HK1231373B - Method of manufacturing enteric soft capsule - Google Patents

Description

Preparation method of enteric-coated soft capsules

Technical Field

The present invention relates to a method for preparing enteric-coated soft capsules, and more specifically, to a method for preparing enteric-coated soft capsules, comprising the following steps: (a) preparing an enteric-coated capsule shell liquid containing gelatin and low-methoxy pectin with an amidation degree of 5-25%, and (b) encapsulating capsule contents by punching using the enteric-coated capsule shell liquid prepared in step (a).

Background Art

Capsules containing various active ingredients have been widely reported. Gelatin and agar are widely used as shell materials for these capsules. However, shells made of materials such as gelatin and agar disintegrate in the acidic environment of the stomach, making it difficult to use acid-labile active ingredients.

In recent years, enteric-coated capsules have been developed. Enteric-coated capsules have an acid-resistant shell, so they disintegrate in the intestines rather than in the stomach, releasing their contents. Enteric-coated capsules are used not only for active ingredients containing acid-labile substances, but also for substances where sustained release is desired for long-term effects, and for substances such as garlic and fish oil that have an unpleasant odor or aftertaste in the breath after digestion in the stomach.

Regarding the preparation method of enteric-coated capsules, a method that has been proposed so far includes the following steps: (a) preparing a solution containing a film-forming water-soluble polymer and an acid-insoluble polymer, and mixing the solution with a suitable plasticizer to form a gel material; (b) casting the gel material into a film or tape using a heat-controlled drum or surface; and (c) forming a soft capsule using a rotational mold technology (reference patent document 1).

In addition, a preparation method of an enteric-coated sustained-release soft capsule is disclosed, characterized in that the method comprises the steps of uniformly mixing gelatin, a polyol as a plasticizer, an alkali metal salt, and water with a concentration of 6-40% by mass of polysaccharides such as carrageenan, agar, and locust bean gum to prepare a soft capsule raw material mixture, and using the soft capsule raw material mixture to contain at least one of garlic, fish oil, propolis, intestinal bacteria, and a protein drug (reference patent document 2). However, two or more polysaccharides are required, and an alkali metal salt is required during mixing, so that the gelation caused by the two polysaccharides is promoted during capsule formation, resulting in a problem of very poor formability (very poor adhesion).

In addition, a method for preparing enteric-coated soft capsules is disclosed, which is characterized by comprising: a preparation step of preparing a capsule shell liquid containing gelatin, water, a plasticizer, and low-methoxy pectin with an esterification degree of 20%-40% and an esterification content of 10 parts by weight to 30 parts by weight relative to 100 parts by weight of gelatin; and a forming step of filling a capsule membrane formed from the capsule shell liquid with the contents using a rotary mode forming device to form a soft capsule; and excluding the step of adding a salt containing a polyvalent metal ion that gelates the low-methoxy pectin to the capsule shell liquid and immersing the formed soft capsule in a gelling liquid containing the polyvalent metal ion (see Patent Document 3).

Prior art literature

Patent Literature

Patent Document 1: Japanese Patent Application No. 2006-505542

Patent Document 2: Japanese Patent Application Laid-Open No. 2009-185022

Patent Document 3: Japanese Patent Application Laid-Open No. 2010-047548

Summary of the Invention

Problems to be solved by the invention

The problem to be solved by the present invention is to provide a method for preparing a soft capsule having enteric solubility and excellent formulation properties.

Means used to solve problems

The present inventors focused on the degree of amidation of pectin used in the capsule shell of enteric soft capsules. Using various pectins with varying degrees of amidation as the capsule membrane material, they discovered that using low-methoxyl pectin with a degree of amidation of 5-25% allowed the preparation of soft capsules with enteric solubility and excellent formulation properties, leading to the present invention.

That is, the present invention relates to the following (1) to (6).

