WO2017030072A1 - 腸溶性カプセル - Google Patents
腸溶性カプセル Download PDFInfo
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- WO2017030072A1 WO2017030072A1 PCT/JP2016/073617 JP2016073617W WO2017030072A1 WO 2017030072 A1 WO2017030072 A1 WO 2017030072A1 JP 2016073617 W JP2016073617 W JP 2016073617W WO 2017030072 A1 WO2017030072 A1 WO 2017030072A1
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- Prior art keywords
- capsule
- carrageenan
- enteric
- gelatin
- alkali
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/11—Encapsulated compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
Definitions
- the present invention relates to a capsule suitable for release in the body, including food, pharmaceuticals, quasi-drugs, etc., and in particular, an intestine that does not dissolve in the stomach but dissolves in the intestine to release the contents.
- the present invention relates to an enteric capsule utilizing solubility.
- Gelatin reversibly changes sol-gel with temperature change, gelation temperature is normal temperature, excellent film forming ability and high mechanical strength of the formed film, easy to dissolve in the body, It is generally used widely because it has many advantages as a base for capsule film, such as having itself nutritional value and being easily absorbed by the body.
- enteric polymer material such as zein, shellac, and Eudragit to form a triple structure.
- enteric polymer material such as zein, shellac, and Eudragit
- a capsule in which low methoxyl pectin is blended into a gelatin capsule film can be mentioned.
- low methoxyl pectin causes insolubilization in the presence of divalent and monovalent cations, so that when the capsule content contains divalent or monovalent cations, enteric properties are controlled. This is difficult, and the ingredients for capsule contents are limited in making capsules.
- disintegration in the intestine may be delayed and may not be absorbed into the body.
- JP 2010-47548 A Japanese Patent Application Laid-Open No. 07-145082
- Patent Document 2 proposes that 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.
- this method is actually implemented, gelatin and carrageenan aggregate and precipitate at the film solution stage, and the gel strength decreases. Stable and continuous production was difficult due to deformation.
- an object of the present invention is to provide a new and useful enteric capsule that solves the above-mentioned problems.
- the present inventor when containing alkali-treated gelatin and carrageenan as the base of the capsule film, regardless of whether divalent or monovalent cations are contained in the capsule contents
- the film becomes insoluble in the acidic range and dissolves quickly in the alkaline range.
- the alkali-treated gelatin and carrageenan can be included not only on the coating side but also on the encapsulation side depending on the formulation. It has been found that entericity can also be imparted to the encapsulating side. Based on these findings, the present inventors have proposed an enteric capsule that is new and useful and can solve the above-described problems.
- the enteric capsule of the present invention is characterized by containing alkali-treated gelatin and carrageenan as enteric agents on the capsule film side or the encapsulated side encapsulated by the capsule film.
- the carrageenan includes ⁇ carrageenan.
- polysaccharide thickeners other than carrageenan are not contained.
- enteric capsule of the present invention when an entericity-imparting agent is contained on the film side, it can be enteric without being restricted by the presence or absence of divalent or monovalent cations in the capsule contents.
- capsule contents What has been conventionally used as the contents of gelatin-based capsules, and further devised from this, and applicable to the contents of gelatin-based capsules are all applicable as the capsule contents of the present invention.
- the capsule contents are typically based on fats and oils, which contain powdered or liquid active ingredients.
- Is a vegetable oil such as soybean oil, olive oil, wheat germ oil, medium-chain fatty acid triglyceride (MCT), beef fat, pork fat or cocoa butter, which is solid at room temperature, including beeswax and monoacylglycerol (monogli) Etc., and mixtures thereof.
- the active ingredient include pharmaceutical ingredients such as bronchodilators and allergic drugs when the use is an oral drug, and in the case of foods, for example, docosahexaenoic acid, various vitamins, and various extract powders. And the like.
- oil solubility not only easy oil solubility but also poor oil solubility may be used as long as dispersibility is ensured.
- the active ingredients are often encapsulated as they are without being dispersed in the oil.
- the form of the active ingredient in that case is not limited to the above-mentioned powder form and liquid form, but may be a gel form, a granule form, a tablet form, a pellet form, or a mixture thereof.
