and odor of a pharmaceutically active substance, and therefore, it is easy to take, and the release of the pharmaceutically active substance and the pharmaceutical stability are excellent. It is to provide a coated preparation.

[0005]

[Means for Solving the Problems] The present inventors have found that, from among various additives that can be used for masking the taste and odor of pharmaceutically active substances, a taste masking coating layer for the purpose of taste masking and a deodorant for the purpose of deodorizing. Appropriate materials were chosen for each of the coating layers. Furthermore, the present inventors solve the above problems by applying a taste masking coating layer to the surface of the inner core containing a pharmaceutically active substance using the above material, and further applying an odor preventing coating layer to the outer layer of the taste masking coating layer. completed. That is, the present invention, in a solid preparation for internal use, a coating layer using an aminoalkyl methacrylate copolymer RS is applied to the inner core surface containing a pharmaceutically active substance, and further, an outer layer of the coating layer,
It is intended to provide a coated preparation having a coating layer composed of only a hydrophobic substance and a water-insoluble inorganic substance.

In selecting the material for the taste masking coating layer, the present inventors selected the aminoalkyl methacrylate copolymer RS (listed in Part II of the Japanese Pharmacopoeia Standard for Pharmaceutical Ingredients) included in the constitution of the present invention as a pharmaceutically active substance. It was found that the material has a small change in composition. In addition, aminoalkyl methacrylate copolymer RS
Has a pH-independent dissolution property, and thus releases the pharmaceutically active substance without being affected by the pH fluctuation of the solution in the digestive tract. However, the aminoalkyl methacrylate copolymer RS is a water-insoluble material used in sustained-release preparations, and has the property of delaying the release of pharmaceutically active substances. Therefore, the present inventors rapidly release a pharmaceutically active substance by blending the taste masking coating layer with aminoalkylmethacrylate copolymer RS, a hydrophobic substance, and a water-insoluble but non-water-repellent inorganic substance in a well-balanced manner. I devised to do it. Further, a water-insoluble inorganic substance that does not exhibit water repellency is blended in the deodorant coating layer for masking the offensive odor generated with time from the pharmaceutically active substance and the acrylic polymer such as aminoalkyl methacrylate copolymer RS. It is difficult to take, which is the tendency to be seen in coated preparations of granules and fine granules made of waxes, that is, the surface is water repellent, which improves the property of aggregating in the mouth. There is.

As a more preferred embodiment of the present invention, there can be mentioned, for example, a coated preparation in which the pharmaceutically active substance in the preparation is one or more selected from amino acids, amino acid salts, amino acid derivatives and peptides. . Examples of the amino acids and amino acid salts include various essential and non-essential amino acids, and examples of the amino acid derivatives include sulfur-containing amino acid derivatives such as taurine. Examples of the peptide include synthetic oligopeptides, peptide hormones, partial hydrolysates of animal and plant proteins, and the like.

As the above aminoalkyl methacrylate copolymer RS, commercially available Eudragit RS (manufactured by Reem Pharma (Germany)) can be preferably used. As the hydrophobic substance, solid waxes, that is, fats and oils,
Wax, hydrocarbon, higher fatty acid, higher fatty acid alcohol,
Examples include higher fatty acid esters and hydroxy higher fatty acid esters. Among the oils and fats, hydrogenated vegetable oil (hardened rapeseed oil, hardened castor oil, hardened coconut oil, etc.), liquid paraffin,
Natural wax etc. can be used conveniently. Only one kind of these hydrophobic substances may be used, or two or more kinds thereof may be appropriately mixed and used. In particular, by using a solid substance and a liquid hydrophobic substance together, a coating layer having desired properties can be obtained. A more preferable example of the combined use of a hydrophobic substance is a combination of hydrogenated vegetable oil and liquid paraffin. The content of the hydrophobic substance in the taste masking coating layer is preferably 5 to 60% by weight, more preferably 30 to 50% by weight. The content of the hydrophobic substance in the deodorant coating layer is 5 to 70% by weight, more preferably 40 to 60% by weight.

