JPH0925228A - Seamless soft capsule - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the coat of a seamless capsule which is easily degradable by using two kinds of materials as essential components and optionally adding an plasticizer and/or a stabilizer. SOLUTION: This coat of a seamless capsule is obtained by using Japan agar and an aqueous polymer as essential components. The aqueous polymer is selected from alginic acid or its salts, an alginic acid derivative, carrageenan and a pectin. The aqueous polymer is preferably added in an amount of 1-150 pts.wt. to 100 pts.wt. of the Japan agar. Optionally, 10-450 pts.wt. of a plasticizer (e.g. a sugar, a sugar alcohol, a polysaccharide or a polyhydric alcohol) is added to the above system based on 100 pts.wt. of the Japan agar. Further, 0.5-30 pts.wt. of a stabilizer is optionally added to the system based on 100 pts.wt. of the Japan agar. The obtained soft capsule easily dissolves even in water or a gastric juice and has little hygroscopicity. It is resistant to be soften, scarcely sticking to each other and also resistant against the coloring and deterioration of the coat. Further, it has properties such as escaping from allergy caused by an animal material.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an easily disintegrating gelatin-free seamless capsule film.

[0002]

2. Description of the Related Art Generally, a film of a soft capsule is produced by using gelatin, which is a material of bone or skin of animals such as cows and pigs, as a base material, and glycerin, sorbitol and the like are added thereto. However, while gelatin has excellent properties for the production of soft capsules, it has the potential of being an antigenicity as a heterologous protein and the possibility of reacting with other drugs derived from the peptide structure-for example, coloring by the aminocarbonyl reaction-
There are problems such as insolubilization that causes disintegration and extension, cracking due to overdrying, physicochemical changes such as sticking due to moisture absorption, and peculiar odor of gelatin. For this reason, the current situation is to purify gelatin, avoid blending substances that are reactive with gelatin, and adjust the humidity by packaging. Furthermore, with the increase of natural orientation in the market, there is a strong demand for development of non-animal soft capsule materials other than gelatin. Therefore, various methods have been proposed so far for producing gelatin-free soft capsules.

Of these, the ones that are relatively well known are:
Soft encapsulation by a combination of alginic acid and polyvalent metal ions, alginic acid and pectin, and metal ions (JP-A 03-68508, JP-A 03-285654,
JP-A-61-44810, JP-A-58-210841
No.), a method using carrageenan and a metal ion (Japanese Patent Laid-Open Publication No. Sho 6-66
No. 0-12943), agar soft capsule (Japanese Patent Laid-Open No. 01-123
No. 193216), an agar and an enteric coating, and a combination of agar and methacrylic acid (JP-A-05-32543 and JP-A-57-32230). Of these,
The combination of alginic acid, carrageenan and pectin with metal ions is encapsulated by utilizing a very strong ionic bond due to the reaction between these polymeric substances and calcium ions, so that the obtained film is water-insoluble.
Capsule formation by agar and a combination of agar and other agents also utilizes the low solubility of agar in water. These methods are inventions in which the possibility that gelatin serves as an antigen and the amino-carbonyl reaction can be avoided, but rather the merit as an enteric coating is emphasized.

[0004]

Therefore, the soft capsules produced by these techniques are unlikely to disintegrate in water and gastric juice. Also, in the case of a film using alginic acid, carrageenan, pectin, etc., since it is immersed in a solution such as a concentrated calcium chloride solution during the manufacturing process, in addition to the amount of metal ions etc. bound and present in the soft capsule skin, However, it is adsorbed in large amounts as anions such as metal ions and chloride ions, and is difficult to remove even by washing in the usual capsule molding process. These anions adversely affect the stability of the drug encapsulated in the capsule, and it is feared that the rheological properties of the film structure change with time during storage of the capsule.

Further, it is also an important issue to make such a soft capsule skin as a capsule skin having good disintegration in the stomach. From this, there has been a strong demand to solve the problems of gelatin, to develop a gelatin-free soft capsule film of safe and stable quality, which is easy to disintegrate in water and gastric juice, and a manufacturing method thereof. Therefore, the present inventors have completed the present invention by discovering that the problems can be solved by the means shown below as a result of detailed studies on these polymers.

[0006]

The present invention is a seamless soft capsule film containing agar and a water-soluble polymer as essential components. The present invention is also a seamless soft capsule in which the film contains agar and a water-soluble polymer as essential constituents. A plasticizer and a stabilizer can be further added to the seamless soft capsule film of the present invention.

