JPH0725663B2 - Method for producing enteric coated soft capsule - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an enteric-coated soft capsule, and more specifically, it can be made completely enteric by a working environment having a high safety. The present invention relates to a method capable of easily producing a soft capsule made of gelatin.

[Prior Art] Conventionally, enteric-coated soft capsules are encapsulated with an enteric substance alone, mixed with an enteric substance and gelatin, and soft-capsule substantially consisting of gelatin. Some are coated with a substance. Among them, as an enteric soft capsule in which a film is formed with an enteric substance on the surface of a soft capsule substantially consisting of gelatin,
A carboxyalkyl cellulose derivative such as hydroxypropylmethyl cellulose phthalate or cellulose acetate phthalate, or a polybasic vinyl polymer having a free carboxyl group composed of (meth) acrylic acid and (meth) acrylic acid ester [eg, trade name Eudragit (Commercially available as Rohm and Farm Co., Ltd.)] is coated on the surface of a soft capsule consisting essentially of gelatin (JP-A-59-88).
See JP 420 publication, Pharmazie, Vol. 39, No. 4, p275-276, 198.
4 etc.)

[Problems to be Solved by the Invention] The conventional method of forming a film of an enteric substance on the surface of a soft capsule substantially made of gelatin has the following problems. That is, (1) since an organic solvent such as alcohol, acetone, or methylene chloride is used as a solvent for coating the film of the enteric substance, adhesion failure is likely to occur at the interface between the film substantially consisting of gelatin and the film.

(2) When an organic solvent other than alcohol is used as a solvent for coating a film of an enteric substance, the organic solvent may remain in the film, so that the safety of the enteric coated soft capsule cannot be ensured.

(3) When an organic solvent is used as a solvent for coating a film of an enteric substance, a step of collecting the organic solvent must be provided, and means for preventing the work environment from being contaminated and a fire explosion risk preventing means. Must be provided.

(4) Since the formed enteric substance film is non-uniform, when a soft capsule formed with this enteric substance film is taken, it dissolves in the stomach or the intestinal solubility varies. And the bioavailability decreases.

The present invention has been made based on the above circumstances.

An object of the present invention is to use a safe working environment without using an organic solvent and without providing special means,
It is an object of the present invention to provide a manufacturing method in which an enteric coated soft capsule having an excellent enteric function cannot be manufactured.

[Means for Solving the Problems] In order to solve the problems, as a result of diligent research by the present inventor, a film of a water-soluble crosslinkable polysaccharide that is crosslinked with a specific cation is formed. When the soft capsule is immersed in a cation aqueous solution having divalent or higher cations, the reaction between the water-soluble cross-linked polysaccharide present on the surface of the soft capsule and the cation in the cation aqueous solution instantaneously proceeds, As a result, they have found that an enteric coating is uniformly formed on the surface of a soft capsule, and arrived at the present invention.

That is, the outline of the present invention that achieves the above-mentioned object is to immerse a soft capsule consisting essentially of gelatin in an aqueous solution of a crosslinkable polysaccharide in which a crosslinkable polysaccharide is dissolved, and then remove the substance from the aqueous solution of the crosslinkable polysaccharide. Is a method for producing an enteric-coated soft capsule, which comprises immersing a soft capsule made of gelatin in a cation aqueous solution having a cation having a valence of 2 or more.

Hereinafter, the method of the present invention will be described in detail.

The soft capsule consisting essentially of gelatin may be any one if it is prepared to have a predetermined water content by mainly adding gelatin and a water retention agent such as glycerin or sorbitol. There is no limitation on the manufacturing method, and the manufacturing method may be, for example, either an air dropping method or a liquid dropping method.
The soft capsule substantially consisting of gelatin may be a dry soft capsule substantially consisting of gelatin or an undried soft capsule substantially consisting of gelatin. Further, the content of the soft capsule substantially consisting of gelatin is not limited, and it may be any oily liquid, granule, powder or the like containing a medicinal substance. Examples thereof include soft gelatin capsules filled with an oily liquid containing vitamin E. However, when using this soft capsule substantially consisting of gelatin as a preparation containing a drug having side effects in the stomach, a soft capsule substantially consisting of gelatin is usually a commercially available one, but , Considering the workability of coating,
Capsules in which the thickness of the substantially gelatin layer of the wall membrane is not very thin are preferred.