- corn starch, dextrin, etc. are blended as excipients, and sucrose fatty acid esters, It is possible to blend calcium phosphate, magnesium stearate and the like.
- the first component of the base of the capsule film is gelatin, and in the present invention, it occupies most of the content, so it can be said that the capsule film is gelatin-based.
- Gelatin is derived from collagen, which is the main protein component of skin, bones, tendons, etc. of cows, sheep, pigs, chickens, or fish, etc. Although it is easy to obtain as an industrial raw material, the origin is not particularly limited.
- Gelatin is a modified collagen obtained by treating the above-mentioned raw materials with acid or alkali and then extracting with warm water. There are acid treatment and alkali treatment in the treatment method. The use of alkali-treated gelatin is intended, and acid-treated gelatin is not intentionally included. The alkali treatment is usually performed by lime treatment, but is not particularly limited. Incidentally, gelatin has been used for a long time as a base for capsule films, but gelatin that has actually been distributed in the market in terms of price is an acid-treated one. There is almost no mention of the processing contents of gelatin in the notation of the material of the product, but if it remains in the notation of “gelatin”, it is acid-treated gelatin. Therefore, the use of alkali-processed gelatin is by no means common sense.
- Gelatin maintains its “gelling ability” regardless of acid treatment or alkali treatment, but is an ampholyte containing both acidic and basic amino acids. Since acid-treated gelatin has a low deamidation rate, the isoelectric point is collagen. Since the number of deamidation differs from molecule to molecule, the isoelectric point distribution is broad. On the contrary, most of the alkali-treated gelatin has been deamidated, so that most of it has an isoelectric point of around 5, and the degree of deamidation for each molecule is uniform and has a sharp isoelectric point distribution.
- the isoelectric point of gelatin as used in the present invention refers to the pH indicated when salt ions are completely removed from a gelatin solution, that is, the isoionic point.
- the pH of human gastric fluid is generally about 1, and the pH of intestinal fluid is about 7. Therefore, in the gastric juice having a low pH, the alkali-treated gelatin is positively (+) charged. On the other hand, in the intestinal juice having a high pH, the alkali-treated gelatin is negatively charged ( ⁇ ).
- the property of charge change of the alkali-treated gelatin in the gastric environment to the intestinal environment is utilized.
- the second component of the capsule film base is carrageenan.
- Carrageenan is a kind of galactan having a sulfate group (SO3-group) and is known to exist in red algae.
- Carrageenans can be classified into three types, ⁇ (kappa) carrageenan, ⁇ (iota) carrageenan, and ⁇ (lambda) carrageenan, depending on the difference in structure and gelation properties. It has one, two, three (SO3-groups). Due to the presence of sulfate ester, carrageenan is always negatively charged (-) in liquids of all pH values. That is, even if the environment changes from the stomach environment to the intestinal environment, carrageenan is always negatively charged (-).
- one sulfate group (SO3-) has one ⁇ (kappa) carrageenan and one sulfate group (SO3-).
- Two ⁇ (Iota) carrageenans have gelling ability, but ⁇ (lambda) carrageenan with three sulfate groups (SO3 ⁇ ) has no gelling ability.
- the above-mentioned properties of carrageenan are utilized and coexist as a compatibility with the alkali-treated gelatin mainly serving as a coating substrate. Therefore, in an intragastric (aqueous) environment, plus (+) charged alkali-processed gelatin coexists with minus (-) charged carrageenan, and the amino group (NH4 +) of gelatin is the carrageenan sulfate group ( Reacts with SO3-) to insolubilize.
- ⁇ carrageenan As described above, there are various types of carrageenan, but in the present invention, it is recommended to use ⁇ carrageenan alone or in combination. Since ⁇ carrageenan has no gelling ability, it suppresses the increase in the gelation temperature of the coating solution prepared by capsule formulation, ensuring the suitability for filling, and improving the disintegration property in the intestinal environment to increase the speed of the coating. It is expected to make it possible to dissolve. When two or more types of carrageenan are used in combination, a blend raw material that has been mixed in advance can also be used. Each carrageenan may be a pure product or may contain a standardized substance. Examples of the standardizing substance include one or more selected from the group consisting of saccharides such as sucrose, glucose, maltose, and lactose, and dextrin.
