JP4341835B2 - Capsule storage container and storage method - Google Patents
Capsule storage container and storage method Download PDFInfo
- Publication number
- JP4341835B2 JP4341835B2 JP2004117721A JP2004117721A JP4341835B2 JP 4341835 B2 JP4341835 B2 JP 4341835B2 JP 2004117721 A JP2004117721 A JP 2004117721A JP 2004117721 A JP2004117721 A JP 2004117721A JP 4341835 B2 JP4341835 B2 JP 4341835B2
- Authority
- JP
- Japan
- Prior art keywords
- capsule
- substance
- sealed
- aldehyde group
- polyoxyethylene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000002775 capsule Substances 0.000 title claims description 99
- 238000000034 method Methods 0.000 title claims description 44
- 238000003860 storage Methods 0.000 title claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 70
- 239000001301 oxygen Substances 0.000 claims description 70
- 229910052760 oxygen Inorganic materials 0.000 claims description 70
- -1 polyoxyethylene cetyl ether Polymers 0.000 claims description 60
- 239000000126 substance Substances 0.000 claims description 42
- 125000003172 aldehyde group Chemical group 0.000 claims description 35
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 30
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 27
- 108010010803 Gelatin Proteins 0.000 claims description 24
- 229920000159 gelatin Polymers 0.000 claims description 24
- 235000019322 gelatine Nutrition 0.000 claims description 24
- 235000011852 gelatine desserts Nutrition 0.000 claims description 24
- 239000008273 gelatin Substances 0.000 claims description 20
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 17
- 238000004806 packaging method and process Methods 0.000 claims description 17
- 238000011049 filling Methods 0.000 claims description 13
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 12
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- 239000002250 absorbent Substances 0.000 claims description 11
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- 238000000576 coating method Methods 0.000 claims description 7
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- 150000005846 sugar alcohols Polymers 0.000 claims description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical class C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical class CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 4
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- 229910052782 aluminium Inorganic materials 0.000 description 8
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- 239000006096 absorbing agent Substances 0.000 description 3
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 3
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- 229920002261 Corn starch Polymers 0.000 description 2
- IROWCYIEJAOFOW-UHFFFAOYSA-N DL-Isoprenaline hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(O)C(O)=C1 IROWCYIEJAOFOW-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
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- 229930006000 Sucrose Natural products 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
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- 150000001299 aldehydes Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
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- 230000003115 biocidal effect Effects 0.000 description 2
- CRPUJAZIXJMDBK-UHFFFAOYSA-N camphene Chemical compound C1CC2C(=C)C(C)(C)C1C2 CRPUJAZIXJMDBK-UHFFFAOYSA-N 0.000 description 2
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- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 2
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- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
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Description
本発明は、カプセル剤の充填物及びカプセル剤皮の処方変更を必要としない、カプセル剤の剤皮の溶解性の悪化を防止するためのカプセル剤の保存容器並びに保存方法に関する。 The present invention relates to a capsule storage container and a storage method for preventing deterioration of the solubility of a capsule shell, which does not require a change in the formulation of the capsule filling and the capsule shell.
カプセル剤は、医薬品の経口固形製剤の中でも、不快な味や臭いのマスキングが容易、製造工程における単位操作が少なく製剤設計が容易、カラーコントロールによる識別性が容易などの理由により広く普及されている剤型である。 Capsules are widely used because of their ease of masking unpleasant taste and odor, ease of unit design in the manufacturing process, easy formulation design, and easy identification by color control. It is a dosage form.
また、薬効成分の様々な放出特性を制御することが可能であり、腸溶性製剤や徐放性製剤とするためにカプセルに充填する顆粒やカプセル本体に対し種々の高分子をコーティングするなどの方法が一般的に取られている。また水に対し難溶性の薬効成分を速やかに溶出させるためにプロピレングリコール、ポリエチレングリコール、ポリソルベート、その他各種ポリオキシエチレン類などを添加する方法も取られている。 In addition, it is possible to control various release characteristics of medicinal ingredients, such as enteric preparations and sustained release preparations, such as coating capsules with granules and capsules with various polymers. Is generally taken. In addition, a method of adding propylene glycol, polyethylene glycol, polysorbate, other various polyoxyethylenes, etc. is also taken in order to quickly elute a medicinal component that is hardly soluble in water.
しかし、カプセル本体を構成するゼラチンは充填物中のアルデヒド基を有する物質又は薬効成分や前記添加剤などから経時的に産生されるアルデヒド類などにより、ゼラチンの分子内又は分子間で架橋や重合を形成し、カプセル剤皮が経時的に不溶化することによって薬効成分の溶出性が悪化しうることが知られている(非特許文献1参照)。従来、このような問題を解決する手段として、カプセル内容物の処方を検討する方法が取られている。例えば特許文献1にはゼラチンカプセル剤の内容物に蛋白質類、アミノ酸類、アミノ基含有の物質、抗酸化剤、リン酸水素ナトリウム等より1種以上を添加する方法が開示されている。特許文献2には、充填物中にフリーラジカル捕獲剤を含有させる方法が開示され、特許文献3にはカプセル充填物中にアミノ酢酸を含有させる方法が開示されている。しかし、前記の方法で用いられる添加剤は、同じく充填物中に含有される薬効成分と配合変化を起こし、含量及び力価低下の原因となり問題である。また医薬品の開発途中又は上市後において前記のようなカプセル充填物に添加剤を加える方法即ち処方変更に関わるような方法は、処方変更前後の製剤について生物学的同等性を証明するための各種試験が必要であり(非特許文献2参照)、製造メーカーに対し多大な負担を強いることになる。また他の手段として、カプセル剤皮の材質をゼラチン以外のものにする方法が取られている。例えば、特許文献4にはアルキル基およびヒドロキシアルキル基、またはヒドロキシアルキル基で置換されたセルロースエーテルを基剤として、これにゲル化剤およびゲル化補助剤を配合してなる医薬用硬質カプセルについて開示されているが、内容物が低粘度の液体は充填できないなど、ゼラチンカプセルに比べ選択できる充填物の許容範囲が狭いという問題がある。 However, gelatin constituting the capsule body is cross-linked or polymerized within or between gelatin molecules by aldehydes produced over time from substances having aldehyde groups in the filling or medicinal ingredients and the aforementioned additives. It is known that the dissolution of the medicinal component may be deteriorated by forming and insolubilizing the capsule skin over time (see Non-Patent Document 1). Conventionally, as a means for solving such a problem, a method of examining the prescription of capsule contents has been taken. For example, Patent Document 1 discloses a method in which one or more kinds of proteins, amino acids, amino group-containing substances, antioxidants, sodium hydrogen phosphate and the like are added to the contents of gelatin capsules. Patent Document 2 discloses a method of incorporating a free radical scavenger in the filling, and Patent Document 3 discloses a method of incorporating aminoacetic acid in the capsule filling. However, the additive used in the above-described method causes a change in formulation with a medicinal component contained in the filler, causing a problem of content and titer reduction. In addition, the method of adding an additive to the capsule filling as described above during the development or after the launch of the drug, that is, the method involving the change of the formulation, is a variety of tests for proving the bioequivalence of the product before and after the change of the formulation. (Refer to Non-Patent Document 2), which places a heavy burden on the manufacturer. As another means, a method of making the capsule skin other than gelatin is used. For example, Patent Document 4 discloses a hard capsule for medicine comprising a cellulose ether substituted with an alkyl group and a hydroxyalkyl group, or a hydroxyalkyl group as a base, and a gelling agent and a gelling aid added thereto. However, there is a problem that the allowable range of fillings that can be selected is narrower than that of gelatin capsules, such that the liquid cannot be filled with low-viscosity contents.
