WO2016195057A1 - Soft capsule preparation - Google Patents

Soft capsule preparation Download PDF

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Publication number
WO2016195057A1
WO2016195057A1 PCT/JP2016/066537 JP2016066537W WO2016195057A1 WO 2016195057 A1 WO2016195057 A1 WO 2016195057A1 JP 2016066537 W JP2016066537 W JP 2016066537W WO 2016195057 A1 WO2016195057 A1 WO 2016195057A1
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Prior art keywords
soft capsule
mass
parts
nalfurafine
capsule
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PCT/JP2016/066537
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French (fr)
Japanese (ja)
Inventor
保彦 佐野
浩士 後藤
祥充 中島
圭 西田
Original Assignee
東海カプセル株式会社
伊藤忠ケミカルフロンティア株式会社
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Application filed by 東海カプセル株式会社, 伊藤忠ケミカルフロンティア株式会社 filed Critical 東海カプセル株式会社
Priority to JP2016550820A priority Critical patent/JP6082503B1/en
Priority to KR1020177034467A priority patent/KR20180013934A/en
Priority to CN201680032582.9A priority patent/CN107613982A/en
Publication of WO2016195057A1 publication Critical patent/WO2016195057A1/en

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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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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

Definitions

  • the present invention relates to a soft capsule containing nalflaphine or an acid addition salt thereof.
  • Nalfurafine is a selective opioid ⁇ receptor agonist and exhibits a strong antipruritic action against central itching involving the opioid system (Patent Document 1). And a soft capsule containing nalflaphine hydrochloride is marketed as an oral pruritus ameliorating agent.
  • nalfurafine is chemically unstable to heat, light, oxygen, and moisture, and it is necessary to take measures such as low-temperature storage, light shielding, and inert gas replacement during storage.
  • hydrophilic polyethylene glycol when used as a base, adhesion and dent of soft capsules due to moisture tend to occur. Therefore, strict moisture management of the soft capsule is required, and the drying process tends to be complicated. Further, since hydrophilic polyethylene glycol is used as a base, it is conceivable that the content stability of nalfurafine is reduced and decomposition products are generated by the water contained in polyethylene glycol.
  • the present invention relates to providing a soft capsule having excellent content stability of nalflaphine or an acid addition salt thereof.
  • the present inventors have found that the content of capsules contains narfrafin or an acid addition salt thereof and gallic acid using a hydrophobic oily base. It has been found that a soft capsule containing propyl and sodium thiosulfate in the film has very good content stability of nalfurafine or an acid addition salt thereof.
  • the present invention relates to the following 1) to 3).
  • the present invention it is possible to produce a capsule containing a stable nalfurafine or an acid addition salt thereof, in which the stability of the content of nalfurafine or an acid addition salt thereof and the generation of a specific decomposition product are suppressed. Also, in the capsule manufacturing process, strict moisture management is not necessary, and the drying process can be simplified.
  • “nalfurafine” is represented by the following (2E) -N-[(5R, 6R) -17- (Cyclopropylmethyl) -4, -35-epoxy-3, 14-dihydroxymorphinan-6-yl ] -3- (furan-3-yl) -N-methylprop-2-enamide monohydrochloride).
  • the acid addition salt of nalfurafine is not particularly limited as long as it is a pharmacologically acceptable salt.
  • hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, etc. Inorganic acid salt, acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate etc
  • Organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and the like. Hydronate, phosphate, tartrate, maleate and methanesulfonate are preferred.
  • a hydrophobic oily base is used as a base for the contents of the soft capsule containing the nalfurafine or an acid addition salt thereof.
  • the hydrophobic oil base include medium chain fatty acid triglycerides, tricaprylin, caproic acid, caprylic acid, oleic acid, linoleic acid, linolenic acid, vegetable oil and the like.
  • vegetable oils include palm oil, olive oil, rapeseed oil, peanut oil, corn oil, soybean oil, cottonseed oil, grape oil, safflower oil, and the like. These may be used alone or as a mixture of two or more. Of these, glycerides of medium chain fatty acids having 8 to 12 carbon atoms are preferred, and glycerin tricaprylate, tri (capryl / capric acid) glycerin, and the like are preferred.
