JPS605568B2 - Soft capsule for encapsulating photolabile drugs and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to soft capsules for containing photolabile drugs.

Soft capsules are capsules formed from softened gelatin obtained by blending gelatin with a plasticizer such as glycerin or sorbitol.

Such soft capsules are used, for example, to produce soft capsule formulations by sandwiching a drug between two softened gelatin sheets and press-molding them into an appropriate shape. Since capsules can contain a certain amount of drugs in a sealed state, they can also contain liquid drugs, and are not only convenient to carry, but also can be administered orally. It has the characteristic of rapidly exerting the pharmacological effects of drugs. Therefore, soft capsule formulations using such Yabu capsules can be used as therapeutic agents for heart diseases,
It is particularly suitable as a therapeutic agent for ischemia and inflammatory disease (angina pectoris). By the way, many of the drugs used as antianginal drugs are unstable to light, and there is a problem that the drugs will decompose in a relatively short period of time if they are simply encapsulated in ordinary soft capsules.

This is a serious drawback as a therapeutic agent for angina pectoris, which absolutely requires rapid onset of pharmacological action and reliable efficacy.

In order to solve these drawbacks, we developed a method for uniformly dispersing dyes that absorb light, such as ``Food Yellow No.
A method has been proposed in which a specific dye and an opacifying agent such as titanium dioxide are uniformly dispersed in a gelatin-based capsule film (Hakama Kosho No. 54-34048).

However, the method of uniformly dispersing dyes etc. in the gelatin film has the disadvantage that if there is non-uniformity in the thickness of the soft capsule film, the light shielding in the thin part of the film is not sufficient.For example, If Uta capsules are manufactured using the general manufacturing method for soft capsules, in which the drug is sandwiched between two softened gelatin sheets and then pressure-molded into an appropriate shape, it becomes a European capsule. The welded part of two gelatin sheets tends to be thinner than other parts, and therefore the light shielding at the welded part becomes insufficient.The present inventors have solved the above-mentioned drawbacks of the prior art. In order to achieve this goal, we focused on a method of uniformly coating the surface of soft capsules with light-shielding agents such as dyes and opacifiers, and as a result of conducting intensive research, we found that if a light-shielding agent is blended with an aqueous solution of a specific polymer, They discovered that uniform coating was possible and arrived at the present invention.

In other words, ``The present invention provides a soft capsule for encapsulating a photolabile drug, which is characterized in that a uniform coating layer of a hydrophilic polymer containing a dye is formed on the surface of a European capsule mainly composed of gelatin. It's a capsule.

The soft capsule before coating in the present invention may be of any known type as long as it is mainly composed of gelatin, and the manufacturing method thereof is not particularly limited.

The commonly adopted method is to mix gelatin with a plasticizer such as glycerin or sorbitol to make a gelatin sheet, sandwich the drug between the two gelatin sheets, and use an appropriate mold to form a sphere or ellipsoid. Alternatively, it is a method of pressure molding into a cylindrical shape or the like. The gelatin sheet contains titanium dioxide,
Opacifying agents such as iron oxide and calcium carbonate, and food yellow 5
Dyes such as No. 1, Tartrazine (Food Yellow No. 4), and Food Red No. 104, or preservatives such as p-aminobenzoic acid, p-oxybenzoic acid ester, sorbic acid, and benzyl alcohol may be added and mixed. In the present invention, a uniform coating layer of a hydrophilic polymer containing a dye is formed on the film surface of a soft capsule produced by a known method as described above.

The dye used is one that can absorb light of a wavelength capable of decomposing the photolabile drug contained in the soft capsule. For example, if the photolabile drug is nifedipine, a dye (Food Yellow No. 4 or No. 5) that absorbs light at a wavelength of 250 to 46 million digits is suitable. In addition, appropriate tar dyes specified by the Pharmaceutical Affairs Law can be used depending on the type of photolabile drug. Examples of hydrophilic polymers include hydroxypropyl cellulose, cellulose acetate phthalate, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, cellulose derivatives such as hydroxyethyl cellulose, polyvinylpyrrolidone, water-lacquer synthetic polymers such as polyvinyl alcohol, gelatin, gum arabic, etc. There is.

Particularly preferred are hydroxypropylcellulose and gelatin. The coating may be done by any known method, such as immersing the soft capsules in an aqueous solution of a hydrophilic polymer containing a dye and then drying them, or spraying the aqueous solution onto the capsules and then drying them. To form a coating layer, it is necessary to use a dye and a hydrophilic polymer in the form of an aqueous solution.

The aqueous solution may contain a small amount of organic solvent in order to adjust the drying rate, etc., but it must be essentially an aqueous solution. In this case, a uniform coating layer cannot be formed.

In the present invention, an aqueous solution of a hydrophilic polymer containing a dye in which an opacifying agent such as titanium dioxide, iron oxide, calcium carbonate, etc. is uniformly dispersed may be used.

There are no particular limitations on the amount of dye, hydrophilic polymer or opacifying agent used, or the thickness of the coating layer.
It can be set arbitrarily within a range such that the decomposition of the photolabile drug contained in the soft capsule due to light is suppressed to a practically acceptable level.

Furthermore, the surface of the European capsule of the present invention on which the coating layer has been formed as described above may be further coated with stearic acid, silicone resin, etc. for the purpose of improving moisture resistance and the like.

Examples of photolabile drugs to be encapsulated in the soft capsule of the present invention include vitamin E and its analogs, vitamin D3 and its analogs, and drugs for treating heart disease, but anti-anginal drugs are particularly preferably used. Examples of these include nifedipine (1,4-dihydro-2,6-dimethyl-4-(2'nitrophenyl)-315-dicarbomethoxypyridine), tubidecarenone, pfetrol hydrochloride, oxprenolol hydrochloride, Examples include indenolol and the like.