また、大気中の酸素による薬効成分の分解・変質を防止するために、保存容器内の酸素濃度を減少させて薬剤を保存する方法が用いられることがある。例えば、特許文献5には易酸化物質の溶液を酸素透過性プラスチック容器に充填、密栓し、脱酸素剤と共に酸素非透過性包囲体により密封又は気密する方法について開示されている。また、特許文献6には個体単位剤形の酸素感受性薬剤と少なくとも一つの酸素吸収体とをその中に入れた酸素透過性の密封又は気密容器を含む医薬キットに関する方法が開示されている。しかしいずれの方法も薬効成分が易酸化性又は酸素感受性であるものについてそれらの分解による含量低下を防止する目的で酸素吸収剤又は脱酸素剤を用いる方法である。 In addition, in order to prevent decomposition and alteration of medicinal components due to oxygen in the atmosphere, a method of storing the drug by reducing the oxygen concentration in the storage container may be used. For example, Patent Document 5 discloses a method of filling an oxygen-permeable plastic container with a solution of an easily oxidizable substance, sealing it, and sealing or air-tightening it with an oxygen-impermeable envelope together with an oxygen scavenger. Patent Document 6 discloses a method relating to a pharmaceutical kit including an oxygen-permeable sealed or airtight container in which an oxygen-sensitive drug in an individual unit dosage form and at least one oxygen absorber are contained. However, any of these methods is a method using an oxygen absorbent or an oxygen scavenger for the purpose of preventing content degradation due to decomposition of those medicinal components that are easily oxidizable or oxygen sensitive.
本発明の目的は、カプセル剤皮の不溶化を防止するための手段であり、前記の従来技術より簡便で効果的な方法を提供することである。 An object of the present invention is a means for preventing insolubilization of a capsule skin, and is to provide a simpler and more effective method than the above-described prior art.
本発明者らは前記課題を解決すべく鋭意研究の結果、密封又は気密容器の空間中の酸素濃度を大気中の酸素濃度よりも少なくすることにより、カプセル剤皮の不溶化を改善することをより簡便に、より効果的に達成することができることを見いだし、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have improved the insolubilization of the capsule skin by making the oxygen concentration in the space of the sealed or airtight container smaller than the oxygen concentration in the atmosphere. It was found that it can be achieved simply and more effectively, and the present invention has been completed.
すなわち、本発明は、
(1)剤皮中にゼラチン類を含むカプセル剤を有する密封又は気密容器であって、該カプセル剤の充填物がアルデヒド基を有する物質又は経時的にアルデヒド基を生成する物質であり、該容器内の酸素濃度が大気中の酸素濃度よりも低いことを特徴とする密封又は気密容器、
(2)アルデヒド基を有する物質又は経時的にアルデヒド基を生成する物質が、多価アルコール類、酸化エチレン誘導体、又は酸化プロピレン誘導体である(1)に記載の密封又は気密容器、
(3)アルデヒド基を有する物質又は経時的にアルデヒド基を生成する物質がプロピレングリコール;ポリエチレングリコール(マクロゴール);ポリソルベート;ラウロマクロゴール;ポリオキシエチレンセチルエーテル;セトマクロゴール;ポリオキシエチレン硬化ヒマシ油;ポリオキシエチレンヒマシ油:ポリオキシエチレンステアリルエーテル;ポリオキシエチレンソルビタンモノラウレート;ポリオキシエチレンポリオキシプロピレングリコールからなる群から選ばれる少なくとも1種である(1)又は(2)のいずれか一項に記載の密封又は気密容器、
(4)容器中の酸素濃度が5%以下である(1)乃至(3)のいずれか一項に記載の密封又は気密容器、
(5)カプセル剤と酸素吸収剤を密封若しくは気密容器中に併存していることを特徴とする(4)に記載の密封又は気密容器、
(6)カプセル剤を収納した容器中の空間中の空気が不活性ガスを含有することを特徴とする(4)に記載の密封又は気密容器、
(7)ゼラチン類がゼラチンである(1)乃至(6)のいずれか一項に記載の密封又は気密容器、
(8)剤皮中にゼラチン類を含むカプセル剤の保存方法であって、該カプセル剤の充填物がアルデヒド基を有する物質又は経時的にアルデヒド基を生成する物質であり、該容器内の酸素濃度を大気中の酸素濃度よりも低くすることを特徴とするカプセル剤の保存方法、
(9)アルデヒド基を有する物質又は経時的にアルデヒド基を生成する物質が、多価アルコール類、ポリオキシエチレンエーテル類、又はポリオキシエチレン鎖をその構造に含む化合物である(8)に記載のカプセル剤の保存方法、
(10)アルデヒド基を有する物質又は経時的にアルデヒド基を生成する物質がプロピレングリコール;ポリエチレングリコール(マクロゴール);ポリソルベート;ラウロマクロゴール;ポリオキシエチレンセチルエーテル;セトマクロゴール;ポリオキシエチレン硬化ヒマシ油;ポリオキシエチレンヒマシ油:ポリオキシエチレンステアリルエーテル;ポリオキシエチレンソルビタンモノラウレート;ポリオキシエチレンポリオキシプロピレングリコールからなる群から選ばれる少なくとも1種である(8)又は(9)のいずれか一項に記載のカプセル剤の保存方法、
(11)容器中の酸素濃度が5%以下である(8)乃至(10)のいずれか一項に記載のカプセル剤の保存方法、
(12)カプセル剤と酸素吸収剤を密封若しくは気密容器中に併存させることを特徴とする(11)に記載のカプセル剤の保存方法、
(13)カプセル剤を収納した容器中の空間中の空気に不活性ガスを含有させることを特徴とする(11)に記載のカプセル剤の保存方法、
(14)ゼラチン類がゼラチンである(8)乃至(13)のいずれか一項に記載のカプセル剤の保存方法、
に関する。
That is, the present invention
(1) A sealed or airtight container having a capsule containing gelatins in a coating, wherein the filling of the capsule is a substance having an aldehyde group or a substance that generates an aldehyde group over time, and the container A sealed or airtight container, characterized in that the oxygen concentration inside is lower than the oxygen concentration in the atmosphere,
(2) The sealed or airtight container according to (1), wherein the substance having an aldehyde group or the substance that generates an aldehyde group over time is a polyhydric alcohol, an ethylene oxide derivative, or a propylene oxide derivative,
(3) A substance having an aldehyde group or a substance that generates an aldehyde group over time is propylene glycol; polyethylene glycol (macrogol); polysorbate; lauromacrogol; polyoxyethylene cetyl ether; cetomacrogol; (1) or (2) which is at least one selected from the group consisting of oil; polyoxyethylene castor oil: polyoxyethylene stearyl ether; polyoxyethylene sorbitan monolaurate; polyoxyethylene polyoxypropylene glycol A sealed or airtight container according to paragraph 1,
(4) The sealed or airtight container according to any one of (1) to (3), wherein the oxygen concentration in the container is 5% or less,
(5) The sealed or airtight container according to (4), wherein the capsule and the oxygen absorbent coexist in a sealed or airtight container,
(6) The sealed or airtight container according to (4), wherein the air in the space in the container containing the capsule contains an inert gas,
(7) The sealed or airtight container according to any one of (1) to (6), wherein the gelatin is gelatin.
