JP6165022B2 - Controlled release soft capsule - Google Patents

Description

  The present invention relates to a controlled release soft capsule.

Generally, gelatin derived from animal protein, carrageenan derived from plant, and the like are used as a film base for soft capsules.
Gelatin has a reversible sol-gel change due to temperature change, excellent film forming ability, high mechanical strength of the formed film, easy disintegration or dissolution in the body, itself has nutritional value. It has many advantages as a film base, such as being easily absorbed into the body. However, since gelatin is easily soluble in gastric acid, in order to make the contents of soft capsules components that lose their efficacy by gastric acid, components that irritate stomach tissue or components that should be sustained release, etc. It is necessary to impart to the soft capsule film a property that it does not disintegrate or dissolve in the stomach, or delays disintegration / elution time to reach the intestines (enteric properties).

  Currently, capsules with enteric properties added to the soft capsule film have been developed by coating the outer surface of the molded capsules with enteric substances such as zein (also known as zein), shellac (also known as shellac), and hydroxypropylmethylcellulose. (Patent Document 1).

Technology that makes capsule film enteric by adding polysaccharides that show acid resistance by gelling with polyvalent metal ions such as calcium ion and magnesium ion, such as alginate, low methoxyl pectin, gellan gum, etc. Has been developed.
As this technique, a technique of gelling polysaccharides by immersing them in an aqueous solution containing polyvalent metal ions after molding of the capsule to form an acid-resistant outer skin on the surface of the capsule film (Patent Document 2), polyvalent metal Developed a technology (Patent Document 3) in which an ion water-insoluble salt (slightly water-soluble salt) is previously contained in a capsule film and a polyvalent metal ion is dissociated in gastric acid to cause a gelation reaction on a polysaccharide. Has been.
Alternatively, a technique for coating with a mixture of shellac and alginic acid polymer has been proposed (Patent Document 4).

JP 2004-18443 A JP 61-151127 A JP-A-4-27352 Special table 2013-519686 gazette

  An object of the present invention is to provide a controlled release soft capsule.

  The inventors of the present invention have studied a technique for making a soft capsule formulation into a controlled-release type. As a result, the conventional single-layer coating is changed to a coating with a plurality of coating agents, which can cause problems such as coating film peeling. The present invention was completed by finding that a soft capsule formulation in which no mutual adhesion occurs can be obtained.

The present invention has the following configuration.
1. A soft capsule preparation comprising two hard water-soluble layers on the surface of a shell layer of the soft capsule preparation , the inner water-insoluble layer being shellac, and the outer water-insoluble layer being mainly containing zein .
2. 2. The soft capsule preparation according to 1, wherein the soft capsule shell layer is mainly composed of carrageenan.
3. The soft capsule according to 1 or 2, wherein the action of the component contained in the soft capsule is sustained for a long time by mixing soft capsule preparations having different main components constituting the two layers of the poorly water-soluble layer Formulation.
4. An immediate-release and sustained-release mixed-packaging soft capsule formulation in which the soft capsule formulation according to any one of 1 to 3 is mixed and packaged with a soft capsule formulation that does not form a poorly water-soluble layer.

According to the present invention, a controlled release soft capsule formulation is provided. In addition, the problem of exfoliation of the coating layer on the outer surface, which causes disintegration in the stomach, is unlikely to occur, and long-term durability can be achieved. And convenience can be improved.
In addition, in the conventional technique in which a capsule containing a polysaccharide is formed in a film, and then the capsule is gelled by immersing the capsule in an aqueous solution containing polyvalent metal ions, moisture is transferred from the immersion liquid to the capsule film, Furthermore, there is a possibility that moisture may reach the contents, but such a problem does not occur in the present invention.
Furthermore, the problem that capsules adhere to each other depending on the type of coating or surface treatment does not occur.
In addition, by packaging the same number of uncoated and coated preparations, if both capsules are taken at once, the uncoated preparation quickly disintegrates, and the coated preparation does not disintegrate in the stomach Or it disintegrates slowly and releases most of the drug in the intestine, thus providing both immediate and sustained effects.

It is a schematic diagram which shows the cross section of the typical soft capsule formulation of this invention. It is a graph which shows the elution amount measurement result with time at the time of the disintegration test in water of the controlled release preparation and the control preparation of the present invention. It is a graph which shows the elution amount measurement result with time at the time of the disintegration test in the disintegration test 1st liquid of the controlled release preparation of the present invention and the control preparation.