(1) A method for preparing enteric soft capsules, characterized in that it comprises the following steps: (a) preparing an enteric capsule shell liquid containing gelatin and low-methoxy pectin with an amidation degree of 5-25%, and (b) using the enteric capsule shell liquid prepared in step (a) to encapsulate capsule contents by a punching method.

(2) The method for preparing the enteric-coated soft capsules as described in (1) above is characterized in that the gel strength of the gelatin is 160-300 Bloom.

(3) The method for preparing the enteric-coated soft capsules as described in (1) or (2) above, characterized in that the degree of esterification of the low-methoxyl pectin is 20-40%.

(4) The method for preparing the enteric-coated soft capsule according to any one of (1) to (3) above, wherein the enteric-coated capsule shell liquid contains 30-35 parts by mass of low-methoxyl pectin relative to 100 parts by mass of gelatin.

(5) A method for preparing enteric-coated soft capsules as described in any one of (1) to (4) above, characterized in that low-methoxyl pectin is dispersed in glycerol and then dissolved in warm water, gelatin is then added and dissolved, and the mixture is filtered and defoamed under reduced pressure (degassing).

(6) The method for preparing the enteric-coated soft capsule according to any one of (1) to (5) above, wherein the encapsulation is performed so that the thickness of the shell of the enteric-coated capsule is 0.3-1.2 mm.

Effects of the Invention

The enteric-coated soft capsules prepared by the method for preparing enteric-coated soft capsules of the present invention have enteric solubility and excellent preparation properties, and therefore can be stored for a long time. The contents can contain acid-unstable substances. Furthermore, even if the contents contain substances such as garlic and fish oil that cause bad odor and aftertaste in breath caused by digestion in the stomach, the bad odor and aftertaste in breath after administration can be prevented.

DETAILED DESCRIPTION

The method for preparing the enteric-coated soft capsules of the present invention is not particularly limited and comprises the following steps: (a) preparing an enteric-coated capsule shell solution containing gelatin and low-methoxyl pectin having an amidation degree of 5-25%, and (b) using the enteric-coated capsule shell solution prepared in step (a) to encapsulate the capsule contents by punching. Enteric solubility refers to the property of dissolving in the intestines rather than in the stomach.

The gelatin used in the present invention is not particularly limited and includes gelatin with a gel strength of 160-300 Bloom, preferably 200-300 Bloom. In addition, two or more gelatins with different gel strengths can be mixed and used. For example, gelatin with a gel strength of 200 Bloom and gelatin with a gel strength of 300 Bloom can be mixed to adjust the gel strength.

In the present invention, low methoxyl pectin (LM pectin) refers to pectin with a degree of esterification (DE) of less than 50%. The degree of esterification is preferably 20-40%, more preferably 22-38%, and even more preferably 22-32%. The degree of esterification refers to the proportion of methyl-esterified galacturonic acid in the total amount of galacturonic acid, and can be calculated by dividing the amount of methyl-esterified galacturonic acid by the total amount of galacturonic acid × 100%.

In the present invention, the degree of amidation (DA) refers to the proportion of amidated species in the total amount of galacturonic acid, which can be calculated by: the amount of amidated galacturonic acid / the total amount of galacturonic acid × 100%. The degree of amidation of the low-methoxyl pectin is, for example, 5-25%, preferably 6-23%, and more preferably 12-23%.

The method for preparing the shell liquid for enteric-coated capsules of the present invention is not particularly limited and includes the following method: the method comprises dissolving low-methoxyl pectin having an amidation degree of 5-25% in water, and then adding gelatin to dissolve the mixture. To ensure the uniformity of the shell liquid, prevent brittleness of the capsule shell, and prevent deformation and poor adhesion of the capsule, the low-methoxyl pectin is preferably dispersed in a plasticizer such as glycerin, then dissolved in warm water, and the prepared shell liquid is filtered through a sieve with a mesh size of 0.5 mm or less, preferably 0.3 mm or less, to remove insoluble matter (e.g., insoluble powder lumps) or impurities. The shell liquid is then further subjected to vacuum decompression and defoaming while in its molten state.

