Capsules that break down in the intestines.

Abstract

By assuming the use of gelatin as a main base material of a capsule coating, provided is a capsule having excellent enteric properties. The enteric capsule contains alkali-treated gelatin and carrageenan as base materials of a capsule coating. In the gastric (aqueous) environment, the alkali-treated gelatin that is positively (+) charged coexists with the carrageenan that is negatively (-) charged and amino (NH4 +) group in the gelatin reacts with sulfate (SO3 -) group in the carrageenan so that the capsule coating is insolubilized. Meanwhile, in the enteric (aqueous) environment, the alkali-treated gelatin that is negatively (-) charged coexists with the carrageenan that is also negatively (-) charged and amino (NH4 +) group in the gelatin repulses with sulfate (SO3 -) group in the carrageenan so that the capsule coating quickly disintegrates and dissolves.

Description

Enteric-coated capsule The present invention relates to a capsule containing food, pharmaceuticals, quasi-drugs, etc. as active ingredients and suitable for release in the body, and particularly to an enteric-coated capsule that utilizes enteric solubility, which does not dissolve in the stomach but dissolves in the intestine to release the contents. Gelatin has many advantages as a base for capsule coatings, such as reversibly changing from sol to gel with temperature changes, having a gelling temperature at room temperature, excellent film-forming ability, high mechanical strength of the formed film, being easily dissolved in the body, and having nutritional value and being easily absorbed by the body. Therefore, it is generally widely used. By the way, if a pharmaceutical capsule dissolves rapidly due to the acidic secretion fluid in the stomach, the drug will be released in the stomach, which is not preferable in terms of side effects and the persistence of drug efficacy. From such a perspective, various enteric-coated capsules have been proposed conventionally. One of them is a capsule with a triple structure obtained by coating the surface of the capsule film with an enteric polymer substance such as zein, shellac, or Eudragit. However, it is difficult to strictly control the conditions during the coating process, and the thickness of the coating layer may vary between lots depending on the technical level of the operator, unevenness in the coating layer may occur in individual capsules, or the coating layer may peel off, etc., which may cause variations in the enteric function. On the other hand, as an example of a capsule film that imparts enteric solubility without performing a coating process, as described in Patent Document 1, a capsule in which low-methoxyl pectin is blended in a gelatin-based capsule film can be mentioned. However, since low-methoxyl pectin causes insolubilization in the presence of divalent and monovalent cations, it is difficult to control enteric solubility when the capsule contents contain divalent and monovalent cations, and the blending raw materials of the capsule contents are limited in capsule formulation. In addition, when the contents containing divalent and monovalent cations are formulated into capsules, delayed disintegration in the intestine and the possibility of not being absorbed by the body are considered. Japanese Patent Application Laid-Open No. 2010-47548, Japanese Patent Application Laid-Open No. 07-145082 In Patent Document 2, a proposal has been made in which gelatin is used as the main base of the capsule film, carrageenan is used in combination, and the pH of the film solution is adjusted to 5 to 3. When this method is actually implemented, gelatin and carrageenan aggregate and precipitate at the film solution stage, resulting in a decrease in gel strength. Therefore, especially during the formulation of soft capsules or seamless capsules, the contents leak or the capsules deform, making stable continuous production difficult. Therefore, an object of the present invention is to provide a novel and useful enteric-coated capsule that solves the above problems. As a result of trial and error, the inventor has found that when alkali-treated gelatin and carrageenan are contained as the base of the capsule film, regardless of whether divalent and monovalent cations are contained in the capsule contents, the film becomes insoluble in the acidic range and rapidly dissolves in the alkaline range. Furthermore, alkali-treated gelatin and carrageenan can be included not only on the film side but also on the encapsulated side depending on the formulation, and when included, enteric solubility can be imparted to the encapsulated side. Based on these findings, the inventors have proposed a novel and useful enteric-coated capsule that can solve the above-mentioned problems. That is, the enteric-coated capsule of the present invention is characterized in that alkali-treated gelatin