- carrageenan 1 to 20 parts by weight is preferable with respect to 100 parts by weight of alkali-treated gelatin because of insolubilization and dissolution of the film due to charging. If it is within this range, the charging effect of carrageenan can be substantially obtained, while it is easy to ensure filling suitability by suppressing the increase in viscosity due to the addition of carrageenan, which is a kind of thickening polysaccharide. .
- carrageenan is a kind of thickening polysaccharide
- other thickening polysaccharides include xanthan gum, galactomannan (LBG), pectin, sodium alginate and the like.
- LBG galactomannan
- pectin sodium alginate
- these are the purpose of preventing capsule film adhesion and capsule deformation due to temperature changes during storage and distribution, i.e. improving heat resistance, preventing adhesion in the oral cavity and esophagus, improving ease of swallowing, improving tongue touch
- it may be added conventionally for other purposes, but it leads to an increase in the viscosity of the coating solution. Therefore, especially when carrageenan is included on the coating side, the above-mentioned purpose is naturally achieved.
- thickening polysaccharides other than carrageenan it is preferable not to include thickening polysaccharides other than carrageenan.
- non-gelatin type such as hydroxypropylmethylcellulose (HPMC), starch, agar, etc. is also used, but this is also purposely in order not to reduce the relative amount of gelatin. It is preferable not to mix.
- the capsule film of the present invention includes plasticizers such as glycerin and sorbitol necessary for capsule formulation, and further, if necessary, colorants, preservatives, sweeteners, etc. Is blended.
- Capsule formulation method On the capsule film side, the above-mentioned capsule film substrate is dissolved in water and stirred to make a homogeneous film solution. Then, the capsule contents are filled and encapsulated and molded into a capsule.
- Capsule types include soft capsules, seamless capsules, and hard capsules, each of which has its own characteristics, but any of these can be formulated by processing in the same manner as existing gelatin capsules.
- the entericity-imparting agent is included on the film side, but it is not limited to this and may be included on the encapsulating side.
- the active ingredient that you want to release in the stomach is included in the film side and dissolved in the stomach, and the active ingredient that you want to release in the intestine is enteric.
- capsules that are included in the capsule contents and dissolved in the intestine are conceivable. Note that the active ingredient desired to be released in the stomach and the active ingredient desired to be released in the intestine are not necessarily different.
- the capsule includes a multiple capsule and a single sphere capsule, and these are also included in the scope of the present invention.
- one or more intermediate layers and capsule contents are on the encapsulating side, and it is conceivable that an entericity-imparting agent is included on these encapsulating sides.
- the active ingredient that is desired to be released in the stomach cannot be contained on the side of the film, so that the film is dissolved in the stomach, and the film is dissolved in the stomach. It can be configured to be stripped.
- the intermediate layer contains the entericity-imparting agent, and separately from it, the active ingredient is contained in the core.
- the intermediate layer can be dissolved in the intestine to release the contents. Since multiple capsules can be formulated as a kind of seamless capsules by a conventional method, such multiple capsules as described above are feasible.
- the capsule film and the capsule contents are composed of the same formulation, and there is no distinction. If only the active ingredient desired to be absorbed in the intestine is focused on and can be included in the capsule film together with the entericity-imparting agent, it is possible to adopt the form of this single sphere capsule.
- Example 1 The following was carried out for verification of the capsule film. With various film compositions, it was placed in water at 85 ° C. and stirred for 10 minutes to dissolve in water to prepare a uniform film solution. Viscosity is the result of measurement with a rotational viscometer (VISCOMETER made by BROOKFIELD). The evaluation criteria for the filling suitability of the coating solution were as follows. ⁇ Evaluation criteria ⁇ : Yield 90% or more when filling ⁇ : Yield 70% or more when filling ⁇ : Fillable ⁇ : Cannot be filled
- the enteric test is based on the Japanese Pharmacopoeia No. 16 and the Japanese Pharmacopoeia No. 1 fluid (artificial gastric juice) and the Japanese Pharmacopoeia No. 2 fluid (artificial intestinal fluid) for the capsule formulation as follows. It is a dissolution test carried out using this.