In the present invention, the method for encapsulating the capsule contents by punching is to feed two gelatin sheets formed by stretching the capsule shell liquid to a pair of forming molds, inject the liquid between the two sheets, and then punch out the contents to form the capsule. The method is not particularly limited and can be a rotary mold method using a cylindrical mold, a flat plate method using a flat plate mold, or other methods for encapsulating the capsule contents. The material of the mold is not particularly limited, and metal molds are preferably metal molds. The rotary mold method and the flat plate method can be carried out using commercially available rotary mode soft capsule production equipment or flat plate soft capsule production equipment. In addition, when using the punching method, a seam is formed due to compression during forming. If the adhesiveness (sealing, adhesion) of the seam is low, the capsule is easily disintegrated. However, the enteric-coated soft capsules prepared by the present invention have a high adhesiveness of the seam because their shells contain low-methoxyl pectin with a degree of amidation of 5-25%, allowing for long-term stable storage.

In the present invention, the contents of the capsule are not particularly limited and may be solid or liquid, such as pharmaceutical ingredients, nutritional supplement ingredients, health food ingredients, etc. Specific examples include substances that cause an unpleasant odor or aftertaste in the breath during digestion in the stomach, such as fish oil, garlic, vitamin B1, so-called egg oil (a traditional health food ingredient, a brown to black liquid obtained by heating egg yolks in an iron pan or other similar medium over a low heat for a long time while stirring), acid-labile intestinal bacteria, such as Streptococcus faecalis, Lactococcus lactis, and Lactobacillus helveticus. Lactic acid bacteria such as Lactobacillus acidophilus (ラクトバチルス·アシドフィダム), Lactobacillus casei (ラクトバチルス·カゼイ), Bifidobacterium such as Bifidobacterium longum (ビフィドバクテリウム·ロンガム), Bifidobacterium bifidum (ビフィドバクテリウム·ビフィダム), ingredients that irritate the stomach such as chili pepper raw materials and capsaicin, iron supplements such as ferrous fumarate and dried ferrous sulfate, heat dissipating agents, analgesics, anti-inflammatory agents, antitumor agents, antibacterial agents, etc. are used in preparations that maintain the effect for a long time through sustained release.

The contents of the capsules may contain, in addition to the above ingredients, necessary hardened oils, medium-chain triglycerides (MCT), EPA, DHA, shark liver oil, cod liver oil and other fats and oils, lecithin, polyglycerol fatty acid esters, alcohols and other additives for adjusting surface activity, buffers, water, gelling agents such as gelatin or carrageenan, pH adjusters, porous fine particle powders such as fumed silica, flavoring agents such as sweeteners, flavorings, solubility aids, viscosity modifiers, antioxidants such as vitamin E, BHT, and BHA, and the like.

In the shell liquid of the enteric capsule of the present invention, the content of low methoxy pectin relative to gelatin is not particularly limited, but the content of low methoxy pectin is preferably 20-40 parts by mass, more preferably 30-35 parts by mass, and even more preferably 31-33 parts by mass relative to 100 parts by mass of gelatin.

In the present invention, when encapsulating the contents of the capsule, the thickness of the outer shell is preferably 0.3-1.2 mm, more preferably 0.4-1.0 mm.

The shell liquid of the enteric-coated capsules of the present invention may contain, as needed, plasticizers such as glycerol, pH regulators such as sodium phosphate, chelating agents such as trisodium citrate and sodium metaphosphate, gelling agents such as calcium lactate and potassium chloride, surfactants such as polyglycerol fatty acid esters and lecithin, sweeteners, flavorings, preservatives, colorants, and the like. Based on considerations of capsule formability and adhesion, it is preferred not to mix gelling agents with the shell liquid. The gelling agent may be added to the capsule at any time after formation (before, during, or after drying) by immersion treatment or spraying.