  • the amount of such a hydrophobic oily base used is 400 parts by mass or more, preferably 1,000 parts by mass or more, more preferably 10,000 parts by mass or more, based on 1 part by mass of nalfurafine or an acid addition salt thereof.
  • the amount is preferably 40,000 parts by mass or more, preferably 200,000 parts by mass or less, more preferably 150,000 parts by mass or less, and still more preferably 120,000 parts by mass or less. Further, it is preferably 400 to 200,000 parts by mass, more preferably 10,000 to 150,000 parts by mass, and considering the capsule size, 40,000 to 120,000 parts by mass is still more preferable.
  • propyl gallate is added as a stabilizer, and the addition amount thereof is preferably 150 parts by mass or more, preferably 300 parts by mass or more, with respect to 1 part by mass of nalfurafine or an acid addition salt thereof.
  • it is 500 mass parts or more
  • it is 20,000 mass parts or less, More preferably, it is 2,000 mass parts or less, More preferably, it is 1,500 mass parts or less.
  • it is preferably 150 to 20,000 parts by mass, more preferably 300 to 2,000 parts by mass, and still more preferably 500 to 1,500 parts by mass.
  • sodium thiosulfate is blended in the capsule film.
  • Sodium thiosulfate may be an anhydrous salt or a hydrated salt, and is preferably sodium thiosulfate pentahydrate.
  • the content of sodium thiosulfate is preferably 150 parts by mass or more, preferably 300 parts by mass or more, more preferably 500 parts by mass or more, preferably 20,000 with respect to 1 part by mass of nalfurafine or an acid addition salt thereof. It is not more than part by mass, more preferably not more than 2,000 parts by mass, still more preferably not more than 1,500 parts by mass. Further, it is preferably 150 to 20,000 parts by mass, more preferably 300 to 2,000 parts by mass, and still more preferably 500 to 1,500 parts by mass.
  • the content contains, for example, a solubilizer, a solubilizing agent, a preservative, a surfactant, a colorant, etc., in addition to the above-described components, as long as the effects of the present invention are not impaired.
  • a film base, a plasticizer, a colorant, a preservative and the like can be blended in the film.
  • solubilizer for example, ethanol, propylene glycol, polyethylene glycol, sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl oleate, glyceryl myristate, polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl Examples include ether and glycerin.
  • solubilizer include cyclodextrin and the like.
  • the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, and benzalkonium chloride.
  • Examples of the surfactant include polysorbate 80, polyoxyl 35 castor oil, and the like.
  • Examples of the colorant include titanium oxide, yellow ferric oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, edible red No. 105, edible red No. 106, and edible red No. 106. It is done.
  • Examples of the film base include gelatin, succinylated gelatin, starch, pullulan, polyvinyl alcohol copolymer, macrogol and the like.
  • Examples of the plasticizer include concentrated glycerin and sugar alcohol.
  • the contents of the soft capsule of the present invention include, for example, nalfrafin or an acid addition salt thereof and propyl gallate dissolved in a solubilizing agent such as ethanol, and this is blended in a hydrophobic oily base, mixed and stirred. Can be manufactured.
  • the film of the soft capsule of the present invention can be produced, for example, by dispersing a base, a plasticizer, and sodium thiosulfate in water, dissolving at 60 ° C. to 90 ° C., and then vacuum degassing.
  • the soft capsule of the present invention is produced by a conventional soft capsule production method, for example, a punching method using a rotary type automatic soft capsule molding machine, a content is placed between two gelatin sheets, and the contents are compressed and punched from both sides with a mold. Using a flat plate method or a dropping method (seamless capsule or the like) using a double nozzle, the contents can be filled into a film, molded and dried.
  • the soft capsule thus obtained has a very high content stability of nalflaphine or an acid addition salt thereof as an active ingredient, as shown in Examples below, and the production of specific decomposition products is suppressed.
  • Example 1 Preparation of Soft Capsule
  • nalfurafine hydrochloride and propyl gallate shown in Table 1 below were dissolved in a predetermined amount of ethanol, and this was dissolved in a predetermined amount of medium chain fatty acid triglyceride [tri (caprylic acid / capric acid) glyceride. (BASF)] was mixed and stirred to prepare a capsule filling composition.