The water-soluble polymer substance in the present invention specifically means, for example, alginic acid, its derivative, pectin and carrageenan, and these water-soluble polymer substances are used alone or in combination of two or more kinds. May be. Alginic acid is usually a sodium salt, but is not limited to a free form or a salt, and is not limited to a kind of salt. Alginic acid may have any M / G ratio and polymerization degree, and is selected according to the properties of the film. Further, more specifically, the alginic acid derivative is propylene glycol alginate, etc., and has a degree of esterification of 10 or more,
Any M / G ratio and degree of polymerization may be used. Various types of pectin are available, but either high methoxy type (esterification degree of 50% or more) or low methoxy type (esterification degree of 25% to 45%) is used. May be. Carrageenan has a sulfate group in the molecule and is of several types (kappa, iota, lambda).
However, any type can be used in the present invention.

The plasticizer in the present invention means a substance selected from, for example, sugars, sugar alcohols, polysaccharides and polyhydric alcohols, and these substances may be used alone or in combination of two or more.

Examples of sugars and sugar alcohols include sucrose, maltose, glucose, sorbitol, maltitol, xylitol, mannitol, erythritol, and two or more kinds may be used. Examples of the polyhydric alcohol include glycerin, and examples of the glycols include polyethylene glycols (molecular weight 400 to 6000).

As the polysaccharides, dextrins such as pa index, partially pregelatinized starch (eg, trade name PCS
(Available from Asahi Kasei Co., Ltd.) can be used.

Stabilizers can also be used in the present invention. The stabilizer means an amino acid, a surfactant, an organic acid or salts thereof, and an inorganic acid. Specific examples of amino acids include aspartic acid, lysine, glycine, serine, alanine, histidine, and phenylalanine. Examples of the surfactant include hydrogenated hydrogenated castor oil polyoxyethylene derivative, sucrose fatty acid ester, and polysorbate. Organic acids, inorganic acids are, for example, citric acid, malic acid, fumaric acid, tartaric acid, lactic acid, phosphoric acid, hydrochloric acid,
These may be salts.

The ratio of the water-soluble polymer to the agar in the present invention is not particularly limited, but it is usually 1 to 150 parts by weight, preferably 10 to 120 parts by weight with respect to 100 parts by weight of the agar. , More preferably 15 to
100 parts by weight. The ratio of the plasticizer to the agar is not particularly limited, but is usually 10 to 450 parts by weight, preferably 20 parts by weight, relative to 100 parts by weight of the agar.
To 300 parts by weight, more preferably 30 to 230 parts by weight.

The ratio of the stabilizer to the agar is not particularly limited, but the stabilizer is usually added to 100 parts by weight of the agar.
0.5 to 30 parts by weight, preferably 1 to 25 parts by weight,
It is more preferably 3 to 20 parts by weight. As the agar in the present invention, commercially available agar can be used as it is.

The soft capsule of the present invention can be manufactured by the following method. Agar, water-soluble polymer, sugar or glycerin are sufficiently mixed, and the mixture is added little by little while stirring in warm water previously heated to 60 to 70 ° C. in a tank with a heating jacket or the like, and uniformly dispersed. In addition, 80
Warm under stirring at ~ 98 ° C to dissolve. After confirming the transparency of the liquid, disappearance of lumps, and homogeneity of the liquid state, cool with gentle stirring. When the liquid temperature reaches 50 to 70 ° C., a stabilizer is added and dissolved to obtain a film liquid. Then, the intended seamless capsule is produced by a usual method. If necessary, a dye, a preservative and the like can be added to the capsule film.

The soft capsule according to the present invention has excellent properties in the following points. 1) It is easily disintegrating and dissolves easily in water and gastric juice.
2) Low hygroscopicity. Hard to soften. Hardness of capsule comrades is unlikely to occur. 3) Coloring and deterioration of the film due to the aminocarbonyl reaction are unlikely to occur. 4) The possibility of allergies due to animal material is avoided.

The mechanism of the constitution of the capsule coating according to the present invention is considered as follows. When agar is dissolved by heating, molecules exist in a random coil state. Taking a three-dimensional network of double helix structure as the temperature decreases,
A gel is formed (sol-gel transition 30-50 ° C). It is thermoplastic (melting point 85-93 ° C). That is, agar gel is difficult to dissolve in water unless it is made strongly alkaline by utilizing the acidic group of agaropectin, which is one of its constituents, or it is heated above its melting point. In the present invention, it is considered that the strong agar network structure forms the skeleton of the capsule film. On the other hand, alginic acid, pectin, and carrageenan are fragile gels when used alone, and are inferior in moldability. By creating a relatively strong network based on agar, which has a strong gel strength, and by allowing hydrophilic substances such as alginic acid and pectin to enter into the network, a pathway for introducing water into the network is constructed and the disintegration of the film It is thought that it has become possible to increase the The hydrophilic substances used here are the water-soluble polymers sodium alginate, propylene glycol alginate, pectin, and carrageenan, and further sugars as plasticizers, sugar alcohols, polyhydric alcohols, polysaccharides, amino acids as stabilizers. , Organic acid salts and inorganic acid salts.