and carrageenan are contained as enteric solubility-imparting agents on the capsule film side or on the encapsulated side encapsulated by the capsule film. Preferably, the carrageenan contains λ-carrageenan. Also preferably, no thickening polysaccharides other than carrageenan are contained. In the enteric-coated capsule of the present invention, when an enteric solubility-imparting agent is included on the film side, it can exhibit enteric solubility without being restricted by the presence or absence of divalent and monovalent cations in the capsule contents. First, a typical enteric-coated capsule that imparts enteric solubility to the capsule film side and dissolves the film in the intestine to release the capsule contents on the encapsulated side will be described below. The types of capsules include soft capsules, seamless capsules, and hard capsules, each of which has its own characteristics and can be applied to any of them. (Capsule contents) Those that have been conventionally used as the contents of gelatin capsules, and those that will be devised in the future and can be applied to the contents of gelatin capsules, all can be applied as the capsule contents of the present invention. In the case of soft capsules and seamless capsules, the capsule contents typically have a base of oil or fat, and contain powdery to liquid active ingredients. Examples of such oils and fats include vegetable oils such as soybean oil, olive oil, and wheat germ oil, medium-chain fatty acid triglycerides (MCT), and fats and oils such as beeswax, monoacylglycerin (monogly), beef tallow, lard, or cocoa butter that are solid near room temperature, or mixtures thereof. As for the types of active ingredients, in the case where the use is for oral pharmaceuticals, for example, drug components such as bronchodilators and allergy medications can be mentioned. In the case of foods, for example, functional components such as docosahexaenoic acid, various vitamins, and various extract powders can be mentioned. Regarding oil solubility, not only easily oil-soluble ones, but also poorly oil-soluble ones are acceptable as long as dispersibility is ensured. In the case of hard capsules, in many cases, the active ingredients are encapsulated as they are without being dispersed in the oil or fat. The form of the active ingredients in that case is not limited to the above-mentioned powdery and liquid forms, and gel-like, granular, tablet-like, pellet-like, or mixtures thereof are also conceivable. In the case of powdery or granular forms, in order to improve fluidity and the like, similar to existing products, corn starch, dextrin, etc. can be blended as excipients, or sucrose fatty acid esters, calcium stearate, magnesium stearate, etc. can be blended as lubricants. (Capsule film) The first component of the base of the capsule film is gelatin. In the present invention, since it occupies most of the content, it can be said that the capsule film is gelatin-based. Gelatin is made from collagen, which is the main protein component of the skin, bones, tendons, etc. of cows, sheep, pigs, chickens, or fish. Gelatin made from bovine bone, cowhide, or pigskin is easily available as an industrial raw material, but the origin is not particularly limited. However, the processing content is limited. Gelatin is a denatured product of collagen obtained by treating the above-mentioned raw materials with acid or alkali and then extracting them with warm water. There are acid treatment and alkali treatment methods for the processing method, but in the capsule film of the present invention, the use of alkali-treated gelatin is intended, and acid-treated gelatin is not intentionally included. In addition, the alkali treatment is usually carried out by lime treatment, but it is not particularly limited. Incidentally, although gelatin has been used as a base for capsule films for a long time, the gelatin that has actually circulated in the market from the price aspect is acid-treated. In the description of the materials of products, there are almost no mentions of the processing content of gelatin, but if it remains at the description of "gelatin", it is acid-treated gelatin. Therefore, the use of alkali-treated gelatin is by no means common sense. Gelatin maintains the "gelation ability" whether it is acid-treated or alkali-treated. It is an amphoteric electrolyte containing both acidic and basic amino acids. In acid-treated gelatin, since the deamidation rate is low, the isoelectric point is often around 8 to 9, which is close to that of collagen. Also, since the degree of deamidation of each molecule is different, the isoelectric point distribution is broad. On the contrary, in alkali-treated gelatin, most of it is deamidated, so most of the isoelectric points are around 5, and the degree of deamidation of each molecule is also uniform, resulting in a sharp isoelectric point distribution. In