- ⁇ Soft capsule> By rotary rotary punching method, oval type No. 6 (film weight: 165 mg, contents weight: 300 mg) capsules were prepared.
- the enteric evaluation criteria were as follows based on the 16th Japanese Pharmacopoeia. (One liquid) ⁇ : 6 capsules do not collapse for 120 minutes ⁇ : 4 or 5 of 6 capsules do not collapse ⁇ 16 or more out of 18 capsules do not collapse for 120 minutes ⁇ : 4 or 5 of 6 capsules do not collapse ⁇ 2 or more of 18 disintegrations in retesting ⁇ : Immediate start of dissolution (two liquids) ⁇ : All 6 capsules disintegrate within 60 minutes ⁇ : 4 or 5 of 6 capsules disintegrate ⁇ Retested to disintegrate 16 to 18 within 18 minutes within 120 minutes ⁇ : 4 of 6 capsules or 5 collapsing / No more than 2 out of 18 in retesting ⁇ : Not collapsing within 60 minutes
- Samples 1 to 6 (invention) shown in Table 1 were prepared by coexisting alkali-treated gelatin and carrageenan, satisfying filling suitability at an appropriate viscosity and satisfying suitability for enteric properties.
- the enteric test (part 2) of sample 6 (containing ⁇ carrageenan) showed good results and was completely dissolved.
- Sample 6-A capsule content containing potassium chloride
- Sample 6-B capsule content containing calcium lactate
- Samples 6-A and 6-B contain divalent and monovalent cations in the capsule contents, and the mass of MCT is reduced by that amount, but the rest is the same as Sample 6 It is configured. Samples 6-A and 6-B also showed results comparable to Sample 6. From this, it was confirmed that even if a divalent or monovalent cation was present, there was no adverse effect.
- Samples 7 to 10 (Comparative Examples) shown in Table 2 are those containing thickening polysaccharides other than carrageenan, which unnecessarily increases the viscosity and deteriorates the filling ability. Also, the characteristics of gelatin as an ampholyte was not used, and it was completely dissolved in the enteric test (1 liquid).
- Samples 11 to 14 (invention) described in Table 3 are obtained by adding other thickening polysaccharides to ⁇ carrageenan, and the filling suitability is reduced due to the increase in viscosity.
- (1 liquid) In the case of (2 liquids), a slightly undissolved residue was generated.
- Samples 15 to 20 (Comparative Examples) shown in Table 4 were formulated with acid-treated gelatin instead of alkali-treated gelatin.
- positive (+) charged acid-treated gelatin was used.
- Samples 21 to 30 (invention) shown in Table 5 were prepared by variously setting the amount of ⁇ carrageenan, and showed a high level of entericity when the amount added was 1.0 part by mass or more. .
- Samples 31 to 34 (invention) shown in Table 6 were obtained by using two types of carrageenan in combination, and those using ⁇ carrageenan in combination with ⁇ carrageenan or ⁇ carrageenan provided a sufficient blending effect of ⁇ carrageenan.
- the increase in viscosity at the stage of the coating solution was suppressed to show a high level of filling suitability and a high level of entericity.
- Example 2 The enteric test was carried out on triple layer seamless capsules (film part / intermediate layer / core) having the following formulation.