The crosslinkable polysaccharide refers to a water-soluble polysaccharide that is crosslinked and hardened by a divalent or higher cation described below. Examples of such polysaccharides include intercellular mucilage polysaccharides, acidic polysaccharides composed of α-1,4 bond of D-galacturonic acid, and more specifically, for example, sodium alginate, calcium-containing Examples thereof include sodium alginate, potassium alginate, ammonium alginate, sodium carrageenan, potassium carrageenan, and low methoxyl pectin. Among these, sodium alginate, low methoxyl pectin and the like are preferable. Low methoxyl pectin has a molecular weight of 50,000 to 150,000,
It is particularly preferably 100,000 to 150,000, and the degree of esterification is preferably 20 to 45%, particularly 25 to 30%.

The divalent or higher cation is a physiologically acceptable metal ion, and examples thereof include calcium ion, copper ion, ferrous ion, ferric ion, zinc ion, barium ion, and aluminum ion. And particularly preferred is calcium ion.

Examples of the compound that imparts calcium include water-soluble calcium salts such as calcium chloride, calcium acetate, calcium hydroxide, monocalcium phosphate, dibasic calcium phosphate, tricalcium phosphate, and calcium lactate. Of these, preferred are It is calcium chloride.

A soft capsule consisting essentially of gelatin is dipped in an aqueous solution of a crosslinkable polysaccharide in which a crosslinking polysaccharide is dissolved, and then a soft capsule consisting essentially of gelatin taken out of the aqueous solution of the crosslinkable polysaccharide is divalent or higher. In carrying out the method of the present invention, which comprises immersing in the cation aqueous solution having the cations, the following operation operations can be mentioned.

That is, a soft capsule consisting essentially of gelatin is immersed in an aqueous solution of a crosslinkable polysaccharide in which a crosslinkable polysaccharide is dissolved,
Then, the soft capsule substantially consisting of gelatin taken out from the aqueous solution of the crosslinkable polysaccharide is immersed in the cation aqueous solution having a cation having two or more valences, and then the soft capsule substantially consisting of gelatin is taken out. This is dried.

The concentration of the crosslinkable polysaccharide in the aqueous solution of the crosslinkable polysaccharide varies depending on the type of the crosslinkable polysaccharide, and can be appropriately determined experimentally, when using sodium alginate as the crosslinkable polysaccharide. , Its concentration is usually
0.5-10% by weight, preferably 1-5% by weight, when low methoxyl pectin is used as a crosslinkable polysaccharide, the concentration is usually 1-30% by weight, preferably 5-15% by weight %.

The time for immersing the soft capsule substantially consisting of gelatin in this aqueous solution of crosslinkable polysaccharide is usually several seconds to 5 minutes, preferably 0.5 to 3 minutes.

The cation concentration of the cation aqueous solution is usually 1 to
It is 20%, preferably 1 to 5%.

The time for immersing the soft capsule substantially consisting of gelatin in this cation aqueous solution is usually several seconds to 5 minutes, preferably about 1 to 3 minutes.

When a soft capsule consisting essentially of gelatin is dipped in the aqueous solution of cross-linking polysaccharide, the cross-linking polysaccharide becomes a gel and adheres to the surface of the soft capsule consisting essentially of gelatin. Then, when this soft capsule consisting essentially of gelatin is dipped in an aqueous cation solution, the crosslinkable polysaccharides attached to the gel are crosslinked by the cations, and the enteric coating forms a soft capsule consisting essentially of gelatin. Thus, an enteric-coated soft capsule is obtained by drying the soft capsule that is substantially gelatin and is formed on the surface of the above.