addition, the isoelectric point of gelatin referred to in the present invention refers to the pH shown when salt ions are completely removed from the gelatin solution, that is, the isoelectric point. The pH of human gastric juice is generally about 1, and the pH of intestinal juice is about 7. Therefore, in the gastric juice with a low pH, alkali-treated gelatin is positively charged. On the other hand, in the intestinal juice with a high pH, alkali-treated gelatin is negatively charged. In the present invention, the property of the charge change of alkali-treated gelatin in this gastric environment - intestinal environment is utilized. The second component of the base of the capsule film is carrageenan. Carrageenan is a type of galactan with a sulfate group (SO3− group) and is known to exist in red algae. Depending on the structural differences and gelling properties, carrageenan can be mainly classified into three types: κ (kappa) carrageenan, ι (iota) carrageenan, and λ (lambda) carrageenan. For every two galactose groups, they have one, two, and three sulfate groups (SO3− groups), respectively. Due to the presence of sulfate esters, carrageenan is always negatively (−) charged in solutions with any pH value. That is, even when the environment changes from the gastric environment to the intestinal environment, carrageenan is always negatively (−) charged. Regarding the gelling properties, the greater the number of sulfate groups (SO3− groups), the lower the gelling ability. Therefore, κ (kappa) carrageenan with one sulfate group (SO3−) and ι (iota) carrageenan with two sulfate groups (SO3−) have gelling ability, while λ (lambda) carrageenan with three sulfate groups (SO3−) does not have gelling ability. In the present invention, the properties of carrageenan described above are utilized and coexist as a partner for alkali-treated gelatin, which mainly bears the film base material. Therefore, in the gastric (aqueous) environment, negatively (−) charged carrageenan coexists with positively (+) charged alkali-treated gelatin, and the amino group (NH4+) of gelatin reacts with the sulfate group (SO3−) of carrageenan to become insoluble. On the other hand, in the intestinal (aqueous) environment, negatively (−) charged carrageenan coexists with negatively (−) charged alkali-treated gelatin, and the amino group (NH4+) of gelatin repels the sulfate group (SO3−) of carrageenan, so it quickly disintegrates or dissolves. As described above, there are different types of carrageenan. In the present invention, it is recommended to use λ carrageenan alone or in combination. Since λ carrageenan has no gelling ability, it is expected to ensure filling suitability by suppressing the increase in the gelling temperature of the film solution prepared for capsule formulation and to enhance the disintegration property in the intestinal environment to enable rapid dissolution of the film. When using two or more types of carrageenan in combination, a pre-mixed blend raw material can also be used. Carrageenan may be a pure product or may contain a standard substance. Examples of the standard substance include one or more selected from the group consisting of saccharides such as sucrose, glucose, maltose, lactose, and dextrin. Regarding the blending ratio of the alkali-treated gelatin and carrageenan, from the relationship between the insolubilization and dissolution of the film due to charging, it is preferable that the carrageenan is 1 to 20 parts by mass with respect to 100 parts by mass of the alkali-treated gelatin. Within this range, while the charging effect of carrageenan can be substantially obtained, the increase in viscosity due to the blending of carrageenan, which is a kind of thickening polysaccharide, is suppressed to such an extent that it is easy to ensure the filling suitability. As described above, carrageenan is a kind of thickening polysaccharide. Other thickening polysaccharides include xanthan gum, galactomannan (LBG), pectin, sodium alginate, etc. These are sometimes added for other purposes, such as preventing the adhesion of the capsule film and the deformation of the capsule due to temperature changes during storage and distribution, that is, improving heat resistance, preventing adhesion in the oral cavity and esophagus, improving ease of swallowing, and improving the feel on the tongue. However, since it leads to an increase in the viscosity of the film solution, especially when the film side contains carrageenan, the above purposes are naturally achieved, so it is preferable not to include thickening polysaccharides other than carrageenan. In addition to gelatin, as film-forming agents, there are also non-gelatin-based ones such as hydroxypropylmethylcellulose (HPMC), starch, and agar. However, in order not to reduce the relative blending amount of gelatin, it is also preferably not intentionally blended. In the capsule film of