[0017]

EXAMPLES The present invention is described in detail below with reference to examples, but the present invention is not limited to these examples. Example 1 28 g of agar and 15 g of sorbit are dispersed in 2000 ml of purified water and dissolved by boiling. 6 after the agar has completely dissolved
Cool to 0-70 ° C., then propylene glycol alginate 6 g, glycerin 20 g, sodium malate 1
g of the mixture is added and dissolved to form a film solution. According to a conventional method, seamless soft capsules containing cottonseed oil in which a drug was dissolved as an internal solution were obtained.

Example 2 50 g of agar and 30 g of sorbit are dispersed in 2000 ml of purified water and dissolved by boiling. After the agar was completely dissolved, it was cooled to about 60 ° C and kept warm, then 18 g of propylene glycol alginate, 34 g of glycerin, 2 parts of aspartic acid.
g, sorbitol 5 g and sodium dihydrogen citrate 1.
Example 1 was prepared by uniformly dissolving 5 g of the mixture to obtain a film solution.
In the same manner as described above, seamless soft capsules as an internal solution were obtained.

Example 3 45 g of agar was dispersed in 1500 ml of purified water, and dissolved by evaporation. After the agar is completely dissolved, cool to 50-60 ° C,
Keep warm, pectin 13g, glycerin 20g, alanine
2.5 g of the mixture was dissolved to produce a film liquid, and seamless soft capsules were obtained in the same manner as in Example 1.

Example 4 After mixing 40 g of agar and 25 g of glycerin, purified water 210 was added.
Disperse in 0 ml and dissolve by boiling. After the agar was completely dissolved, the mixture was cooled to 60 to 70 ° C. and kept warm, and then a mixture of 30 g of carrageenan, 5 g of sorbit, 4 g of glycine and 1 g of sodium dihydrogen citrate was added and dissolved to obtain a film solution. Seamless soft capsules were obtained in the same manner as in Example 1.

Comparative Example 1 50 g of agar and 25 g of glycerin are dispersed in 2000 ml of purified water and dissolved by boiling. Using this as a comparative film, seamless soft capsules were obtained in the same manner as in Example 1. Comparative Example 2 20 g of gelatin and 6 g of glycerin were added to 1000 ml of purified water.
Disperse in, and heat at 70-80 ° C. to dissolve. Using this as a comparative film, seamless soft capsules were obtained in the same manner as in Example 1. Regarding Examples 1 to 4 and Comparative Examples 1 and 2, immediately after production, a freezer (−20 ° C.), 45 ° C., 40 ° C. 75% R
Various physical properties of the capsules after storage for 1 week and 1 to 3 months under each condition of H were measured and shown in Tables 1 to 4. Table 5 summarizes the characteristics of the gelatin capsule and the agar-based capsule according to the present invention.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

Claims (11)

[Claims] 1. A seamless soft capsule film containing agar and a water-soluble polymer as essential components. 2. A seamless soft capsule film comprising agar, a water-soluble polymer and a plasticizer. 3. A seamless soft capsule film comprising agar, a water-soluble polymer, a plasticizer and a stabilizer. 4. The seamless soft capsule film according to claim 1, wherein the water-soluble polymer is one or more substances selected from alginic acid or a salt thereof, an alginic acid derivative, carrageenan and pectin. 5. The plasticizer is one or more substances selected from sugars, sugar alcohols, polysaccharides and polyhydric alcohols.
Or the seamless soft capsule film described in 3. 6. The soft capsule film according to claim 3, wherein the stabilizer is one or more substances selected from amino acids, surfactants, organic acids or salts thereof, and inorganic acids. 7. The seamless soft capsule film according to claim 1, wherein the water-soluble polymer is 1 to 150 parts by weight with respect to 100 parts by weight of agar. 8. A plasticizer of 10 parts by weight per 100 parts by weight of agar.
The seamless soft capsule film according to claim 2, which is 450 parts by weight. 9. Stabilizer is added to 100 parts by weight of agar in an amount of 0.
The seamless soft capsule film according to claim 3, which is 5 to 30 parts by weight. 10. In a seamless soft capsule,
A seamless soft capsule whose film contains agar and water-soluble polymer as essential components. 11. The seamless soft capsule according to claim 10, wherein the water-soluble polymer is alginic acid, an alginic acid derivative, carrageenan, or pectin.