(8) A method for preserving a capsule containing gelatin in the coating, wherein the capsule filling is a substance having an aldehyde group or a substance that generates an aldehyde group over time, and oxygen in the container A method of storing capsules, characterized in that the concentration is lower than the oxygen concentration in the atmosphere
(9) The substance according to (8), wherein the substance having an aldehyde group or a substance that generates an aldehyde group over time is a compound containing a polyhydric alcohol, a polyoxyethylene ether, or a polyoxyethylene chain in its structure. How to store capsules,
(10) A substance having an aldehyde group or a substance that generates an aldehyde group over time is propylene glycol; polyethylene glycol (macrogol); polysorbate; lauromacrogol; polyoxyethylene cetyl ether; cetomacrogol; (8) or (9) which is at least one selected from the group consisting of oil; polyoxyethylene castor oil: polyoxyethylene stearyl ether; polyoxyethylene sorbitan monolaurate; polyoxyethylene polyoxypropylene glycol A method for storing a capsule according to one item,
(11) The method for storing a capsule according to any one of (8) to (10), wherein the oxygen concentration in the container is 5% or less,
(12) The method for preserving a capsule according to (11), wherein the capsule and the oxygen absorbent coexist in a sealed or airtight container,
(13) The method for preserving a capsule according to (11), wherein an inert gas is contained in the air in the space of the container containing the capsule,
(14) The method for storing a capsule according to any one of (8) to (13), wherein the gelatin is gelatin.
About.
本発明により、カプセル剤皮の不溶化を防止することができ、カプセル剤内の充填物及びカプセル剤皮の処方変更を必要としない、より簡便で効果的なカプセル剤の保存容器及び保存方法を提供することができる。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a simpler and more effective capsule storage container and storage method that can prevent insolubilization of the capsule skin and do not require a change in the formulation of the filler and capsule skin in the capsule. can do.
本発明において酸素濃度を通常状態よりも少なくする、とは大気中の酸素濃度20.8%よりもカプセル剤の入った容器内に存在する気体中の酸素濃度を低くすることをいう。 In the present invention, to make the oxygen concentration lower than the normal state means to lower the oxygen concentration in the gas existing in the container containing the capsule than the oxygen concentration in the atmosphere of 20.8%.
本発明においてカプセル剤とは、カプセル剤皮に充填物が充填されたものをいう。本発明では、カプセル剤皮に含まれるゼラチンがカプセル剤の充填物により分子内又は分子間で架橋や重合を形成し、カプセル剤皮が不溶化することを防止するために、例えば、カプセル剤と酸素吸収剤又は脱酸素剤を併存させた密封又は気密容器、及びカプセル剤と酸素吸収剤又は脱酸素剤を密封又は気密容器に併存させることを特徴とするカプセル剤の保存方法が提供される。本発明においてカプセル剤皮が不溶化する原因となる物質はアルデヒド基を有する物質又は経時的にアルデヒド基を生成する物質をいう。 In the present invention, the capsule refers to a capsule filled with a filler. In the present invention, in order to prevent gelatin contained in the capsule shell from forming a cross-link or polymerization within the molecule or between the molecules by the capsule filler and insolubilizing the capsule shell, for example, the capsule and oxygen Provided is a sealed or airtight container in which an absorbent or oxygen scavenger coexists, and a capsule storage method characterized by coexisting a capsule and an oxygen absorbent or oxygen scavenger in a sealed or airtight container. In the present invention, the substance that causes the capsule skin to become insoluble refers to a substance having an aldehyde group or a substance that generates an aldehyde group over time.
本発明に用いられるカプセル剤とは、その剤皮中にゼラチン類をわずかでも含有するものであれば、特に限定されない。例えば一般的にカプセル剤は硬カプセル剤と軟カプセル剤に分類されるが、いずれも本発明で用いられるカプセル剤に含まれる。またゼラチン類とは、例えば、いわゆるゼラチン、コハク化ゼラチンのようなゼラチンの一部を化学修飾したもの、又はそれらと他の高分子との組合せなど全て含まれる。 The capsule used in the present invention is not particularly limited as long as it contains even a small amount of gelatin in the coating. For example, capsules are generally classified into hard capsules and soft capsules, both of which are included in the capsules used in the present invention. The gelatins include, for example, all so-called gelatins, those obtained by chemically modifying a part of gelatin such as succinated gelatin, and combinations thereof with other polymers.
本発明に用いられる密封又は気密容器とは、その材料・形状などに限定されるものではないが、容器の一部又は全体が酸素の透過率が低い包装材料により構成されたもの又は、酸素吸収剤を含んだ包装材料により構成されたもので、意図的に開封しない限りにおいては、密封又は気密容器内へ浸入する酸素の量が少ないものが好ましい。酸素の透過率が低い包装材料とは、酸素透過度が200cc/m2・atm・24h以下のものが好ましく、20cc/m2・atm・24h以下のものがより好ましい。酸素の透過率が低い包装材料としては、例えばガラス、アルミ箔、アルミニウム、ブリキ、ティンフリースチールなどの金属類、高密度ポリエチレン、高密度ポリエチレン、延伸ポリエチレン、ナイロン、ポリプロピレン、アイオノマー、セロファン、フッ素樹脂、ポリアミド、ポリエステル、ポリビニルアルコール、ポリ塩化ビニル、ポリ塩化ビニリデン、ポリカーボネート、ポリスチレン、ポリ酢酸ビニル、フッ素樹脂、エチレン−プロピレン共重合体、エチレン−酢酸ビニル共重合体、エチレン−エチルアクリレート共重合体、塩化ビニル−プロピレン共重合体又は塩化ビニリデン−塩化ビニル共重合体などのプラスチック及びそれらの複合体などが含まれる。酸素吸収剤を含んだ包装材料とはポリエチレン、ポリプロピレン、ポリ塩化ビニル等、主に食品や医療用の容器に用いられる包装材料に酸素吸収剤を混合した包装材料である。 The sealed or airtight container used in the present invention is not limited to the material and shape thereof, but a part or the whole of the container is constituted by a packaging material having a low oxygen permeability, or oxygen absorption. As long as it is made of a packaging material containing an agent and is not intentionally opened, a material with a small amount of oxygen entering the sealed or airtight container is preferable. The packaging material with low oxygen permeability preferably has an oxygen permeability of 200 cc / m 2 · atm · 24 h or less, and more preferably 20 cc / m 2 · atm · 24 h or less. Examples of packaging materials with low oxygen permeability include metals such as glass, aluminum foil, aluminum, tin, and tin-free steel, high-density polyethylene, high-density polyethylene, drawn polyethylene, nylon, polypropylene, ionomer, cellophane, and fluororesin , Polyamide, polyester, polyvinyl alcohol, polyvinyl chloride, polyvinylidene chloride, polycarbonate, polystyrene, polyvinyl acetate, fluororesin, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, Plastics such as vinyl chloride-propylene copolymer or vinylidene chloride-vinyl chloride copolymer and composites thereof are included. The packaging material containing an oxygen absorbent is a packaging material obtained by mixing an oxygen absorbent with a packaging material mainly used for food or medical containers such as polyethylene, polypropylene, and polyvinyl chloride.