  • a predetermined amount of gelatin, succinylated gelatin, concentrated glycerin, D-sorbitol solution, sodium thiosulfate and titanium oxide shown in Table 1 below were stirred and dispersed in an appropriate amount of purified water, and stirred and dissolved at 60 ° C.
  • a gelatin film was prepared by vacuum defoaming.
  • a soft capsule was prepared by a punching method using a rotary fully automatic soft capsule molding machine using the capsule filling composition and the gelatin film.
  • 2.5 ⁇ g of Remitch capsule 2.5 ⁇ g of nalfurafine hydrochloride in one capsule (manufactured by Toray Industries, Inc.)] was used.
  • Table 2 shows the components of the comparative product.
  • Example 2 Stability Test The soft capsule prepared in Example 1 was put in a glass bottle and stored at 80 ° C. for 1 week in a sealed state. After the storage period, the content and degradation products of nalflaphine hydrochloride in each soft capsule were measured by HPLC method. The measurement results are shown in Tables 3 and 4.
  • the product of the present invention had a high residual ratio of nalfurafine hydrochloride and a remarkable content stability compared to the comparative product. Further, as is clear from Table 4, the product of the present invention did not increase the 10 ⁇ -OH form observed in the comparative product, and showed a remarkable inhibitory effect of the 10 ⁇ -OH form, which is a decomposition product of nalfrafin.
  • Example 3 Preparation of Soft Capsule Soft capsules were prepared in the same manner as in Example 1 in the predetermined amounts shown in Table 5 below. Further, in the same manner as in Example 1, 2.5 ⁇ g of Remitch capsules [2.5 ⁇ g of nalfurafine hydrochloride in one capsule (manufactured by Toray Industries, Inc.)] was used as a comparative product.
  • Example 4 Stability Test The soft capsule prepared in Example 3 was PTP / pillow packed and stored for 6 months at 40 ° C. and 75% RH. After 1 month, 3 months, and the end of the storage period, the content and degradation products of nalflaphine hydrochloride in each soft capsule were measured by HPLC. The measurement results are shown in Tables 6 and 7.
  • the product of the present invention had a high residual ratio of nalfurafine hydrochloride and a remarkable content stability compared to the comparative product. Further, as apparent from Table 7, the product of the present invention did not increase the decomposition products observed in the comparative product, and showed a remarkable inhibitory effect on the decomposition products of narfrafin.

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Abstract

Provided is a soft capsule preparation that shows an excellent content stability of Nalfurafine or an acid addition salt thereof. The soft capsule preparation consists of a capsule core comprising Nalfurafine or an acid addition salt thereof, a hydrophobic oily base and propyl gallate, and a capsule coating comprising sodium thiosulfate.

Description

ソフトカプセル剤Soft capsule
　本発明は、ナルフラフィン又はその酸付加塩を含有するソフトカプセル剤に関する。 The present invention relates to a soft capsule containing nalflaphine or an acid addition salt thereof.
　ナルフラフィン（Nalfurafine）は、選択的オピオイドκ受容体作動薬として、オピオイドシステムが関与する中枢性の痒みに対して強力な止痒作用を示す（特許文献１）。そして、ナルフラフィン塩酸塩を含有したソフトカプセル剤が経口そう痒症改善剤として上市されている。 Nalfurafine is a selective opioid κ receptor agonist and exhibits a strong antipruritic action against central itching involving the opioid system (Patent Document 1). And a soft capsule containing nalflaphine hydrochloride is marketed as an oral pruritus ameliorating agent.
　しかしながら、ナルフラフィンは、熱、光、酸素、水分に対して化学的に不安定であり、保存時には、低温保存、遮光、不活性ガス置換等の手段を講じる必要がある。 However, nalfurafine is chemically unstable to heat, light, oxygen, and moisture, and it is necessary to take measures such as low-temperature storage, light shielding, and inert gas replacement during storage.
　このため、ナルフラフィン又はその酸付加塩を含有するカプセル剤は、水及びポリエチレングリコールに、水溶性の酸化防止剤であるチオ硫酸ナトリウムを配合することにより、その安定性が確保されている（特許文献２）。 For this reason, the stability of capsules containing nalfurafine or an acid addition salt thereof is ensured by blending water and polyethylene glycol with sodium thiosulfate, which is a water-soluble antioxidant (Patent Literature). 2).