In addition, in order to adjust the thickness of the enteric coating and the dissolution time,
Repeating (1) a step of immersing the soft capsules substantially made of gelatin in the crosslinkable polysaccharide aqueous solution, (2) a step of immersing the soft capsule in the cation aqueous solution, (2) and (3) a drying step in this order are repeated an appropriate number of times. Is also good. Further, the dissolution time of the enteric coating film can be adjusted by adding an auxiliary agent described below to the aqueous solution of the crosslinkable polysaccharide and appropriately increasing or decreasing the amount of the auxiliary agent.

The auxiliary agent is for improving the properties of the film formed on the outer periphery of the soft capsule which is substantially made of gelatin, and imparts plasticity to the film to control the enteric rate. Examples of such auxiliaries include water-soluble polyhydric alcohols, glycerol fatty acid esters,
Acetylated monoglycerides, phthalic acid esters, citric acid esters and the like can be mentioned. Preferred are glycerol, erythritol, arabitol, sorbitol, propylene glycol, polypropylene glycol, ethylene glycol, polyethylene glycol, and other 2- to 6-valent glycols. Examples thereof include polyhydric alcohols and glycerol fatty acid esters such as acetin, diacetin and triacetin.

The content of the auxiliary agent in the aqueous solution of the crosslinkable polysaccharide is usually 1 to 20% by weight, preferably 5 to 10% by weight.

[Operation] The enteric-coated soft capsule according to the present invention comprises water and the first pharmacopoeia.
It has a property that it is not easily dissolved in a liquid and is easily dissolved in a second liquid of pharmacopoeia.

Next, the operation of the present invention will be specifically described with reference to test examples.

(Test Example) Samples 1 to 1 of the enteric coated soft capsules obtained in Examples 1 to 6 described later
6 and the 10th revised Japanese Pharmacopoeia disintegration test was performed.

The results are shown in Table 1.

EFFECTS OF THE INVENTION According to the present invention, an intestine having excellent enteric properties that does not easily dissolve in the pharmacopoeial first liquid within, for example, 2 hours and dissolves in the pharmacopoeia second liquid in a short time. Soluble soft capsules can be provided.

In addition, since this enteric coated soft capsule is manufactured without using any organic solvent, a means for recovering the organic solvent as in the past, preventing the contamination of the working environment, or preventing fire or explosion is required. It is possible to manufacture safely without the need to provide.

Furthermore, this enteric-coated soft capsule is obtained by immersing a soft capsule consisting essentially of gelatin in an aqueous solution of a crosslinkable polysaccharide, and then by immersing it in an aqueous solution containing a cation to crosslink the crosslinkable polysaccharide and to obtain moisture resistance. Since a uniform film is formed, it is possible to improve the adhesion at the interface between the surface of the soft capsule substantially made of gelatin and the film.

[Examples] Hereinafter, the present invention will be described more specifically by showing Examples. Needless to say, the present invention is not limited to this embodiment.

Example 1 An undried soft capsule consisting essentially of gelatin was immersed in a 1% aqueous sodium alginate solution for 1 minute, then taken out, and then immersed in a 5% aqueous calcium chloride solution for 1 minute. Then, the sodium alginate adhering to the surface of the soft capsule consisting essentially of gelatin was gelled. The enteric coated soft capsule according to the present invention was obtained by drying the capsule taken out from the calcium chloride aqueous solution at room temperature.

The diameter of this enteric coated soft capsule was 4.0 mm.

(Example 2) An undried soft capsule consisting essentially of gelatin was immersed in a 2% aqueous sodium alginate solution for 0.5 minutes, taken out, and then immersed in a 3% aqueous calcium chloride solution for 0.5 minutes. Then, the sodium alginate adhering to the surface of the soft capsule consisting essentially of gelatin was gelled. The enteric coated soft capsule according to the present invention was obtained by drying the capsule taken out from the calcium chloride aqueous solution at room temperature.