The form of the photolabile drug to be encapsulated in the soft capsule is not particularly limited, and any known form can be used.

For example, in the case of nifedipine, a liquid composition consisting of nifedipine, polyalkylene glycol, and glycerin (Japanese Patent Publication No. 54-34048), a composition consisting of nifedipine, polyethylene glycol, and polyoxyethylene sorbitan monooleate (Japanese Patent Publication No. 55/1989) are available. -22631), a composition comprising nifedipine, a polyoxyethylene derivative, and glycerin and/or propylene glycol (No.
In the case of vitamin D3 and its analogs, there is an oil-based solution of vitamin D3 or its analogs (Japanese Patent Application Laid-Open No. 54-84023). These compositions may contain known formulation aids such as aromatics and sweeteners. By using the soft capsule of the present invention, it is possible to prevent the decomposition and deterioration of the photolabile drug contained therein, and it is convenient to carry, and when administered orally, the pharmacological effects of the contained drug can be improved. Therefore, it is possible to provide a soft capsule formulation that can rapidly exhibit the following effects.

Hereinafter, the present invention will be explained in detail with reference to Examples.

Note that all parts in the examples are parts by weight. Example 1~
4. Comparative Examples 1 and 2 [Manufacture of soft capsules] 75.5 parts of gelatin, 23.2 parts of concentrated glycerin, ethyl paraoxybenzoate 1. A uniform composition for a European capsule film was prepared by a conventional method using Ikarigun and 0.3 part of propyl paraoxybenzoate.

Separately, 345 parts of nifedipine, Macrocor (
400) 780 parts of glycerin, 45 parts of glycerin, 12 parts of sodium saccharin, and 12 parts of peppermint oil were mixed and stirred thoroughly for about 1 hour to prepare a homogeneous solution containing the drug.

From the composition for soft capsule coating and the drug solution, soft capsules were produced by a conventional method (punching method) using an automatic filling and closing machine.

The thickness of the capsule film is about 0.8 skin, and each capsule contains about 300 9 drug solutions (nifedipine is about low 9)
was filled. [Coating on soft capsules] A coating solution having the composition shown in Table 1 was prepared.

The soft capsules obtained as described above (approximately 500 ml hard) were placed in a rotating chamber, and a 40 ml coating liquid was added to the capsules at a rate of 10 ml/min, and the rotary chesso bar was rotated (2 ml/min). pm) for 2 hours.
Thereafter, it was dried by blowing 60 qo of hot air into it. A uniform coating layer was formed when any coating liquid was used. Table 1 [Photostability and testing of coated European capsules] The European capsules coated with each coating liquid as described above were placed about 1 skin distance from a north window in a building, avoiding direct sunlight. Stored for ~8 weeks.

The residual rate of nifedipine in the soft capsule was determined at regular intervals, and the results were as shown in Table 2.

Table 2 Table 2 shows that in Examples 1 to 4 of the present invention, the decomposition of nifedipine was sufficiently suppressed even after 8 weeks of storage.

On the other hand, it can be seen that in the coating layer containing no dye (Comparative Examples 1 and 2), nifedipine rapidly decomposed as the storage period became longer.

The quantitative determination of nifedipine was carried out as follows. Cut the European capsules (5 pieces), take out the contents, wash the inner wall of the soft capsule with ether, and mix this with the contents.

After removing the ether from this liquid, take the contents equivalent to two soft capsules and add methanol to make exactly 100'. Next, take exactly 20' of this solution and add methanol to make exactly 100' to prepare a sample solution.

Measure the absorbance A of the skin at a wavelength of 35 cm for the sample solution using methanol as a control. The amount of nifedipine contained in the soft capsule is determined by the following formula. A Average weight of the contents of the European capsule (No. 9) 1 Amount of nifedipine in the European capsule (No. 9) = Sample collection amount equivalent to 3 x soft capsules x 5000 Scale Turtle Comparative Example 3 1.1 parts of titanium oxide and 0.2 parts of Yellow No. 5 were added and mixed to 100 parts of the composition for soft capsule coating of Example 1 to obtain a uniform colored composition.

L Example 1 from this colored composition and the drug solution of Example 1
Soft capsules were produced in the same manner as in the case of . This sensitive capsule has a welded part that is thinner than other parts, and a photostability test of the drug content (residual rate of nifedipine) was conducted under the same conditions as in Example 1. It was as shown in Table 3.

Table 3 From a comparison of Tables 2 and 3, it is clear that those obtained with the known technique have inferior photostability than those of the present invention.

Claims (1)

[Scope of Claims] 1. A method for encapsulating a photolabile drug, characterized in that a uniform coating layer of a hydrophilic polymer containing a dye is formed on the surface of a soft capsule mainly composed of gelatin. Soft capsule. 2. A soft capsule for encapsulating a photolabile drug according to claim 1, wherein an opacifying agent is uniformly dispersed in the coating layer. 3. A soft capsule for encapsulating a photolabile drug according to claim 1, wherein the dye is Food Yellow No. 4 or No. 5. 4. A soft capsule for encapsulating a photolabile drug according to claim 1, wherein the hydrophilic polymer is gelatin or hydroxypropylcellulose. 5. A soft capsule for encapsulating a photolabile drug characterized by uniformly coating the membrane surface of a soft capsule mainly composed of gelatin with an aqueous solution of a hydrophilic polymer containing a dye, and then drying it. Manufacturing method. 6. A method for producing a soft capsule for encapsulating a photolabile drug according to claim 5, which uses an aqueous solution of a hydrophilic polymer in which an opacifying agent is uniformly dispersed.