　しかしながら、親水性のポリエチレングリコールを基剤として使用すると、水分を起因としたソフトカプセル剤同士の付着及び凹みが起きやすくなる。そのため、ソフトカプセル剤の厳密な水分管理が必要となり、乾燥工程が煩雑となりやすい。また、親水性のポリエチレングリコールを基剤として使用しているために、ポリエチレングリコールに含有する水によってナルフラフィンの含量安定性の低下及び分解物の生成が考えられる。 However, when hydrophilic polyethylene glycol is used as a base, adhesion and dent of soft capsules due to moisture tend to occur. Therefore, strict moisture management of the soft capsule is required, and the drying process tends to be complicated. Further, since hydrophilic polyethylene glycol is used as a base, it is conceivable that the content stability of nalfurafine is reduced and decomposition products are generated by the water contained in polyethylene glycol.
特許第３５３１１７０号公報Japanese Patent No. 3531170 特許第３７４３４４９号公報Japanese Patent No. 3743449
　本発明は、ナルフラフィン又はその酸付加塩の優れた含量安定性を有するソフトカプセル剤を提供することに関する。 The present invention relates to providing a soft capsule having excellent content stability of nalflaphine or an acid addition salt thereof.
　本発明者らは、ナルフラフィン又はその酸付加塩を含有するソフトカプセル剤について鋭意研究を重ねた結果、カプセルの内容物中に、疎水性の油性基剤を用いてナルフラフィン又はその酸付加塩及び没食子酸プロピルを含有させ、皮膜中にチオ硫酸ナトリウムを含有させたソフトカプセル剤が、ナルフラフィン又はその酸付加塩の含量安定性が極めて良好であることを見出した。 As a result of intensive research on soft capsules containing nalfurafine or an acid addition salt thereof, the present inventors have found that the content of capsules contains narfrafin or an acid addition salt thereof and gallic acid using a hydrophobic oily base. It has been found that a soft capsule containing propyl and sodium thiosulfate in the film has very good content stability of nalfurafine or an acid addition salt thereof.
　すなわち、本発明は、以下の１）～３）に係るものである。
　１）カプセル内容物中にナルフラフィン又はその酸付加塩、疎水性の油性基剤及び没食子酸プロピルを含有し、カプセル皮膜中にチオ硫酸ナトリウムを含有するソフトカプセル剤。
　２）ナルフラフィン又はその酸付加塩１質量部に対し、疎水性の油性基剤４００～２００，０００質量部、没食子酸プロピル１５０～２０，０００質量部を含有する１）のソフトカプセル剤。
　３）ナルフラフィン又はその塩１質量部に対し、チオ硫酸ナトリウム１５０～２０，０００質量部を含有する１）又は２）のソフトカプセル剤。 That is, the present invention relates to the following 1) to 3).
1) A soft capsule containing nalfrafin or an acid addition salt thereof, a hydrophobic oily base and propyl gallate in the capsule contents and sodium thiosulfate in the capsule film.
2) A soft capsule of 1) containing 400 to 200,000 parts by weight of a hydrophobic oily base and 150 to 20,000 parts by weight of propyl gallate per 1 part by weight of nalfurafine or an acid addition salt thereof.
3) The soft capsule of 1) or 2) containing 150 to 20,000 parts by weight of sodium thiosulfate with respect to 1 part by weight of nalfurafine or a salt thereof.
　本発明を用いることにより、ナルフラフィン又はその酸付加塩の優れた含量安定性及び特定の分解物の生成が抑制された、安定なナルフラフィン又はその酸付加塩を含有するカプセル剤を製造することができ、またカプセルの製造工程において、厳密な水分管理が必要なくなり、乾燥工程を簡略化することができる。 By using the present invention, it is possible to produce a capsule containing a stable nalfurafine or an acid addition salt thereof, in which the stability of the content of nalfurafine or an acid addition salt thereof and the generation of a specific decomposition product are suppressed. Also, in the capsule manufacturing process, strict moisture management is not necessary, and the drying process can be simplified.