本発明において、前記密封又は気密容器中の酸素濃度を大気中の酸素濃度よりも少なくする方法は特に限定されないが、例えば、酸素吸収剤を併存させる方法、密封又は気密容器内の気体を不活性ガスで置換する方法、又は密封又は気密容器内を真空にする方法などがあげられる。これらの方法により密封又は気密容器中の酸素濃度を大気中の酸素濃度よりも減少させることに加えて、密封又は気密容器自体の容積を小さくすることも好ましい。カプセル剤と併存させる酸素吸収剤は酸素と結合しやすい物質であれば良いが、安全性の観点から主に食品や医療用の輸液製剤で用いられる脱酸素剤が好ましい。本発明に用いられる脱酸素剤としては、例えば鉄粉などの鉄系脱酸素剤、アスコルビン酸、カテコール又はそれらの塩などの非鉄系脱酸素剤が含まれ、一般に市販されているもので十分である。本発明は、脱酸素剤の形態や併存させる具体的な包装仕様に限定されるものではないが、例えばカプセル剤の大入り包装の場合、カプセル剤が収納されたガラス、プラスチック、金属などの酸素透過性の低い容器又は酸素吸収剤を含んだ包装材料で構成された容器内に市販の脱酸素剤をそのまま投入し、金属やプラスチックなどの蓋材で密栓するか、容器の内層に脱酸素剤をラミネートするか、あるいは蓋材の内側に装着するなどして、カプセル剤と脱酸素剤を併存させれば良い。PTP包装やSP包装などのユニット包装の場合、ポリプロピレン、ポリ塩化ビニル又はポリ塩化ビニリデンなどのプラスチック又はそれらの複合体で構成されるPTP用に成形されたフィルムにカプセル剤を充填し、アルミ箔フィルムなどの適当な蓋材で蒸着されたPTPシートを適当な数量ごとに集積し、さらに集積されたPTPシートと脱酸素剤をアルミピロー包装などの酸素透過性が低い容器に収納し密封するか、あるいは内層に脱酸素剤をラミネートされたアルミピロー包装などの酸素透過性が低い容器に、前記の集積されたPTPシートを収納して密封するか、あるいはPTP用に成形された酸素透過性の低いフィルムの内側又は蓋材の内側に脱酸素剤をラミネートさせることも可能である。脱酸素剤によって酸素濃度又は絶対量を下げる方法は、前記不活性ガス置換方法や真空方法などに比べ、充分量以上の脱酸素剤を併存させることによって、容器内の酸素濃度又は絶対量を下げるだけでなく、容器材質の酸素透過性及び容器のピンホールなどに起因する、容器内に浸入してくる酸素も除去できる点、包装用に特別な設備を必要としない点において優れる。前記不活性ガスとしては、例えば、窒素、ヘリウム又は二酸化炭素などがあげられるが、これらに限定されるものではない。前記の方法によって密封又は気密包装を意図的に開封しない限り、密封又は気密容器内の酸素濃度は5%以下であることが好ましく、さらには2%以下であることがより好ましい。また医薬品の場合、通常3年間の有効期間が設定されるが、本発明で用いられる脱酸素剤の有効期間としては、有効期間の長いものがより好ましいが、短いものであってもカプセル剤の剤皮の溶解性の悪化を防止するという本発明の目的は充分達成される。 In the present invention, a method for reducing the oxygen concentration in the sealed or airtight container to be lower than the oxygen concentration in the atmosphere is not particularly limited. For example, a method of coexisting an oxygen absorbent, a gas in the sealed or airtight container is inert. Examples include a method of replacing with gas, or a method of evacuating a sealed or airtight container. In addition to reducing the oxygen concentration in the sealed or hermetic container to be lower than the oxygen concentration in the atmosphere by these methods, it is also preferable to reduce the volume of the sealed or hermetic container itself. The oxygen absorbent coexisting with the capsule may be any substance that easily binds to oxygen, but from the viewpoint of safety, an oxygen scavenger mainly used in food and medical infusion preparations is preferable. Examples of the oxygen scavenger used in the present invention include iron-based oxygen scavengers such as iron powder, and non-ferrous oxygen scavengers such as ascorbic acid, catechol or salts thereof, and commercially available products are sufficient. is there. The present invention is not limited to the form of the oxygen scavenger or the specific packaging specifications to be coexisted. For example, in the case of a large-capacity packaging of capsules, oxygen such as glass, plastic, and metal in which the capsules are stored. Put a commercially available oxygen scavenger as it is in a container made of a low-permeability container or a packaging material containing an oxygen absorber, and seal it with a lid such as metal or plastic, or remove the oxygen scavenger on the inner layer of the container. The capsule agent and the oxygen scavenger may be coexistent by laminating or attaching to the inside of the lid. In the case of unit packaging such as PTP packaging and SP packaging, a film formed for PTP made of plastic such as polypropylene, polyvinyl chloride or polyvinylidene chloride or a composite thereof is filled with an capsule, and an aluminum foil film PTP sheets deposited with an appropriate lid material such as, etc. are accumulated in appropriate quantities, and the accumulated PTP sheets and oxygen scavenger are stored in a container with low oxygen permeability such as aluminum pillow packaging and sealed, Alternatively, the collected PTP sheet is housed and sealed in a container with low oxygen permeability such as an aluminum pillow package in which an oxygen scavenger is laminated on the inner layer, or the oxygen permeability that is molded for PTP is low. It is also possible to laminate an oxygen scavenger on the inside of the film or the inside of the lid. The method of lowering the oxygen concentration or absolute amount with an oxygen scavenger lowers the oxygen concentration or absolute amount in the container by coexisting a sufficient amount of oxygen scavenger in comparison with the inert gas replacement method or vacuum method. In addition, it is excellent in that oxygen entering the container due to oxygen permeability of the container material and the pinhole of the container can be removed, and that no special equipment is required for packaging. Examples of the inert gas include, but are not limited to, nitrogen, helium, carbon dioxide, and the like. Unless the sealed or airtight package is intentionally opened by the above method, the oxygen concentration in the sealed or airtight container is preferably 5% or less, more preferably 2% or less. In the case of pharmaceuticals, an effective period of 3 years is usually set. As the effective period of the oxygen scavenger used in the present invention, a long effective period is more preferable, but even a short one can be used as a capsule. The object of the present invention to prevent deterioration of the solubility of the coating is sufficiently achieved.