The diameter of this enteric-coated soft capsule was 5.0 mm.

(Example 3) Concentration of dry soft capsules consisting essentially of gelatin
Soak it in a 2.5% sodium alginate aqueous solution for 1 minute, take it out, and then soak it in a 4% calcium chloride aqueous solution for 0.5 minutes to remove the sodium alginate adhering to the surface of the soft gelatin capsules. It gelled. The enteric coated soft capsule according to the present invention was obtained by drying the capsule taken out from the calcium chloride aqueous solution at room temperature.

The diameter of this enteric coated soft capsule was 3.0 mm.

(Example 4) An undried soft capsule consisting essentially of gelatin was immersed in an aqueous solution of sodium alginate having a concentration of 3% for 1 minute, taken out, and then immersed in an aqueous solution of calcium chloride having a concentration of 5% for 1 minute. Then, the sodium alginate adhering to the surface of the soft capsule consisting essentially of gelatin was gelled. The enteric coated soft capsule according to the present invention was obtained by drying the capsule taken out from the calcium chloride aqueous solution at room temperature.

The diameter of this enteric coated soft capsule was 1.0 mm.

(Example 5) A dry soft capsule consisting essentially of gelatin was immersed in a 4% concentration sodium alginate aqueous solution for 2 minutes, taken out, and then immersed in a 5% concentration calcium chloride aqueous solution for 2 minutes. Then, the sodium alginate adhering to the surface of the soft capsule consisting essentially of gelatin was gelled. The enteric coated soft capsule according to the present invention was obtained by drying the capsule taken out from the calcium chloride aqueous solution at room temperature.

The diameter of this enteric-coated soft capsule was 5.0 mm.

(Example 6) A dry soft capsule consisting essentially of gelatin was dipped in a 5% aqueous solution of sodium alginate for 3 minutes, taken out, and then dipped in a 5% aqueous solution of calcium chloride for 2 minutes. Then, the sodium alginate adhering to the surface of the soft capsule consisting essentially of gelatin was gelled. The enteric coated soft capsule according to the present invention was obtained by drying the capsule taken out from the calcium chloride aqueous solution at room temperature.

The diameter of this enteric coated soft capsule was 3.0 mm.

(Example 7) An undried soft capsule consisting essentially of gelatin was treated with low methoxyl pectin (concentration of esterification: 25%, 10% concentration).
(Molecular weight; 150,000) Immerse in an aqueous solution for 1 minute, then remove this, and then soak in an aqueous solution of calcium chloride having a concentration of 5% for 1 minute to remove low methoxyl pectin attached to the surface of a soft capsule consisting essentially of gelatin. It gelled.
The enteric coated soft capsule according to the present invention was obtained by drying the capsule taken out from the calcium chloride aqueous solution at room temperature.

The diameter of this enteric coated soft capsule was 4 mm. According to the disintegration test of the 10th revised Japanese Pharmacopoeia, the disintegration time of the intestinal soft capsule with the second liquid of the pharmacopoeia was 1.3 minutes.

Example 8 This example 8 relates to the production of soft capsules with a single coating of sodium alginate.

2.5% sodium alginate aqueous solution [NSPM grade, manufactured by Kibun Food Chemifa] is discharged from the outer tube (8 mm diameter) of the double cylindrical nozzle in the soft capsule manufacturing device (manufactured by Taisho Pharmaceutical Co., Ltd.), Further, the sodium alginate aqueous solution and the oil are added so that the core oil [soybean oil containing erythromycin (manufactured by Ajinomoto Co.)] is discharged from the inner tube (2 mm diameter) of the double cylindrical tube nozzle. From the outer tube and the inner tube of the double-cylindrical tube nozzle, they were simultaneously dropped into a carrier liquid [Panasate 810, manufactured by NOF Corporation, fatty acid glyceride] kept at 20 to 25 ° C.
The double droplets dropped in this carrier liquid are kept at 20-25 ° C.
A soft capsule was formed by transferring the solution to a 5% aqueous solution of calcium chloride, which is a cross-linking solution kept warm in the above, and solidifying in this cross-linking solution.