DETAILED DESCRIPTION

Example 1

[Disintegration test]

(Preparation of Soft Capsules)

The capsule shell solution of the present invention was prepared by dispersing 24 parts by mass of pectin (DE30, DA17) in 30 parts by mass of glycerin and dissolving the solution in warm water (80°C). 60 parts by mass of gelatin (300 Bloom) and 16 parts by mass of gelatin (200 Bloom) were added and dissolved at 70°C. The solution was filtered through a 100-mesh sieve (0.15 mm opening) and then defoamed under reduced pressure. Furthermore, a control coating solution was prepared by dissolving 30 parts by mass of glycerin in warm water at 80°C, adding 100 parts by mass of gelatin (200 Bloom), dissolving the solution at 70°C, filtering through a 100-mesh sieve (0.15 mm opening), and then defoaming under reduced pressure. Each capsule shell solution had fluidity at 60°C and could be used in a rotary device.

Next, using a rotary soft capsule preparation apparatus (manufactured by Fuji Capsule Co., Ltd.), 250 mg of the capsule contents (fish oil containing DHA and EPA) were encapsulated in a membrane sheet approximately 0.8 mm thick, formed from the aforementioned capsule shell solution of the present invention or the control shell solution. Subsequently, the Oval-5 soft capsules were rotary dried for 12 hours in a dehumidified environment at 30°C and 35% humidity to produce the Oval-5 soft capsules. The resulting capsules had a membrane thickness of 0.5 mm after drying, and a very good adhesion ratio (thickness of the thinnest joint surface divided by average membrane thickness; visually measured) of 85%.

(result)

Soft capsules made with the capsule shell solution of the present invention and soft capsules made with a control shell solution were taken, and the odor of exhaled breath was examined 60 minutes later. The soft capsules made with the capsule shell solution of the present invention did not produce a fishy odor, while the soft capsules made with the control shell solution did produce a fishy odor.

Example 2

Formulation and enteric dissolution test 1

(Preparation of Soft Capsules)

31.5 parts by mass of pectin shown in Table 1 below was dispersed in 40 parts by mass of glycerin and dissolved in warm water (80°C). 79 parts by mass of gelatin (300 Bloom) and 21 parts by mass of gelatin (200 Bloom) were further added and dissolved at 70°C. The mixture was filtered through a 60-mesh sieve (0.25 mm opening) and then defoamed under reduced pressure to prepare a capsule shell liquid. In the table, DE represents the degree of esterification (%) of each pectin, and DA represents the degree of amidation (%) of each pectin.

Table 1

Types of pectin DE DA Pectin-1 31-38 12-18 Pectin-2 26-34 16-19 Pectin-3 30-35 6-12 Pectin-4 22-27 20-23 Pectin-5 33-38 0

Then, using a flat-plate soft capsule preparation device (manufactured by Fuji Capsule Co., Ltd.), medium-chain fatty acid triglycerides (MCT: coconard MT: manufactured by Kao Corporation) were encapsulated as capsule contents in an average amount of 0.45 mL per capsule in a shell sheet with a thickness of about 0.8 mm formed by extending the above-mentioned capsule shell liquid. Then, the Oval-5 type soft capsules were prepared by standing and drying for 18 hours at 25°C without adjusting the humidity. The soft capsules prepared using shell liquids containing pectin-1 to pectin-4 were used as example products 1-4, and the soft capsules prepared using pectin-5 were used as comparative products. The shell thickness of the prepared soft capsules after drying was 0.5 mm, and the bonding rate (thickness of the joint surface of the thinnest part ÷ average shell thickness; visual measurement) was 60%, which is good for capsules prepared by the flat plate method.