The present invention relates to a soft capsule formulation in which a plurality of poorly water-soluble layers are provided on the outer layer of a soft capsule formulation exhibiting gastric solubility to impart release controllability.
The present invention can be applied to a capsule preparation containing a drug solution or the like prepared by a conventional method. In the present invention, two or more poorly water-soluble layers are formed outside the soft capsule shell layer. Zein is suitable for the poorly water-soluble layer of the outer layer. Shellac is suitable for the inner water-insoluble layer.
The film for forming the soft capsule shell layer may be any commonly used water-soluble film material such as gelatin, alginic acid, and carrageenan, but is preferably gelatin or carrageenan. Particularly preferred is carrageenan.
Encapsulation of the chemical solution or the encapsulated solution in the film-forming composition can be performed using various known methods such as a rotary method, a seamless method, and a flat plate method.
In addition, a laminate method is formed by sandwiching an encapsulated solution between two capsule film compositions formed into a sheet shape, and a flat plate method is applied as necessary, such as pressing the laminate from both sides with a mold and punching it. May be.

  Shellac and zein can be used as long as they are used as pharmaceuticals or food coating agents. For example, “Shellac” manufactured by Gifu Shellac Factory, “Rack Glaze 32E” manufactured by Nippon Shellac Industrial Co., Ltd. and the like can be exemplified. Examples of zein include “Zein DP” manufactured by Kobayashi Inc.

  In order to form the poorly water-soluble layer, a method is selected in which the surface of the soft capsule is sequentially coated with a desired poorly water-soluble substance. Spray or apply a soft capsule formulation prepared by encapsulating the desired drug in a conventional manner and drying it, and then dissolve or disperse the substance that forms the desired poorly water-soluble layer in a volatile solvent, etc. Volatilization method (top method), method of immersing capsules after drying in a solution in which a substance that forms a poorly water-soluble layer is dissolved or dispersed in a volatile solvent, and volatilizing the volatile solvent (dip method) There are no particular restrictions on the method. The method of forming the poorly water-soluble layer of the inner layer (shellac) and the outer layer (zein) in the first step may be changed.

In addition, as a provision amount of a hardly water-soluble layer, 0.1 mass%-5 mass% are preferable with respect to the total mass of a capsule, More preferably, it is 0.5 mass%-5 mass%, Most preferably, it is 1 mass. % To 4% by mass.
FIG. 1 shows a schematic diagram of the structure of the soft capsule preparation of the present invention.

The controlled release soft capsule preparation thus obtained can be confirmed to have a significant delay in disintegration time in the disintegration test determined by the Japanese Pharmacopoeia, compared to those without a coating, and an obvious release controllability can be confirmed.
In addition, it is possible to confirm whether or not the capsules adhere to each other by storing the soft capsule preparation in a hermetic container and conducting a storage test under an accelerated condition of 40 ° C. and 75% RH.

Examples, comparative examples and test examples are shown below, and the present invention will be described in more detail.
1. Preparation of Soft Capsule Formulation Soft capsule shells with carrageenan coatings of the specifications shown in Table 1 were prepared by a rotary die method in which coating heat sealing, capsule molding, and content liquid filling were simultaneously performed.

2. Coating of soft capsule (1) Preparation of shellac coating solution A solution having the composition shown in Table 2 below was used as a shellac coating solution.

(2) Preparation of zein coating solution A solution having the composition shown in Table 3 below was used as a zein coating solution.

(3) Coating operation of poorly water-soluble layer on soft capsule
This was performed using a DRIACOATER DRC-200 manufactured by Paulek.
1) Shellac coating
200 g (419 capsules) of soft capsules were placed in the coating pan and heated to an intake temperature of 40 ° C. and an exhaust temperature of 38 ° C. at a rotation speed of 20 rpm. Then, after the product temperature reached 38 ° C., the coating solution was sprayed under the conditions of 1.5 g / min and spraying pressure 1.0 kg / cm ² . After spraying the coating liquid, drying was performed for 5 minutes with the intake air kept at 40 ° C. to finish the coating.
After drying, the intake air heater was turned off and allowed to cool for 5 minutes, and the capsules were collected from the coating pan.

2) Zein coating
In the same manner as in 1), 200 g (419 capsules) of soft capsules were placed in the coating pan and heated to an intake temperature of 50 ° C and an exhaust temperature of 40 ° C at a rotation speed of 20 rpm. Subsequently, after the product temperature reached 40 ° C., the coating liquid was sprayed under the conditions of 1.5 g / min and spraying pressure 1.0 kg / cm ² . After spraying the coating liquid, the coating was completed by drying for 5 minutes while keeping the intake air at 50 ° C.
After drying, the intake air heater was turned off and the capsule was recovered from the coating pan by cooling for 5 minutes.