the present invention, in addition to the base materials of alkali-treated gelatin and carrageenan, plasticizers such as glycerin and sorbitol necessary for formulating the capsule, and further, coloring agents, preservatives, sweeteners, etc. are blended as required. (Method for formulating into capsules) For the capsule film side, the above-mentioned capsule film base materials are dissolved in water and stirred together to form a homogeneous film solution. Then, the capsule contents are filled, enclosed, and molded to formulate into a capsule preparation. The types of capsules include soft capsules, seamless capsules, and hard capsules, each of which has its own characteristics, but any of them can be formulated by treating them in the same way as existing gelatin capsules. In the above description, the enteric coating agent is included on the film side, but it is not limited to this, and it may be included on the encapsulated side. For example, when there is an active ingredient that needs to be released in both the stomach and the intestine, a capsule can be considered in which the active ingredient to be released in the stomach is included on the film side and dissolved in the stomach, and the active ingredient to be released in the intestine is included on the capsule content side together with the enteric coating agent and dissolved in the intestine. Note that the active ingredient to be released in the stomach and the active ingredient to be released in the intestine are not necessarily different. For example, when it is desired to maintain the blood concentration of (a certain) active ingredient, it is desired to release the active ingredient in both the stomach and the intestine. By including the active ingredient on both the film side and the encapsulated side, it is possible to ensure that not all of the active ingredient is released in the stomach and the remaining part is brought to the intestine and released in the intestine. In addition, capsules also include multiple capsules and single spherical capsules, and these are also included in the scope of the present invention. In a multiple capsule, one or more intermediate layers and the capsule content (core or nucleus) are on the encapsulated side, and it is conceivable to include an enteric coating agent on these encapsulated sides. In the case of a multiple capsule, when the active ingredient to be released in the stomach cannot be included on the film side, it can be included in the intermediate layer closer to the film, and the film is dissolved in the stomach and the intermediate layer is exposed in the stomach. Also, for the active ingredient to be released in the intestine, similarly, when it cannot be included in the capsule content together with the enteric coating agent, the enteric coating agent can be included in the intermediate layer, and the active ingredient can be included in the nucleus separately. The intermediate layer can be dissolved in the intestine and its content can be released. Since multiple capsules can be formulated by a standard method as a type of seamless capsule, the above-mentioned multiple capsules are feasible. A single spherical capsule is composed of the same formulation for the capsule film and the capsule content, and there is no distinction. If we focus only on the active ingredient to be absorbed in the intestine and it can be included in the capsule film together with an enteric coating agent, it is also conceivable to adopt the form of this single spherical capsule. (Example 1) The following was carried out for the verification of the capsule film. With various film compositions, they were put into water at 85 °C and stirred for 10 minutes to dissolve them in water to prepare a homogeneous film solution. The viscosity is the measurement result by a rotational viscometer (VISCOMETER manufactured by BROOKFIELD). The evaluation criteria for the filling suitability of the film solution were as follows. 〔Evaluation criteria〕 ◎: Filling yield 90% or more ○: Filling yield 70% or more △: Filling possible ×: Filling impossible The enteric test is an elution test carried out on the capsule formulations prepared as follows using Japanese Pharmacopoeia First Solution (artificial gastric juice) and Japanese Pharmacopoeia Second Solution (artificial intestinal juice) based on the Japanese Pharmacopoeia 16th Edition. <Soft capsule> By the rotary punching method, oval No. 6 (film weight: 165 mg, content weight: 300 mg) MCT-filled capsules were manufactured. <Seamless capsule> By the in-drop method in liquid, MCT-filled capsules with a major axis of about 6 mm Φ (film weight: 20 mg, content weight: 100 mg) were manufactured. <Hard capsule> By the dipping method, hard capsules of size No. 1 (empty capsule weight: about 78 mg) were manufactured. Then, corn starch was filled. The evaluation criteria for enteric property were as follows based on the