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Abstract
Description
このような観点から、従来から、種々の腸溶性カプセルが提案されている。
これらの知見に基づいて、新規且つ有用で、上記した課題も解決できる腸溶性カプセルを提案するに至った。
すなわち、本発明の腸溶性カプセルは、カプセル皮膜側またはカプセル皮膜により被包された被包側に、アルカリ処理ゼラチン及びカラギナンを腸溶性付与剤として含有することを特徴とするものである。
好ましくは、カラギナンにはλカラギナンが含まれている。
また、好ましくは、カラギナン以外の増粘多糖類は含まれていない。
なお、カプセル剤の種類には、ソフトカプセル、シームレスカプセル、ハードカプセルがあり、それぞれ、特色があるが、そのいずれにも適用される。
(カプセル内容物)
従来からゼラチン系カプセルの内容物として利用されてきたもの、更にはこれから案出されるもので、ゼラチン系カプセルの内容物に適用できるものは、全て、本発明のカプセル内容物として適用される。
カプセル内容物は、ソフトカプセルやシームレスカプセルの場合には、油脂を基剤とし、そこに粉末状乃至液状の有効成分が含まれたものが典型的なものとなっているが、この油脂の例としては、大豆油、オリ-ブ油、小麦胚芽油等の植物油、中鎖脂肪酸トリグリセリド(MCT)、またミツロウ、モノアシルグリセリン(モノグリ)をはじめとする常温付近で固体の牛脂、豚脂あるいはカカオ脂等の油脂類、あるいはこれらの混合物が挙げられる。
有効成分の種類としては、用途が経口医薬品の場合は、例えば、気管支拡張剤、アレルギー用薬等の薬剤成分が挙げられ、食品の場合には、例えば、ドコサヘキサエン酸、各種ビタミン類、各種エキス粉末等の機能性成分が挙げられる。なお、油溶性に関しては、易油溶性だけでなく、分散性が担保されるならば、難油溶性でもよい。
カプセル皮膜の基剤の第一成分はゼラチンであり、本発明では、含有量の大部分を占めることから、カプセル皮膜はゼラチン系であると言える。
ゼラチンは、牛、羊、豚、鶏、あるいは魚等の皮、骨、腱などの主タンパク成分であるコラーゲンを由来原料としたものであり、牛骨、牛皮又は豚皮を原料としたゼラチンが工業原料として入手し易くなっているが、由来は特に限定されない。
なお、アルカリ処理は、通常は、石灰処理により行われるが、特に限定されない。
因みに、カプセル皮膜の基剤としてゼラチンは古くから用いられているが、価格面から市場で実際に流通してきたゼラチンは酸処理したものである。商品の材料の表記には、ゼラチンの処理内容まで言及したものは殆ど無いが、「ゼラチン」の表記に留まっていれば、酸処理ゼラチンである。従って、アルカリ処理ゼラチンの使用は常識的なことでは決してない。
人間の胃液のpHは一般的には約1、腸液のpHは約7である。従って、pHの低い胃液内では、アルカリ処理ゼラチンはプラス(+)に帯電する。一方、pHの高い腸液内では、アルカリ処理ゼラチンはマイナス(-)に帯電する。本発明では、この胃内環境~腸内環境でのアルカリ処理ゼラチンの帯電変化の性質を利用している。
カラギナンは、硫酸基(SO3-基)をもつガラクタンの一種であり、紅藻類に存在していることが知られている。カラギナンは、構造の違いやゲル化特性により、主にκ(カッパ)カラギナン、ι(イオタ)カラギナン、λ(ラムダ)カラギナンの3種類に分類でき、ガラクトース基2つに対して、それぞれ、硫酸基(SO3-基)を1つ、2つ、3つ有している。硫酸エステルの存在により、あらゆるpH値の液中においてカラギナンは常にマイナス(-)帯電する。すなわち、胃内環境~腸内環境と環境が変わっても、カラギナンは常にマイナス(-)帯電する。
従って、胃内(水性)環境では、プラス(+)に帯電したアルカリ処理ゼラチンに、マイナス(-)に帯電したカラギナンが共存することになり、ゼラチンのアミノ基(NH4+)がカラギナンの硫酸基(SO3-)と反応して不溶化する。
一方、腸内(水性)環境では、マイナス(-)に帯電したアルカリ処理ゼラチンに、マイナス(-)に帯電したカラギナンが共存することになり、ゼラチンのアミノ基(NH4+)はカラギナンの硫酸基(SO3-)に対して反発するので、速やかに崩壊乃至溶解する。
カラギナンは、それぞれ純粋品でもよいし、標準化物質を含んだものも利用することができる。標準化物質としては、ショ糖、ブドウ糖、マルトース、乳糖等の糖類及びデキストリンからなる群から選ばれた1種又は2種以上が挙げられる。
また、造膜剤としては、ゼラチンの他に、ヒドロキシプロピルメチルセルロース(HPMC)、澱粉、寒天など非ゼラチン系もあるが、ゼラチンの相対的配合量を低下させないためにも、こちらも意図的には配合させないことが好ましい。