3. Evaluation of soft capsule formulation The following three items were evaluated.
(1) Test product The soft capsule preparation shown in Table 4 below was tested.
In Example 1, the outer shell of a soft capsule was formed with carrageenan, 2 mg of shellac was coated, and then 2 mg of zein was coated on the outermost layer. In Example 2, 5 mg of shellac was coated on the same capsule, and then 5 mg of zein was coated on the outermost layer. In Comparative Examples 1 and 2, 6 mg and 8 mg of shellac are coated on the same capsule. Comparative Examples 3 and 4 are the same capsules coated with 5 mg and 10 mg of zein. The structure of the soft capsules of Examples 1 and 2 has the structure shown in FIG.

(2) Disintegration and dissolution confirmation test Based on the Japanese Pharmacopoeia, the test solution was tested using water at 37 ° C and the first disintegration test solution under the condition without a disk. In order to confirm the dissolution behavior, the disintegration test solution was sampled over time, and the absorbance was measured. Since the capsule content solution containing lecithin is suspended with the disintegration test solution, a calibration curve was prepared at an absorbance of 660 nm, and this was used as the elution index as the turbidity of the disintegration test solution. The relative value with respect to the absorbance at the time of complete disintegration was defined as the elution amount (%) at each time.
(3) Sticking test (adhesion test)
20 soft capsule preparations coated in an aluminum-coated polyethylene bag with a chuck (Unipack) were placed in an aluminum-sealed state and stored in a thermostatic bath set at 40 ° C. and 50 ° C., and the adhesion between the capsules was tested.

4). Results (1) Disintegration, dissolution confirmation test, adhesion test results The test results are shown in Table 4 below.

In soft capsules (Comparative Examples 1 and 2) having a coating layer of shellac alone, significant release controllability was achieved at 80 minutes and 155 minutes, but adhesion between the capsules was intense, acceleration, severe conditions (40 ° C, 50 It has been found that it cannot withstand storage at a temperature of ℃) or long-term storage. On the other hand, soft capsules having a coating layer of zein alone (Comparative Examples 3 and 4) showed satisfactory results in the adhesion test, but the disintegration time was short, and there was no significant difference between those without coating. It was not confirmed. Moreover, when the coating layer was formed with zein alone, a phenomenon was observed in which zein peeled off from the capsule surface during the disintegration test.
On the other hand, the soft capsules of Examples 1 and 2 in which the first layer is coated with shellac and the second layer (outermost surface layer) is coated with zein have a disintegration time of 50 minutes and 180 minutes, and the capsules also adhere to each other. There wasn't.
That is, when shellac was coated on the first layer and zein was coated on the second layer, the disintegration time was 50 minutes or more, and a release-controllable soft capsule could be obtained. Furthermore, compared with the 6 mg coat of shellac, the coat amount of Example 1 was 4 mg, and the coat layer could be made thin.

1) Elution volume over time
Table 5 and Fig. 2 show the results of measuring the dissolution rate over time, measuring the disintegration solution with water, using Example 1 as the test sample and no coating as the control, and the disintegration solution as the first solution as determined by the Japanese Pharmacopoeia. The results measured in Table 6 are shown in Table 6 and FIG.

When the disintegrant is water, as shown in FIG. 2, the uncoated control shows an elution rate of slightly less than 40% in 30 minutes and almost 60% in 60 minutes, whereas Example 1 is almost eluted up to 30 minutes. No, the elution rate is 20% even at 60 minutes. Thus, it is clear that most of the contents are released in the intestine (without disintegrating in the stomach) when ingested.
In the case where the disintegrating liquid is the first liquid for the disintegration test, as shown in FIG. 3, the target is fully released in 2 hours, whereas the example releases only about 50% even after 2 hours. It can be confirmed that the release control is achieved so that the release is possible.

Claims (4)

A soft capsule preparation comprising two hard water-soluble layers on the surface of a shell layer of the soft capsule preparation , the inner water-insoluble layer being shellac, and the outer water-insoluble layer being mainly containing zein . The soft capsule preparation according to claim 1, wherein the soft capsule shell layer is mainly composed of carrageenan. By main constituent of layer of sparingly water-soluble layer of the two layers mix different soft capsule formulation according to claim 1 or 2, characterized in that is long-lasting action of the components contained in the soft capsules Soft capsule formulation. An immediate-release and sustained-release mixed-packaging soft capsule formulation obtained by mixing and packaging the soft capsule formulation according to any one of claims 1 to 3 with a soft capsule formulation that does not form a poorly water-soluble layer.