The resulting soft capsules were evaluated for formulation properties and enteric solubility. The formulation properties were evaluated for the fluidity of the shell liquid (whether there were any obstacles when injecting it into the device), with ◎ indicating no obstacles at all, ○ indicating almost no obstacles, △ indicating slight obstacles, and × indicating obstacles preventing injection. Furthermore, the adhesiveness of the capsules during formation (the adhesion between the sheets) was evaluated, with ◎ indicating very good, ○ indicating good, △ indicating slightly poor, and × indicating poor.

Enteric solubility was evaluated by the disintegration test shown below. In the disintegration test using the first solution (37°C), observation results after 120 minutes were as follows: ○ indicates no disintegration, and × indicates disintegration. In the disintegration test using the second solution, observation results after 30 minutes were as follows: ○ indicates complete disintegration, and × indicates incomplete disintegration.

The disintegration test of the prepared soft capsule was carried out after modification according to the method described in the literature (Explanation of the Japanese Pharmacopoeia, 16th edition (Explanation of the Japanese Pharmacopoeia), published by Tokyo Hirokawa Shoten B589 (2011)). The disintegration tester used was NT-40H (manufactured by Fuji Sangyo Co., Ltd.). 18 capsules were tested without using an auxiliary plate (Example products 1-4) and with using an auxiliary plate (Example product 2 only) using the reagent "Disintegration test 1st liquid/Dissolution test 1st liquid (Disintegration test 1st liquid/Dissolution test 1st liquid)" (pH 1.2) manufactured by Kanto Chemical Co., Ltd. and the reagent "Disintegration test 2nd liquid (Disintegration test 2nd liquid)" (pH 6.8) manufactured by Kanto Chemical Co., Ltd. The capsule was ruptured or its shell was opened or damaged. It was regarded as disintegration.

(result)

The results of investigation of preparation property and enteric solubility are as shown in Table 2.As shown in Table 2, preparation property aspect, implementation product 1-4 is all good.In addition, enteric solubility aspect, embodiment product 1-4 (the situation without auxiliary plate), according to the disintegration test that adopts the 1st liquid, after 120 minutes, 18 soft capsules all had no disintegration, according to the test of the disintegration test the 2nd liquid using new capsule, disintegration occurred after 5 minutes, and after 30 minutes, 18 soft capsules all disintegrated.About implementation product 2 (the situation with auxiliary plate), according to the disintegration test that adopts the 1st liquid, after 120 minutes, 18 soft capsules all had no disintegration, according to the test of the disintegration test the 2nd liquid using new capsule, opening occurred after 3 minutes, and after 30 minutes, 18 soft capsules all disintegrated.

Therefore, it can be seen that soft capsules with excellent preparation properties and enteric solubility can be prepared by punching out an enteric capsule shell liquid containing gelatin and low methoxy pectin with an amidation degree of 5-25%.

Table 2

Example 3

Formulation and enteric dissolution test 2

(Preparation of Soft Capsules)

20 parts by weight of each of pectin-1, pectin-2, and pectin-4 shown in Table 1 were dispersed in 40 parts by weight of glycerin and dissolved in warm water (80°C). 79 parts by weight of gelatin (300 Bloom) and 21 parts by weight of gelatin (200 Bloom) were further added and dissolved at 70°C. The mixture was filtered through a 60-mesh sieve (0.25 mm opening) and defoamed under reduced pressure to prepare a capsule shell liquid.

Then, using a flat-plate soft capsule preparation apparatus (manufactured by Fuji Capsule Co., Ltd.), Oval-5 type soft capsules were prepared using MCT as the content using the same method as described above. Soft capsules prepared using pectin-1, pectin-2, and pectin-4, respectively, were designated as Examples 5-7.

The obtained soft capsules were evaluated for formulation properties and enteric solubility using the same methods as above. The results are shown in Table 3.

Table 3

(result)

In Example products 5-7, the shell fluidity in the formulation properties was slightly inferior to that of Example products 1, 2, and 4, but there was basically no problem; the adhesiveness was slightly inferior to that of Example products 1-4; and the enteric solubility was as good as that of Example products 1-4.