The water-insoluble inorganic substances include talc,
Hydrous silicon dioxide, titanium oxide, light anhydrous silicic acid, synthetic magnesium silicate, dried aluminum hydroxide gel,
Included are precipitated calcium carbonate and calcium sulfate.
Among them, talc or hydrous silicon dioxide is particularly preferable.
The content of the water-insoluble inorganic substance in the taste masking coating composition is preferably 5 to 60% by weight, more preferably 3% by weight.
It is 0 to 50% by weight. The amount of the water-insoluble inorganic compound contained in the deodorant coating layer is 5 to 70% by weight,
More preferably, it is 40 to 60% by weight.

The above-mentioned pharmaceutically active substances include amino acid compositions for the purpose of nutritional supplementation, amino acid compositions for liver failure, amino acid compositions for renal failure, amino acid compositions for cancer, and branches which are amino acid compositions according to various pathological conditions. Chain amino acid compositions and the like.

[0011]

The coated preparation of the present invention uses the aminoalkylmethacrylate copolymer RS, which has a low pH-dependent solubility as a material for the taste masking layer, and which does not undergo a compounding change with the pharmaceutically active substance. There is.
Therefore, the coated preparation of the present invention has less variation in the release property of the pharmaceutically active substance, less color change over time, and less deterioration in the dissolution characteristics. Furthermore, the outermost layer of the coated preparation of the present invention is provided with an odor preventive coating layer that masks the unpleasant odor generated from the inner core and the aminoalkyl methacrylate copolymer RS, and has an excellent odor preventive effect as well as a taste masking effect. There is. Examples and test examples are shown below,
The present invention will be described more specifically.

[0012]

【Example】

Example 1 Amino acids of Group A, Group B, and Group C having the weights shown in Table 1 were mixed for each group, and 50 g (1% by weight) of hydroxypropylcellulose H type (manufactured by Nippon Soda) was added to the Group A mixture. ,
39 g (1.5% by weight) in group B mixture, 3 in group C mixture
6g (1.5wt%) was added and mixed respectively. An appropriate amount of a mixture of ethanol and water was added to each of these mixtures, and the mixture was kneaded, granulated by an extrusion granulator, granulated by a granulator and dried. The resulting dried granules (granules) of each group are 12 to 4
The granules were classified so as to have a particle size of 2 mesh, 5% by weight of the taste masking coating layer having the composition shown in Table 2 was coated on the surface of the granules, and the deodorant coating layer having the composition shown in Table 3 was further prepared. The surface of the taste masking coating layer was coated with 4% by weight thereof. The granules of each group were mixed so that the weight ratio of amino acids of group A, group B and group C was 50:26:24 to obtain a coated preparation of amino acid-containing granules.

[0013]

[Table 1]

[0014]

[Table 2]

[0015]

[Table 3]

Example 2 L-Arginine (250 g), talc (1 g) and hydrous silicon dioxide (1 g) were mixed, and a plain tablet having an outer diameter of 8.5 mm and a weight of about 252 mg was tabletted with a tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho). . The surface of this plain tablet was coated with a flavoring coating layer having the composition shown in Table 2 at 4% by weight of the plain tablet weight.
Further, an odor preventing coating layer having a composition shown in Table 3 was coated on the surface of the taste masking coating layer in an amount of 3% by weight based on the weight of the uncoated tablets to obtain L-arginine-containing coated tablets.

Then, a coated preparation of amino acid-containing granules for testing was prepared. Comparative Formulation Three types of comparative formulations (Comparative Formulations 1, 2, and 3) were prepared in the same manner as in Example 1 except that the materials shown in Table 4 were used instead of the taste masking layer and the deodorant coating layer of Example 1.
3) was obtained. Further, Comparative Formulation 4 was obtained in the same manner as in Example 1 except that the deodorant coating was not applied to the formulation of Example 1.