カプセル皮膜側は、上記したカプセル皮膜基材を共に水に溶解させ撹拌させて均質な皮膜溶液とする。そして、カプセル内容物を充填・封入すると共に成形して、カプセル剤に製剤化する。
カプセル剤の種類には、ソフトカプセル、シームレスカプセル、ハードカプセルがあり、それぞれ、特色があるがそのいずれにも、既存のゼラチン系カプセルと同様に処理することで製剤化できる。
例えば、胃と腸の両方でそれぞれ放出させたい有効成分が有る場合、胃で放出させたい有効成分を皮膜側に含ませて胃内で溶解させ、腸で放出させたい有効成分を腸溶性付与剤と共にカプセル内容物側に含ませて腸内で溶解させるカプセル剤が考えられる。
なお、胃で放出させたい有効成分と腸で放出させたい有効成分は必ずしも別とは限らない。例えば(ある)有効成分の血中濃度を持続させたい場合には、有効成分を胃と腸の両方で放出させたいが、その有効成分を皮膜側と被包側の両方に含ませた構成にすることで、有効成分を胃で全て放出させずに残りを確実に腸までもってきて腸で放出させることができる。
多重カプセルでは、1以上の中間層とカプセル内容物(芯乃至核)が被包側になっており、これら被包側に腸溶性付与剤を含ませることが考えられる。多重カプセルにすれば、胃で放出させたい有効成分を皮膜側に含ませることができない場合に、皮膜寄りの中間層に含ませて、皮膜を胃内で溶解し、その中間層を胃内で剥きだしにする構成にできる。また、腸で放出させたい有効成分についても、同様に、カプセル内容物に腸溶性付与剤と共に含ませることができない場合に、中間層に腸溶性付与剤を含ませ、それとは別に核に有効成分を含ませておき、その中間層を腸内で溶解し、その内容物を放出させる構成にできる。
多重カプセルはシームレスカプセルの一種として定法により製剤化できるので、上記のような多重カプセルは実現可能なものである。
腸で吸収させたい有効成分のみに着目し、腸溶性付与剤と共にカプセル皮膜に含ませることができるのであれば、この単一球カプセルの形態を採用することも考えられる。
以下は、カプセル皮膜の検証のために実施したものである。
各種皮膜組成で、85℃の水に入れ、10分間攪拌させることで水に溶解させて均質な皮膜溶液を作製した。
粘度は回転粘度計(BROOKFIELD製VISCOMETER)による測定結果である。
皮膜溶液の充填適性の評価基準は以下の通りとした。
〔評価基準〕
◎:充填時歩留まり90%以上
○:充填時歩留まり70%以上
△:充填可能
×:充填不可
<ソフトカプセル>
ロータリー式回転打ち抜き法により、オーバル型No.6(皮膜重量:165mg、内容物重量:300mg)のMCT充填カプセルを製造した。
<シームレスカプセル>
液中滴下法により、長径:約6mmΦ(皮膜重量:20mg、内容物重量:100mg)のMCT充填カプセルを製造した。
<ハードカプセル>
浸漬法により、ハードカプセル1号(空カプセル重量:約78mg)の空カプセルを製造した。その後に、コーンスターチを充填した。
(一液)
◎:6カプセル全て120分崩壊なし
○:6カプセルのうち4個又は5個崩壊なし・再試験にて18個中16個以上120分崩壊なし
△:6カプセルのうち4個又は5個崩壊なし・再試験にて18個中2個以上の崩壊がある
×:直ぐに溶出開始
(二液)
◎:6カプセル全て60分以内に崩壊する
○:6カプセルのうち4個又は5個崩壊し・再試験にて18個中16個以上120分以内に崩壊する
△:6カプセルのうち4個又は5個崩壊し・再試験にて18個中2個以上の崩壊しない
×:60分以内に崩壊しない
特に、検体6(λカラギナンを配合)の腸溶性試験(2液)結果が良く、完全に溶解していた。
また、検体6との比較用に、検体6-A(カプセル内容物に塩化カリウムを配合)、検体6-B(カプセル内容物に乳酸カルシウムを配合)についても試験を行った。検体6-A、6-Bは、カプセル内容物中に二価・一価の陽イオンが含まれており、その分だけMCTの質量分が減っているが、それ以外は、検体6と同じ構成になっている。検体6-A、6-Bも、検体6に対して遜色ない結果を示した。これから、二価・一価の陽イオンが存在しても、悪影響は無いことが確認された。
Claims (6)
- カプセル皮膜側またはカプセル皮膜により被包された被包側に、アルカリ処理ゼラチン及びカラギナンを腸溶性付与剤として含有し、アルカリ処理ゼラチン以外のゼラチンを含有せず、且つ、カラギナンと結合するカウンターイオンを含有しないことを特徴とするゼラチン系腸溶性カプセル。
- 請求項1に記載した腸溶性カプセルにおいて、