Japanese Pharmacopoeia 16th Edition. (First solution) ◎: None of the 6 capsules disintegrated within 120 minutes ○: Among the 6 capsules, 4 or 5 did not disintegrate. In the retest, 16 or more out of 18 did not disintegrate within 120 minutes △: Among 6 capsules, 4 or 5 do not disintegrate, and in the retest, there are 2 or more disintegrations among 18 capsules. ×: Elution starts immediately. (Two liquids) ◎: All 6 capsules disintegrate within 60 minutes. ○: Among 6 capsules, 4 or 5 disintegrate, and in the retest, 16 or more among 18 capsules disintegrate within 120 minutes. △: Among 6 capsules, 4 or 5 disintegrate, and in the retest, 2 or more among 18 capsules do not disintegrate. ×: Does not disintegrate within 60 minutes. Specimens 1 to 6 (the present invention) described in Table 1 coexist with alkali-treated gelatin and carrageenan, have appropriate viscosity to satisfy filling suitability, and also satisfy suitability as enteric coating. In particular, the result of the enteric coating test (two liquids) of Specimen 6 (blended with λ-carrageenan) was good and it was completely dissolved. Also, for comparison with Specimen 6, tests were also conducted on Specimen 6-A (blended with potassium chloride in the capsule content) and Specimen 6-B (blended with calcium lactate in the capsule content). Specimens 6-A and 6-B contain divalent and monovalent cations in the capsule content, and the mass fraction of MCT is reduced accordingly, but otherwise, they have the same composition as Specimen 6. Specimens 6-A and 6-B also showed results comparable to Specimen 6. From this, it was confirmed that even in the presence of divalent and monovalent cations, there is no adverse effect. Specimens 7 to 10 (comparative examples) described in Table 2 are blended with thickening polysaccharides other than carrageenan, have unduly high viscosity resulting in poor filling suitability, and the characteristics of gelatin as an ampholyte are not utilized, and they completely dissolved in the enteric coating test (one liquid). Specimens 11 to 14 (the present invention) described in Table 3 are those with other thickening polysaccharides added to λ-carrageenan. Due to the increase in viscosity, the filling suitability decreased, and in the enteric coating test, there was some elution in (one liquid) and some remaining undissolved in the reverse in (two liquids). Samples 15 to 20 (comparative examples) described in Table 4 were prepared by incorporating acid-treated gelatin instead of alkali-treated gelatin. At the stage of preparing the film solution, negatively charged carrageenan coexisted with positively charged acid-treated gelatin, and the amino groups (NH4+) of gelatin underwent a neutralization reaction with the sulfate groups (SO3−) of carrageenan, resulting in aggregation and cloudiness. Therefore, the gelling ability of gelatin was impaired and the filling suitability decreased. Also, in the enteric solubility test (two solutions), almost all of it remained undissolved. Samples 21 to 30 (the present invention) described in Table 5 had various amounts of λ-carrageenan incorporated. When the amount incorporated was 1.0 part by mass or more, enteric solubility at a high level was exhibited. Samples 31 to 34 (the present invention) described in Table 6 used two types of carrageenan in combination. When λ-carrageenan was used in combination with κ-carrageenan or ι-carrageenan, the compounding effect of λ-carrageenan was sufficiently obtained, the increase in viscosity at the stage of the film solution was suppressed, high-level filling suitability was exhibited, and high-level enteric solubility was also exhibited. (Example 2) The enteric solubility test was carried out on triple-layer seamless capsules (film part, intermediate layer, core) with the following formulation. All of Samples 35 to 36 (the present invention) described in Table 8 exhibited enteric solubility at a high level.

Claims

Page 1 of 1 page of Claims 1. Enteric disintegrating capsules of gelatin-based composition, which contain alkaline-modified gelatin and carrageenan as enteric disintegrating agents on the capsule coating side or on the coated side of the capsule coating, but do not contain gelatin other than alkaline-modified gelatin, and counterions are not bound to carrageenan.

2. Enteric disintegrating capsules according to Claims 1, in which carrageenan contains A, carrageenan.

3. Enteric disintegrating capsules according to Claims 2, which...

4. Enteric disintegrating capsules under any one of Patents 1 through 3, which are soft capsules, seamless capsules, or hard capsules; 5. Enteric disintegrating capsules under any one of Patents 1 through 3, which are soft capsules or seamless capsules; 6. Enteric disintegrating capsules under any one of Patents 4 or 5, in which alkali-modified gelatin and carrageenan are incorporated into the coated side as enteric disintegrating agents;