[0018]

[Table 4]

Test Example 1 Color Change Example 1 and 3 types of comparative formulations (Comparative formulations 1, 2, 3)
Each was placed in a glass bottle and sealed tightly, and then stored in a constant temperature bath at 60 ° C., and the yellowing degree (Δb) over time was measured with a color difference meter (Sigma 80 type manufactured by Nippon Denshoku Industries Co., Ltd.). The measurement result is shown in FIG.

Test Example 2 Elutability Among the various amino acids shown in Table 1, the most eluting l-tyrosine was used as an index, and the coated preparation of the present invention of Example 1 and three types of comparative preparations (Comparative Preparation 1, The elution properties of 2, 3) were compared. For comparison of dissolution properties, three types of test liquids with different pH (pH 1.2, 4.0, 6.9) were used, and the dissolution test was conducted according to the Japanese Pharmacopoeia Dissolution Test Method 2 Paddle Method. It was After each test substance (4.44 g) was added to the test solution, the elution rate of L-tyrosine after 30 minutes was measured by a liquid chromatography method, and the measurement results are shown in Table 5.
It was shown to. As a result of the test, the coated preparation of the present invention of Example 1 was
Comparative preparation 2 whose dissolution changes depending on the pH of the test solution 2
Also, unlike Comparative Preparation 3, all test solutions showed a high dissolution rate. Therefore, it was revealed that the coated preparation of the present invention releases the pharmaceutically active substance without depending on the pH of the solution in the digestive tract, like the comparative preparation 1 using the water-soluble material.

[0021]

[Table 5]

Test Example 3 Elution Rate 5 minutes, 10 minutes after the test substance was charged in the same manner as in Test Example 2 except that the coated preparation of the present invention of Example 1 was used as the test substance and the test liquid was water. , 15 minutes, 20 minutes, 25 minutes, 30 minutes,
And the elution rate of L-tyrosine after 1 hour was measured, and the results are shown in FIG. As a result of the test, the coated preparation of the present invention showed that the water-insoluble material used in the sustained-release preparation was aminoalkyl methacrylate copolymer R.
Even though S is included in the taste masking coating layer,
It has been found that by mixing a hydrophobic substance and an inorganic substance that is water-insoluble but does not exhibit water repellency in a well-balanced manner, the pharmaceutically active substance is released promptly after administration.

Test Example 4 Sensory Test The coated preparation of the present invention and Comparative Preparation 4 of Example 1 were used as test substances, and 4.44 g of each was packaged in a package and stored in a thermostat at 60 ° C. for 7 days. After the abuse by heating, each test substance 4.
Eighty-four panelists were allowed to each contain 44 g of the oral cavity, and the presence or absence of bad taste and offensive odor was evaluated, and the results are shown in Table 6.
As a result of the test, it was found that the coated preparation of the present invention was easy to take because all eight panelists did not feel any bad taste or offensive odor when taking the preparation. Comparative Formulation 4, which did not have the deodorant coating layer, did not have a bad taste, but it was evaluated that all panelists felt an offensive odor, and the deodorant effect of the deodorant coating layer was recognized.

[0024]

[Table 6]

[0025]

Industrial Applicability As described above, according to the present invention, the taste and odor of a pharmaceutically active substance can be effectively masked, and therefore, it is easy to take and the release of the pharmaceutically active substance and the pharmaceutical stability are excellent. A solid preparation for oral administration can be provided.

[Brief description of drawings]

FIG. 1 is a diagram showing a color change over time.

FIG. 2 is a diagram showing the results of a dissolution test.

Claims (2)

[Claims] 1. A solid preparation for internal use, wherein a coating layer using an aminoalkyl methacrylate copolymer RS is applied to the inner core surface containing a pharmaceutically active substance, and a hydrophobic substance and water-insoluble substance are further applied to the outer layer of the coating layer. A coated preparation characterized by comprising a coating layer consisting of only the above-mentioned inorganic substances. 2. The coated preparation according to claim 1, wherein the pharmaceutically active substance is one or more selected from amino acids, amino acid salts, amino acid derivatives and peptides.