　本発明において、「ナルフラフィン」とは、は下記で表される(2E)-N-[(5R,6R)-17-(Cyclopropylmethyl)-4, 5-epoxy-3, 14-dihydroxymorphinan-6-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride）を意味する。 In the present invention, “nalfurafine” is represented by the following (2E) -N-[(5R, 6R) -17- (Cyclopropylmethyl) -4, -35-epoxy-3, 14-dihydroxymorphinan-6-yl ] -3- (furan-3-yl) -N-methylprop-2-enamide monohydrochloride).
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　ナルフラフィンの酸付加塩としては、薬理学的に許容される塩であれば特に限定されず、例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、ヨウ化水素酸塩、リン酸塩等の無機酸塩、酢酸塩、乳酸塩、クエン酸塩、シュウ酸塩、グルタル酸塩、リンゴ酸塩、酒石酸塩、フマル酸塩、マンデル酸塩、マレイン酸塩、安息香酸塩、フタル酸塩等の有機カルボン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、カンファ―スルホン酸塩等の有機スルホン酸塩等が挙げられ、中でも塩酸塩、臭化水素酸塩、リン酸塩、酒石酸塩、マレイン酸塩、メタンスルホン酸塩が好ましい。 The acid addition salt of nalfurafine is not particularly limited as long as it is a pharmacologically acceptable salt. For example, hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, etc. Inorganic acid salt, acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate etc Organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and the like. Hydronate, phosphate, tartrate, maleate and methanesulfonate are preferred.
　上記ナルフラフィン又はその酸付加塩を含有するソフトカプセル剤の内容物には、基剤として、疎水性の油性基剤が用いられる。
　疎水性の油性基剤としては、例えば、中鎖脂肪酸トリグリセリド、トリカプリリン、カプロン酸、カプリル酸、オレイン酸、リノール酸、リノレン酸、植物油等が挙げられる。ここで植物油としては、ヤシ油、オリーブ油、ナタネ油、落花生油、コーン油、ダイズ油、綿実油、ぶどう油、紅花油等が挙げられる。これらは単独でも２種以上の混合物でもよい。このうち、炭素数８～１２の中鎖脂肪酸のグリセリドが好ましく、トリカプリル酸グリセリン、トリ（カプリル・カプリン酸）グリセリン等が好適である。 A hydrophobic oily base is used as a base for the contents of the soft capsule containing the nalfurafine or an acid addition salt thereof.
Examples of the hydrophobic oil base include medium chain fatty acid triglycerides, tricaprylin, caproic acid, caprylic acid, oleic acid, linoleic acid, linolenic acid, vegetable oil and the like. Examples of vegetable oils include palm oil, olive oil, rapeseed oil, peanut oil, corn oil, soybean oil, cottonseed oil, grape oil, safflower oil, and the like. These may be used alone or as a mixture of two or more. Of these, glycerides of medium chain fatty acids having 8 to 12 carbon atoms are preferred, and glycerin tricaprylate, tri (capryl / capric acid) glycerin, and the like are preferred.
　斯かる疎水性の油性基剤の使用量は、ナルフラフィン又はその酸付加塩１質量部に対して４００質量部以上、好ましくは１，０００質量部以上、より好ましくは１０，０００質量部以上、更に好ましくは４０，０００質量部以上であり、好ましくは２００，０００質量部以下、より好ましくは１５０，０００質量部以下、更に好ましくは１２０，０００質量部以下である。また、好ましくは４００～２００，０００質量部、より好ましくは１０，０００～１５０，０００質量部であり、カプセルサイズを考えると、４０，０００～１２０，０００質量部が更に好ましい。 The amount of such a hydrophobic oily base used is 400 parts by mass or more, preferably 1,000 parts by mass or more, more preferably 10,000 parts by mass or more, based on 1 part by mass of nalfurafine or an acid addition salt thereof. The amount is preferably 40,000 parts by mass or more, preferably 200,000 parts by mass or less, more preferably 150,000 parts by mass or less, and still more preferably 120,000 parts by mass or less. Further, it is preferably 400 to 200,000 parts by mass, more preferably 10,000 to 150,000 parts by mass, and considering the capsule size, 40,000 to 120,000 parts by mass is still more preferable.