本発明においてカプセル剤の充填物とは、薬効成分、添加剤又は薬効成分と添加剤の混合物を指す。充填物はアルデヒド基を有する物質又は経時的にアルデヒド基を有するようになる可能性のある物質、例えば水酸基を有する物質などが挙げられるが、これらを含むものである以外は特に限定されない。アルデヒド基を有する物質又は経時的にアルデヒド基を有するようになる可能性のある物質のうち、薬効成分に分類されるものとしては、例えば、塩酸フルラゼパム、クロラゼプ酸二カリウムなどの催眠鎮静剤、抗不安剤;トルフェナム酸、メフェナム酸、アセメタシン、インドメタシン、ジクロフェナクナトリウム、アンピロキシカム、ケトプロフェン、ピロキシカム、ブコローム、プラノプロフェン、メロキシカムなどの解熱鎮痛消炎剤;レボドパ、ドロキシドパなどの抗パーキンソン剤;アモキサピン、パモ酸ヒドロキシジンなどの精神神経用剤;フェニルプロパノールアミン配合剤などの総合感冒剤;ダントロレンナトリウムなどの骨格筋弛緩剤;塩化カルプロニウム、臭化チキジウム、ナパジシル酸アクラトニウムなどの自律神経剤;臭化ブトロピウム、臭化チメピジウム、フロプロピオンなどの鎮痙剤;dl−塩酸イソプロテレノールなどの鎮暈剤;クラテグスエキス、ピモベンダン、ユビデカレノンなどの強心剤;塩酸アセブトロール、塩酸アルプレノロール、塩酸アプリンジン、塩酸ピルジカイニド、塩酸ピルメノール、塩酸メキシレチン、ジソピラミドなどの不整脈用剤;スピロノラクトン、トリアムテレン、フロセミドなどの利尿剤;カプトプリル、ウラピジル、塩酸カルテオロール、塩酸ニカルジピン、塩酸バルニジピン、塩酸ブニトロロール、塩酸プロプラノロール、テルミサルタン、ピンドロールなどの血圧降下剤;塩酸ジルチアゼム、硝酸イソソルビド、ジピリダモール、ニフェジピンなどの血管拡張剤;クロフィブラート、フェノフィブラート、エラスターゼ、ソイステロール、フルバスタチンナトリウム、ポリエンホスファチジルコリンなどの高脂血症用剤;チトクロムC、ニコチン酸トコフェロールなどのその他の循環器官用薬;クエン酸ペントキシベリン、ジプロフィリン・メトキシフェナミン配合剤などの鎮咳剤;塩酸アンブロキソールなどの去たん剤;テオフィリン、塩酸イソプレナリン・プロナーゼなどの気管支拡張剤;カゼイ菌製剤;耐性乳酸菌配合剤;塩酸ロペラミドなどの止しゃ剤、整腸剤、カンゾウ抽出成分配合剤、塩酸ロキサチジンアセタート、ニザチジン、ウロガストロン、塩酸セトラキサート、塩酸ベネキサートベータデクス、エンプロスチル、オルノプロスチル、ゲファルナート、スルピリド、ソファルコン、テプレノン、プラウノトール、ランソプラゾールなどの消化性潰瘍用剤;サナクターゼ配合剤、サンプローゼ配合剤、ジアスターゼ配合剤、膵臓性消化酵素配合剤、ヒロダーゼ配合剤、ビオジアスターゼ配合剤、モルシン配合剤などの健胃消化剤;ピコスルファートナトリウム、ジオクチルジソジウムスルホサクシネート・カサントラノールなどの下剤、浣腸剤;ケノデオキシコール酸、ヒメクロモンなどの利胆剤;塩酸トロピセトロン、塩酸セビメリン水和物、フェニペントールなどのその他の消化器官用薬;カリジノゲナーゼ、ダナゾール、ミトタン、メピチオスタンなどのその他のホルモン剤;グルタミン酸・アラニン・アミノ酢酸配合剤などの泌尿器官用剤;トリベノシドなどの痔疾用剤;ウラジロガシエキス、塩酸タムスロシン、セルニチンポーレンエキス、ピネン・カンフェン配合剤などのその他の泌尿生殖器官及び肛門用薬;セイヨウトチノキ種子エキスなどのその他の個々の器官系用医薬品;アルファカルシドール、カルシトリオール、エトレチナートなどのビタミンA及びD剤;コバマミド、メコバラミンなどのビタミンB剤;酢酸トコフェロールなどのビタミンE剤;フィトナジオン、メナテトレノンなどのビタミンK剤;チアミンジスルフィド・B6・B12配合剤;フルスルチアミン・B2・B6・B12配合剤;ベンフォチアミン・B6・B12配合剤などの混合ビタミン剤;フマル酸第一鉄などの無機質製剤;トラネキサム酸などの止血剤;イコサペント酸エチル、シロスタゾールなどのその他の血液・体液用薬;プロパゲルマニウムなどの肝臓疾患用剤;塩酸トリエンチン、球形吸着炭、D−ペニシラミンなどの解毒剤;アロプリノールなどの痛風治療剤;塩化リゾチーム、セミアルカリプロティナーゼ、プロナーゼなどの酵素製剤;シクロスポリン、タクロリムス水和物、ミコフェノール酸モフェチル、メトトレキサートなどの他に分類されない代謝性医薬品;リン酸エストラムスチンナトリウムなどのアルキル化剤;テガフール、ドキシフルリジン、シタラビンオクホスファート、ヒドロキシカルバミド、テガフール・ウラシル、テガフール・ギメラシル・オテラシル配合剤などの代謝拮抗剤;エトポシドなどの抗腫瘍性植物成分製剤;塩酸プロカルバジン、トレチノイン、メシル酸イマチニブ、ウベニメクスなどのその他の腫瘍用薬;ヨウ化ナトリウム(123I)などの放射性医薬品;dl−マレイン酸クロルフェニラミン、フマル酸クレマスチンなどの抗ヒスタミン剤;イブジラスト、塩酸アゼラスチン、塩酸エピナスチン、タザノラスト、トシル酸スプラタスト、トラニラスト、フマル酸エメダスチン、フマル酸ケトチフェン、プランルカスト水和物などのその他のアレルギー用薬;安中散、茵ちん蒿湯、黄連解毒湯、三黄瀉心湯、麻黄附子細辛湯などの漢方製剤;塩酸クリンダマイシン、塩酸リンコマイシン、一硫酸カナマイシン、コリスチンメタンスルホン酸ナトリウム、セフチブテン、アモキシシリン、アンピシリン、塩酸タランピシリン、シクラシリン、セファクロル、セファトリジンプロピレングリコール、セファドロキシル、セファレキシン、セフィキシム、セフジニル、ホスホマイシンカルシウムなどの主としてグラム陽性・陰性菌に作用するもの;ミデカマイシン、アジスロマイシン水和物などの主としてグラム陽性菌、マイコプラズマに作用するもの;塩酸テトラサイクリン、塩酸デメチルクロルテトラサイクリン、塩酸ドキシサイクリン、塩酸ミノサイクリンなどの主としてグラム陽性・陰性菌、リケッチア,クラミジアに作用するもの;サイクロセリン、リファンピシンなどの主として抗酸菌に作用するもの;アンピシリン・クロキサシリン、アンピシリン・ジクロキサシリンなどのその他の抗生物質製剤(複合抗生物質製剤を含む。);クロファジミンなどの抗ハンセン病剤;塩酸ロメフロキサシン、シノキサシン、ナリジクス酸、チアンフェニコールなどの合成抗菌剤;アンプレナビル、エファビレンツ、ガンシクロビル、サキナビル、サニルブジン、ジダノシン、メシル酸サキナビル、リトナビル、リバビリン、硫酸インジナビルエタノール付加物、リン酸オセルタミビル、ロピナビル・リトナビルなどの抗ウイルス剤;イトラコナゾール、フルコナゾールなどのその他の化学療法剤;イオポダートナトリウムなどのX線造影剤;メチラポンなどの機能検査用試薬;硫酸モルヒネなどのあへんアルカロイド系麻薬などが挙げられるが、これらに限定されるものではない。 In the present invention, the capsule filling refers to a medicinal component, an additive, or a mixture of a medicinal component and an additive. Examples of the filler include a substance having an aldehyde group or a substance that may have an aldehyde group over time, for example, a substance having a hydroxyl group, but is not particularly limited except that it contains these. Among substances having an aldehyde group or substances that may have an aldehyde group over time, those classified as medicinal ingredients include hypnotic sedatives such as flurazepam hydrochloride and dipotassium chlorazepate, Anxiolytics; antipyretic analgesics such as tolfenamic acid, mefenamic acid, acemetacin, indomethacin, diclofenac sodium, ampiroxicam, ketoprofen, piroxicam, bucolome, pranoprofen, meloxicam; antiparkinsonian agents such as levodopa, droxidopa; amoxapine, pamoic acid Psychiatric and neurological agents such as hydroxyzine; general cold medicines such as phenylpropanolamine compound; skeletal muscle relaxants such as dantrolene sodium; autonomic nerves such as carpronium chloride, thixium bromide, and acratonium napadisylate Antispasmodic agents such as butropium bromide, thimepidium bromide, furopropion; antipruritic agents such as dl-isoproterenol hydrochloride; cardiotonic agents such as cratesug extract, pimobendan, ubidecarenone; acebutolol hydrochloride, alprenolol hydrochloride, aprindine hydrochloride, pildicinide hydrochloride , Arrhythmic agents such as spirmenol hydrochloride, mexiletine hydrochloride, disopyramide; diuretics such as spironolactone, triamterene, furosemide; Depressants: Vasodilators such as diltiazem hydrochloride, isosorbide nitrate, dipyridamole, nifedipine; clofibrate, fenofibrate, et Hyperlipidemic agents such as stase, soysterol, fluvastatin