カラギナンにはλカラギナンが含まれていることを特徴とする腸溶性カプセル。 - 請求項2に記載した腸溶性カプセルにおいて、
腸溶性付与剤としては、カラギナン以外の増粘多糖類は含まれていないことを特徴とする腸溶性カプセル。 - 請求項1から3のいずれかに記載した腸溶性カプセルにおいて、
ソフトカプセル、シームレスカプセルまたはハードカプセルであることを特徴とする腸溶性カプセル。 - 請求項1から3のいずれかに記載した腸溶性カプセルにおいて、
ソフトカプセルまたはシームレスカプセルであることを特徴とする腸溶性カプセル。 - 請求項4または5に記載した腸溶性カプセルにおいて、
被包側に、アルカリ処理ゼラチン及びカラギナンが腸溶性付与剤として含まれていることを特徴とする腸溶性カプセル。
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CN201680046664.9A CN107921142B (zh) | 2015-08-19 | 2016-08-10 | 肠溶胶囊 |
DK16837062.5T DK3338804T3 (da) | 2015-08-19 | 2016-08-10 | Enterisk kapsel |
US15/748,140 US10493036B2 (en) | 2015-08-19 | 2016-08-10 | Enteric capsule |
KR1020187003864A KR102519593B1 (ko) | 2015-08-19 | 2016-08-10 | 장용성 캡슐 |
EP16837062.5A EP3338804B1 (en) | 2015-08-19 | 2016-08-10 | Enteric capsule |
SG11201800516TA SG11201800516TA (en) | 2015-08-19 | 2016-08-10 | Enteric capsule |
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EP3764973A4 (en) * | 2018-03-15 | 2022-01-05 | R.P. Scherer Technologies, LLC | STOMACH-RESISTANT SOFT GEL CAPSULES |
RU2815635C2 (ru) * | 2018-03-15 | 2024-03-19 | Р.П. Шерер Текнолоджиз, Ллк | Энтеросолюбильные капсулы из мягкого желатина |
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CN107296801B (zh) * | 2017-08-09 | 2020-03-17 | 安徽黄山胶囊股份有限公司 | 一种羟丙基甲基纤维素植物空心胶囊 |
JP2023521322A (ja) | 2020-04-03 | 2023-05-24 | ループオキシー・セラピューティクス・インコーポレイテッド | 腸酸素化治療 |
WO2021210683A1 (ja) * | 2020-04-17 | 2021-10-21 | 三生医薬株式会社 | 耐熱性カプセル及びそれを含む飲食品 |
EP4398876A1 (en) * | 2021-09-29 | 2024-07-17 | Lpoxy Therapeutics, Inc. | Enteric aerobization therapy |
WO2024080269A1 (ja) * | 2022-10-11 | 2024-04-18 | アリメント工業株式会社 | 咀嚼性ソフトカプセル剤 |
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JP5878669B1 (ja) | 2016-03-08 |
US10493036B2 (en) | 2019-12-03 |
CN107921142A (zh) | 2018-04-17 |
US20180221288A1 (en) | 2018-08-09 |
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JP2017039657A (ja) | 2017-02-23 |
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PH12018500228B1 (en) | 2018-08-13 |
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