Industrial applicability

The enteric-coated soft capsule of the present invention has excellent enteric solubility and preparation properties, and can be used in the fields of medicines, nutritional supplements, and health foods.

Claims (17)

1. A method for preparing enteric-coated soft capsules, characterized by comprising the following steps: (a) Prepare an enteric-coated capsule shell solution containing gelatin and low-methoxyl pectin with an amidation degree of 5-25%, and (b) The enteric capsule shell liquid prepared in step (a) is used to encapsulate the capsule contents by a punching method. 2. The method for preparing enteric-coated soft capsules according to claim 1, wherein the gelatin has a gel strength of 160-300 Bloom. 3. The method for preparing enteric-coated soft capsules as described in claim 1 or 2 above, characterized in that the degree of esterification of the low-methoxyl pectin is 20-40%. 4. The method for preparing enteric-coated soft capsules as described in claim 1 or 2 above, characterized in that, relative to 100 parts by weight of gelatin, the enteric-coated capsule shell liquid contains 30-35 parts by weight of low-methoxyl pectin. 5. The method for preparing enteric-coated soft capsules as described in claim 1 or 2 above, characterized in that the low-methoxyl pectin is dispersed in glycerol and then dissolved in warm water, followed by the addition of gelatin for dissolution, and the mixture is filtered and defoamed under reduced pressure. 6. The method for preparing enteric-coated soft capsules as described in claim 1 or 2 above, characterized in that the encapsulation makes the thickness of the outer shell of the enteric-coated capsule 0.3-1.2 mm. 7. The method for preparing enteric-coated soft capsules as described in claim 3, characterized in that, relative to 100 parts by weight of gelatin, the enteric-coated capsule shell liquid contains 30-35 parts by weight of low-methoxyl pectin. 8. The method for preparing enteric-coated soft capsules as described in claim 3 above, characterized in that the low-methoxyl pectin is dispersed in glycerol and then dissolved in warm water, followed by the addition of gelatin for dissolution, and the mixture is filtered and defoamed under reduced pressure. 9. The method for preparing enteric-coated soft capsules as described in claim 3 above, characterized in that the encapsulation makes the thickness of the outer shell of the enteric-coated capsule 0.3-1.2 mm. 10. The method for preparing enteric-coated soft capsules as described in claim 4 above, characterized in that the low-methoxyl pectin is dispersed in glycerol and then dissolved in warm water, followed by the addition of gelatin for dissolution, and the mixture is filtered and defoamed under reduced pressure. 11. The method for preparing enteric-coated soft capsules as described in claim 7 above, characterized in that the low-methoxyl pectin is dispersed in glycerol and then dissolved in warm water, followed by the addition of gelatin for dissolution, and the mixture is filtered and defoamed under reduced pressure. 12. The method for preparing enteric-coated soft capsules as described in claim 4 above, characterized in that the encapsulation makes the thickness of the outer shell of the enteric-coated capsule 0.3-1.2 mm. 13. The method for preparing enteric-coated soft capsules as described in claim 5 above, characterized in that the encapsulation makes the thickness of the outer shell of the enteric-coated capsule 0.3-1.2 mm. 14. The method for preparing enteric-coated soft capsules as described in claim 7 above, characterized in that the encapsulation makes the thickness of the outer shell of the enteric-coated capsule 0.3-1.2 mm. 15. The method for preparing enteric-coated soft capsules as described in claim 8, characterized in that the encapsulation results in a capsule shell thickness of 0.3-1.2 mm. 16. The method for preparing enteric-coated soft capsules as described in claim 10, characterized in that the encapsulation results in a capsule shell thickness of 0.3-1.2 mm. 17. The method for preparing enteric-coated soft capsules as described in claim 11, characterized in that the encapsulation results in a capsule shell thickness of 0.3-1.2 mm.