sodium and polyenephosphatidylcholine; other cardiovascular agents such as cytochrome C and tocopherol nicotinate; pentoxyberine citrate, diprofylline / methoxyphenamine Antitussives; Antidepressants such as ambroxol hydrochloride; Bronchodilators such as theophylline and isoprenaline hydrochloride / pronase; Casei bacteria preparations; Resistant lactic acid bacteria combination agents; Antistagnation agents such as loperamide hydrochloride; Satidine acetate, nizatidine, urogastron, cetraxate hydrochloride, benexate hydrochloride betadex, enprostil, ornoprostil, gefarnate, sulpiride, sofalcone, teprenone, prunotol, lansoprazole Peptic ulcer agents such as: Sanactase combination agent, Samprose combination agent, Diastase combination agent, Pancreatic digestive enzyme combination agent, Hyrodase combination agent, Biodiastase combination agent, Morsin combination agent, etc .; Picosulfate sodium Laxatives such as dioctyl disodium sulfosuccinate / casantlanol, enemas; astringents such as chenodeoxycholic acid and hymechromone; other gastrointestinal drugs such as tropisetron hydrochloride, cevimeline hydrochloride hydrate, Other hormonal agents such as caridinogenase, danazol, mitotane, mepithiostan; urinary organ agents such as glutamic acid, alanine, and aminoacetic acid combination agents; gonorrheal agents such as tribenoside; vulgari extract, tamsulosin hydrochloride, cernitine pollen extract, pinene camphene Other urogenital and anal drugs such as combinations; Other individual organ system drugs such as horse chestnut seed extract; Vitamin A and D drugs such as alphacalcidol, calcitriol, etretinate; Cobamide, mecobalamin, etc. Vitamin B preparations; Vitamin E preparations such as tocopherol acetate; Vitamin K preparations such as phytonadione and menatetrenone; Thiamine disulfide / B 6 / B 12 combination preparations; Fursultiamine / B 2 / B 6 / B 12 combination preparations; Benfotiamine -Mixed vitamin preparations such as B 6 and B 12 combinations; Inorganic preparations such as ferrous fumarate; Hemostatic agents such as tranexamic acid; Other blood and body fluids such as ethyl icosapentate and cilostazol; Propagermanium Liver disease agent: Trientine hydrochloride, spherical adsorbed charcoal, D- Antidote such as nicillamine; Gout therapeutic agent such as allopurinol; Enzyme preparation such as lysozyme chloride, semi-alkali proteinase and pronase; Metabolic drugs not classified elsewhere such as cyclosporine, tacrolimus hydrate, mycophenolate mofetil, methotrexate; phosphorus Alkylating agents such as estramustine sodium; antimetabolite agents such as tegafur, doxyfluridine, cytarabine ocphosphate, hydroxycarbamide, tegafur uracil, tegafur, gimeracil, and oteracil; antitumor plant component preparations such as etoposide; Other oncology drugs such as procarbazine hydrochloride, tretinoin, imatinib mesylate, ubenimex; radiopharmaceuticals such as sodium iodide ( 123 I); chlorpheniramine maleate Antihistamines such as clemastine fumarate; ibudilast, azelastine hydrochloride, epinastine hydrochloride, tazanolast, suplatast tosilate, tranilast, emedastine fumarate, ketotifen fumarate, pranlukast hydrate; Chinese herbal preparations such as 茵 蒿 蒿, Houren Deto, San-koshinto, Mao-bushi-saishin-to; clindamycin hydrochloride, lincomycin hydrochloride, kanamycin monosulfate, sodium colistin methanesulfonate, ceftibbutene, amoxicillin, ampicillin, Acts mainly on gram-positive and negative bacteria such as tarampicillin hydrochloride, cyclacillin, cefaclor, cephatridin propylene glycol, cefadroxyl, cephalexin, cefixime, cefdinir, fosfomycin calcium ; Acting on gram-positive bacteria such as midecamycin and azithromycin hydrate, mainly acting on mycoplasma; Acting mainly on gram-positive and negative bacteria such as tetracycline hydrochloride, demethylchlortetracycline hydrochloride, doxycycline hydrochloride, minocycline hydrochloride, rickettsia, chlamydia Those that mainly act on acid-fast bacteria such as cycloserine and rifampicin; Other antibiotic preparations (including complex antibiotic preparations) such as ampicillin / cloxacillin and ampicillin / dicloxacillin. ); Anti-Hansen's disease agents such as clofazimine; Synthetic antibacterial agents such as lomefloxacin hydrochloride, synoxacin, nalidixic acid, thianphenicol; amprenavir, efavirenz, ganciclovir, saquinavir, sanylvudine, didanosine, saquinavir mesylate, ritonavir, ribavirin, indinavir sulfate Antiviral agents such as ethanol adducts, oseltamivir phosphate, lopinavir and ritonavir; other chemotherapeutic agents such as itraconazole and fluconazole; X-ray contrast agents such as iopodate sodium; functional testing reagents such as metyrapone; morphine sulfate, etc. Examples of such alkane alkaloid drugs are not limited to these.