The soft capsules were allowed to stand in a room at a temperature of 23 ° C. and a relative humidity of 40% for 48 hours and dried to obtain sodium alginate-only coated enteric coated soft capsules having a diameter of 6 mm.

Using the disintegration tester of the Japanese Pharmacopoeia, the enteric coated soft capsules were placed one by one in a test tank containing the first liquid and the second liquid of the Japanese Pharmacopoeia. And let the test tank penetrate up and down,
The time required for the capsule coating to dissolve and the content liquid to begin to come out was measured. This test was conducted on 5 capsules and the average value was obtained.

The results are shown in Table 2.

Reference Example 1 This Reference Example 2 relates to the production of soft capsules having a mixed coating of gelatin and sodium alginate.

90% gelatin and 10% sodium alginate are contained from the outer tube (8 mm diameter) of the double cylindrical tube nozzle in the seamless soft capsule manufacturing device [the device similar to that described in JP-A-61-114915]. The core oil [soybean oil containing erythromycin (Ajinomoto (Ajinomoto (Ajinomoto) Carrier fluid) [Panasate 810, NOF Corporation] which is kept at 20 to 25 ° C. from the outer and inner tubes of the double cylindrical tube nozzle so that the aqueous solution and the oil are discharged. ), Fatty acid glyceride]. The double droplets dropped in this carrier liquid were transferred to a 5% calcium chloride aqueous solution, which is a crosslinking liquid kept at 20 to 25 ° C., and solidified in this crosslinking liquid to form soft capsules. .

The soft capsules were pre-dried in a room with a temperature of 23 ° C and relative humidity of 40% for 8 hours using a coating pan, and then allowed to stand for 48 hours for further drying to obtain a diameter of 6m.
m, soft capsules of gelatin-sodium alginate mixed coating were obtained.

Also, as the aqueous solution discharged from the outer tube of the double cylindrical tube nozzle, an aqueous solution containing 70% gelatin and 30% sodium alginate, and an aqueous solution containing 50% gelatin and 50% sodium alginate, respectively, are used to prepare the above-mentioned formulation. Thus, a gelatin-sodium alginate mixed coating soft capsule having a diameter of 6 mm was obtained.

Solubility tests were conducted on these three types of soft capsules in the same manner as in Example 8. The results are shown in Table 2.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Masato Nara, 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Tomohiro Otsuki 3-24-1, Takada, Toshima-ku, Tokyo Taisho (72) Inventor Ritsuko Aoki 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Kazuo Hayashi 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Tomiya Hosoi, 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor, Murayama Fu, 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. In-company (56) Reference JP 58-88420 (JP, A) JP 58-172313 (JP, A) JP 56-49153 (JP, A) JP 59-88420 (JP, A) )

Claims (6)

[Claims] 1. A soft capsule consisting essentially of gelatin is immersed in an aqueous solution of crosslinkable polysaccharide in which a crosslinkable polysaccharide is dissolved, and then a soft capsule consisting essentially of gelatin is taken out from the aqueous solution of crosslinkable polysaccharide. A method for producing an enteric coated soft capsule, which comprises immersing in an aqueous cation solution having divalent or higher cations. 2. The method for producing an enteric coated soft capsule according to claim 1, wherein the soft gelatin capsule is an undried gelatin soft capsule. 3. The method for producing an enteric coated soft capsule according to claim 1, wherein the gelatin soft capsule is a dry gelatin soft capsule. 4. The method for producing an enteric coated soft capsule according to claim 1, wherein the crosslinkable polysaccharide is sodium alginate. 5. The enteric-coated soft capsule according to any one of claims 1 to 4, wherein the crosslinkable polysaccharide is low methoxyl pectin. 6. The method for producing an enteric coated soft capsule according to any one of claims 1 to 5, wherein the cation is calcium ion.