またアルデヒド基を有する物質又は経時的にアルデヒド基を有する可能性のある物質のうち、添加剤に分類されるものとしては、例えば、乳糖、白糖、ブドウ糖、マンニトール、ソルビトール、キシリトール、エリスリトールなどの糖類又はその誘導体;バレイショデンプン、トウモロコシデンプン(コーンスターチ)、ヒドロキシプロピルスターチ、デキストリン、プルランなどのデンプン類又はその誘導体;結晶セルロース、微結晶セルロース、ヒドロキシプロピルセルース、カルメロース、メチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルエチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、エチルセルロース、カルメロースナトリウム、カルメロースカルシウム、クロスカルメロースナトリウムなどのセルロース類又はその誘導体;ポリビニルアルコール、ポビドン、クロスポビドン、ポリビニルアセタールジエチルアミノアセテート、アミノアクリルメタクリレートコポリマーE、アミノアクリルメタクリレートコポリマーRS、メタクリル酸コポリマーL、メタクリル酸コポリマーLD、メタクリル酸コポリマーSなどの合成高分子;アラビアゴム末、ゼラチン、精製ゼラチン、寒天などの天然高分子;ステアリン酸、ステアリン酸マグネシウム、ステアリン酸マグネシウム、ステアリン酸カルシウム、オレイン酸、オレイン酸ナトリウムなどの脂肪酸又はその誘導体;アルギン酸、アルギン酸ナトリウム、アスコルビン酸、アスコルビン酸ステアリン酸エステル、アスコルビン酸ナトリウム、アスパラギン、アスパラギン酸、アスパラギン酸ナトリウム、アスパラギン酸マグネシウム、アラニン、アルギニン、イソロイシン、グリシン、グルタミン、グルタミン酸、システイン、セリン、スレオニン、チロシン、トリプトファン、バリン、フェニルアラニン、プロリン、メチオニン、リジン、ロイシンなどのアミノ酸類;これらの誘導体又はペプチド類;プロピレングリコール、ポリエチレングリコール、ラウロマクロゴール、セトマクロゴール等の多価アルコール;ポリソルベート、ポリオキシエチレンセチルエーテル、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレンステアリルエーテル、ポリオキシエチレンソルビタンモノラウレート又はその他各種ポリオキシエチレン鎖をその構造に含む酸化エチレン誘導体;ポリオキシエチレンポリオキシプロピレングリコール等の酸化プロピレン誘導体;ショ糖脂肪酸エステルなどの界面活性剤などが挙げられる。もちろん前記にあげた以外の物質であってもアルデヒド基を有する物質又は経時的にアルデヒド基を有する可能性のある物質は全て本発明のカプセル剤の充填物に含まれる。 Among substances having an aldehyde group or substances that may have an aldehyde group over time, those classified as additives include saccharides such as lactose, sucrose, glucose, mannitol, sorbitol, xylitol, and erythritol. Or derivatives thereof; potato starch, corn starch (corn starch), hydroxypropyl starch, dextrin, pullulan and other starches or derivatives thereof; crystalline cellulose, microcrystalline cellulose, hydroxypropylcellulose, carmellose, methylcellulose, hydroxypropylmethylcellulose, carboxymethyl Ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, ethylcellulose, carmelo Celluloses such as sodium, carmellose calcium and croscarmellose or derivatives thereof; polyvinyl alcohol, povidone, crospovidone, polyvinyl acetal diethylaminoacetate, aminoacryl methacrylate copolymer E, aminoacryl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid Synthetic polymers such as copolymer LD and methacrylic acid copolymer S; natural polymers such as gum arabic powder, gelatin, purified gelatin, and agar; stearic acid, magnesium stearate, magnesium stearate, calcium stearate, oleic acid, sodium oleate, etc. Fatty acids or derivatives thereof; alginic acid, sodium alginate, ascorbic acid, ascorbic acid stearate Ter, sodium ascorbate, asparagine, aspartic acid, sodium aspartate, magnesium aspartate, alanine, arginine, isoleucine, glycine, glutamine, glutamic acid, cysteine, serine, threonine, tyrosine, tryptophan, valine, phenylalanine, proline, methionine, lysine Amino acids such as leucine; derivatives or peptides thereof; polyhydric alcohols such as propylene glycol, polyethylene glycol, lauromacrogol, and cetomacrogol; polysorbate, polyoxyethylene cetyl ether, polyoxyethylene hydrogenated castor oil, polyoxy Ethylene castor oil, polyoxyethylene stearyl ether, polyoxyethylene sorbitan monolaurate or other various polymers And ethylene oxide derivatives containing a reoxyethylene chain in the structure; propylene oxide derivatives such as polyoxyethylene polyoxypropylene glycol; and surfactants such as sucrose fatty acid esters. Of course, even substances other than those mentioned above, all substances having an aldehyde group or substances which may have an aldehyde group over time are included in the filling of the capsule of the present invention.
また前記にあげた多価アルコール類、酸化エチレン誘導体、又は酸化プロピレン誘導体としては、具体的にはプロピレングリコール;ポリエチレングリコール(マクロゴール);ポリソルベート;ラウロマクロゴール;ポリオキシエチレンセチルエーテル;セトマクロゴール;ポリオキシエチレン硬化ヒマシ油;ポリオキシエチレンヒマシ油:ポリオキシエチレンステアリルエーテル;ポリオキシエチレンソルビタンモノラウレート;ポリオキシエチレンポリオキシプロピレングリコールなどが挙げられ、中でもプロピレングリコール;ポリエチレングリコール(マクロゴール):200、300、400、540、600、900、1000、1100、1200、1300、1400、1450、1500、1600、1700、1800、1900、2000、2100、2200、2300、2400、2500、2600、2700、2800、2900、3000、3250、3350、3500、3750、4000、4250、4500、4750、5000、5500、6000、6500、7000、7500、8000又は20000;ポリソルベート:20、21、40、60、61、65、80、81、85又は120;ラウロマクロゴール;ポリオキシエチレンセチルエーテル;セトマクロゴール1000;ポリオキシエチレン硬化ヒマシ油:5、10、20、40、50、60、100;ポリオキシエチレンヒマシ油:3、10、20、35、40、50、60;ポリオキシエチレンステアリルエーテル;ポリオキシエチレンソルビタンモノラウレート;ポリオキシエチレン(105)ポリオキシプロピレン(5)グリコール;ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール;ポリオキシエチレン(20)ポリオキシプロピレン(20)グリコール;ポリオキシエチレン(200)ポリオキシプロピレン(70)グリコール;ポリオキシエチレン(42)ポリオキシプロピレン(67)グリコール;ポリオキシエチレン(54)ポリオキシプロピレン(39)グリコールからなる群から選ばれる少なくとも1種が好ましく、この中でもポリエチレングリコール(マクロゴール)の類が好ましい。 Specific examples of the polyhydric alcohols, ethylene oxide derivatives or propylene oxide derivatives mentioned above include propylene glycol; polyethylene glycol (macrogol); polysorbate; lauromacrogol; polyoxyethylene cetyl ether; Polyoxyethylene hydrogenated castor oil; polyoxyethylene castor oil: polyoxyethylene stearyl ether; polyoxyethylene sorbitan monolaurate; polyoxyethylene polyoxypropylene glycol, among others, propylene glycol; polyethylene glycol (macrogol) : 200, 300, 400, 540, 600, 900, 1000, 1100, 1200, 1300, 1400, 1450, 1500, 1600, 1700, 180 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3250, 3350, 3500, 3750, 4000, 4250, 4500, 4750, 5000, 5500, 6000, 6500, 7000 7500, 8000 or 20000; Polysorbate: 20, 21, 40, 60, 61, 65, 80, 81, 85 or 120; Lauromacrogol; Polyoxyethylene cetyl ether; Setocmacrogol 1000; Polyoxyethylene hydrogenated castor oil : 5, 10, 20, 40, 50, 60, 100; polyoxyethylene castor oil: 3, 10, 20, 35, 40, 50, 60; polyoxyethylene stearyl ether; polyoxyethylene sorbitan monolaure Polyoxyethylene (105) polyoxypropylene (5) glycol; polyoxyethylene (160) polyoxypropylene (30) glycol; polyoxyethylene (20) polyoxypropylene (20) glycol; polyoxyethylene (200) At least one selected from the group consisting of polyoxypropylene (70) glycol; polyoxyethylene (42) polyoxypropylene (67) glycol; polyoxyethylene (54) polyoxypropylene (39) glycol is preferred, and among these, polyethylene The class of glycols (macrogol) is preferred.
次に本発明を実施例により更に具体的に説明する。
実施例1
経時的にアルデヒドを生成する物質としてポリエチレングリコール(マクロゴール600)282mgを日局2号ハードゼラチンカプセルに充填したカプセル剤10カプセルをPTPに充填した後、1パッケージの非鉄系脱酸素剤モデュランV(1.5g)(日本化薬フードテクノ)とともにアルミ箔ラミネートフィルムでピロー包装された酸素透過度が極めて低い密封容器中に封入し、60℃の熱苛酷環境下で2ヶ月間保存した。
Next, the present invention will be described more specifically with reference to examples.
Example 1
Capsules filled with 282 mg of polyethylene glycol (Macrogol 600) as a substance that generates aldehyde over time in a Japanese Pharmacopoeia No. 2 hard gelatin capsule were filled in PTP, and then one package of non-ferrous oxygen scavenger Modran V ( 1.5 g) (Nippon Kayaku Food Techno) was sealed in a sealed container with an extremely low oxygen permeability, which was pillow-wrapped with an aluminum foil laminate film, and stored for 2 months in a severe heat environment at 60 ° C.
実施例2
実施例1で作製したカプセル剤10カプセルをPTPに充填した後、1パッケージの鉄系脱酸素剤モデュランS(2g)(日本化薬フードテクノ)とともにアルミ箔ラミネートフィルムでピロー包装された酸素透過度が極めて低い密封容器中に封入し、60℃の熱苛酷環境下で2ヶ月間保存した。
Example 2
After filling the capsules of 10 capsules prepared in Example 1 into PTP, oxygen permeability of pillow packaged with aluminum foil laminate film together with one package of iron-based oxygen absorber Modran S (2 g) (Nippon Kayaku Food Techno) Was sealed in an extremely low sealed container and stored for 2 months in a severe heat environment at 60 ° C.
比較例1
実施例1で作製したカプセル剤10カプセルをPTPに充填した後、アルミ箔ラミネートフィルムでピロー包装された酸素透過度が極めて低い密封容器中に封入し、60℃の熱苛酷環境下2ヶ月間保存した。
Comparative Example 1
After 10 capsules prepared in Example 1 were filled in PTP, they were sealed in a sealed container with a very low oxygen permeability that was pillow-wrapped with an aluminum foil laminate film, and stored for 2 months in a 60 ° C. heat-harvest environment. did.
酸素濃度測定
実施例1、実施例2及び比較例1で得られた60℃の熱苛酷環境下で2ヶ月間保存したカプセル剤について、開封直前の密封容器に、リーク防止を目的に2cm角の粘着ゴム板(東レエンジニアリング社製)を貼り付け、粘着ゴム板貼り付け部からガスタイトシリンジにて一定量のガスを抜取り、抜き取ったガスについて、ガスクロマトグラフィー分析(検出器:熱伝導度型検出器(TCD)、カラム:モレキュラーシーブ)を行った。酸素濃度は得られたガスクロマトグラフィーのチャート上の酸素ピークと窒素のピークの面積和に対する酸素ピーク面積の比として算出した。酸素濃度を測定した結果を表1に示す。
Oxygen Concentration Measurement The capsules obtained in Example 1, Example 2 and Comparative Example 1 stored for 2 months in a severe heat environment at 60 ° C. were placed in a sealed container immediately before opening in a 2 cm square for the purpose of preventing leakage. Adhesive rubber plate (manufactured by Toray Engineering Co., Ltd.) is affixed, a certain amount of gas is extracted from the adhesive rubber plate affixed part with a gas tight syringe, and the extracted gas is analyzed by gas chromatography (detector: thermal conductivity type detection) (TCD), column: molecular sieve). The oxygen concentration was calculated as the ratio of the oxygen peak area to the sum of the areas of the oxygen peak and nitrogen peak on the obtained gas chromatography chart. The results of measuring the oxygen concentration are shown in Table 1.
カプセルの溶解試験
実施例1、実施例2及び比較例1で得られた60℃の熱苛酷環境下で2ヶ月間保存したカプセル剤について、日本薬局方溶出試験パドル法にてシンカーに入れたカプセルが溶解する時間を測定した結果を表2に示す。
Capsule dissolution test
About the capsule which was obtained in Example 1, Example 2 and Comparative Example 1 and stored for 2 months under the severe heat environment at 60 ° C., the time required for the capsule placed in the sinker to dissolve by the Japanese Pharmacopoeia dissolution test paddle method The results of measuring are shown in Table 2.
表1
ガスクロマトグラフィ分析
比較例1 実施例1 実施例2
酸素濃度 21% <1% 1%
Table 1
Gas chromatography analysis
Comparative Example 1 Example 1 Example 2
Oxygen concentration 21% <1% 1%
表2
カプセル溶解試験(日本薬局方溶出試験パドル法)
パドル回転数:100rpm
試験液:水900mL(液温37℃)
2ヶ月保存前 2ヶ月保存後
比較例1 実施例1 実施例2
カプセル溶解時間 <15分 >60分 <15分 <15分
Table 2
Capsule dissolution test (Japanese Pharmacopoeia dissolution test paddle method)
Paddle rotation speed: 100rpm
Test liquid: 900 mL of water (liquid temperature 37 ° C.)
Before storage for 2 months After storage for 2 months
Comparative Example 1 Example 1 Example 2
Capsule dissolution time <15 minutes> 60 minutes <15 minutes <15 minutes
表1に示すように、脱酸素剤の併存により、実施例においては密封容器内の酸素濃度は1%以下に減少した。カプセル剤皮の溶解性は表2に示すように、カプセル剤を熱過酷環境下において2ヶ月保存する前は15分以内にカプセル剤皮が溶解してカプセル剤の充填物であるポリエチレングリコールが試験液中に均一に分散されたのに対し、カプセル剤を脱酸素剤なしで熱過酷環境下において2ヶ月保存した後(比較例1:酸素濃度21%)は、カプセル剤皮が著しく不溶化し、60分以上たっても溶解しきらなかった。一方、カプセル剤を脱酸素剤と併存させて熱過酷環境下において2ヶ月保存した場合(実施例1:酸素濃度1%及び実施例2:酸素濃度1%)はいずれも2ヶ月保存前と同様に15分以内にカプセル剤皮が溶解し、ポリエチレングリコールが試験液中に均一に分散された。このことから、剤皮中にゼラチン類を含有するカプセル剤を、該カプセル剤を封入した容器内の酸素濃度を大気中の酸素濃度より低い状態として保存することにより、カプセル剤皮の不溶化が顕著に防止されることが明らかとなった。 As shown in Table 1, due to the coexistence of the oxygen scavenger, the oxygen concentration in the sealed container was reduced to 1% or less in the examples. As shown in Table 2, the solubility of the capsule skin is shown in Table 2. Before the capsule is stored in a severe heat environment for 2 months, the capsule skin dissolves within 15 minutes, and polyethylene glycol, which is a capsule filler, is tested. Although the capsules were uniformly dispersed in the liquid, after the capsules were stored for 2 months in a severe heat environment without an oxygen scavenger (Comparative Example 1: Oxygen concentration 21%), the capsule skin was remarkably insoluble, Even after 60 minutes or more, it was not completely dissolved. On the other hand, when the capsule was coexisting with the oxygen scavenger and stored for 2 months in a severe heat environment (Example 1: oxygen concentration 1% and Example 2: oxygen concentration 1%), both were the same as before storage for 2 months The capsule skin dissolved within 15 minutes, and the polyethylene glycol was uniformly dispersed in the test solution. From this fact, capsule capsules containing gelatins in the shell are stored in a state where the oxygen concentration in the container in which the capsule is sealed is lower than the oxygen concentration in the atmosphere. It became clear that it was prevented.
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