　本発明において、没食子酸プロピルは、安定剤として添加するものであり、その添加量はナルフラフィン又はその酸付加塩１質量部に対して、好ましくは１５０質量部以上、好ましくは３００質量部以上、より好ましくは５００質量部以上であり、好ましくは２０，０００質量部以下、より好ましくは２，０００質量部以下、更に好ましくは１，５００質量部以下である。また、好ましくは１５０～２０，０００質量部、より好ましくは３００～２，０００質量部、更に好ましくは５００～１，５００質量部である。 In the present invention, propyl gallate is added as a stabilizer, and the addition amount thereof is preferably 150 parts by mass or more, preferably 300 parts by mass or more, with respect to 1 part by mass of nalfurafine or an acid addition salt thereof. Preferably it is 500 mass parts or more, Preferably it is 20,000 mass parts or less, More preferably, it is 2,000 mass parts or less, More preferably, it is 1,500 mass parts or less. Further, it is preferably 150 to 20,000 parts by mass, more preferably 300 to 2,000 parts by mass, and still more preferably 500 to 1,500 parts by mass.
　本発明において、チオ硫酸ナトリウムは、カプセル皮膜中に配合される。チオ硫酸ナトリウムをカプセル皮膜中に配合することにより、分解物の生成を抑制できる。
　チオ硫酸ナトリウムは、無水塩であっても含水塩であってもよく、好ましくはチオ硫酸ナトリウム五水和物である。
　チオ硫酸ナトリウムの含有量は、ナルフラフィン又はその酸付加塩１質量部に対して、好ましくは１５０質量部以上、好ましくは３００質量部以上、より好ましくは５００質量部以上であり、好ましくは２０，０００質量部以下、より好ましくは２，０００質量部以下、更に好ましくは１，５００質量部以下である。また、好ましくは１５０～２０，０００質量部、より好ましくは３００～２，０００質量部、更に好ましくは５００～１，５００質量部である。 In the present invention, sodium thiosulfate is blended in the capsule film. By blending sodium thiosulfate into the capsule film, generation of decomposition products can be suppressed.
Sodium thiosulfate may be an anhydrous salt or a hydrated salt, and is preferably sodium thiosulfate pentahydrate.
The content of sodium thiosulfate is preferably 150 parts by mass or more, preferably 300 parts by mass or more, more preferably 500 parts by mass or more, preferably 20,000 with respect to 1 part by mass of nalfurafine or an acid addition salt thereof. It is not more than part by mass, more preferably not more than 2,000 parts by mass, still more preferably not more than 1,500 parts by mass. Further, it is preferably 150 to 20,000 parts by mass, more preferably 300 to 2,000 parts by mass, and still more preferably 500 to 1,500 parts by mass.
　本発明のソフトカプセル剤には、本発明の効果を損なわない範囲で、前記成分以外に、内容物には、例えば可溶化剤、溶解補助剤、保存剤、界面活性剤、着色剤等を配合することができ、皮膜には、例えば皮膜基剤、可塑剤、着色剤、保存剤等を配合することができる。 In the soft capsule of the present invention, the content contains, for example, a solubilizer, a solubilizing agent, a preservative, a surfactant, a colorant, etc., in addition to the above-described components, as long as the effects of the present invention are not impaired. For example, a film base, a plasticizer, a colorant, a preservative and the like can be blended in the film.
　ここで、可溶化剤としては、例えばエタノール、プロピレングリコール、ポリエチレングリコール、セスキオレイン酸ソルビタン、ラウリン酸ソルビタン、パルミチン酸ソルビタン、オレイン酸グリセリル、ミリスチン酸グリセリル、ポリオキシエチレンラウリルエーテル、ポリオキシエチレンノニルフェニルエーテル、グリセリン等が挙げられる。
　溶解補助剤としては、例えばシクロデキストリン等が挙げられる。
　保存剤としては、例えばパラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、塩化ベンザルコニウム等が挙げられる。
　界面活性剤としては、例えばポリソルベート80、ポリオキシル35ヒマシ油等が挙げられる。
　着色剤としては、例えば酸化チタン、黄色三二酸化鉄、食用黄色４号、食用黄色５号、食用赤色３号、食用赤色１０２号、食用赤色１０５号、食用赤色１０６号、三二酸化鉄等が挙げられる。
　皮膜基剤としては、例えばゼラチン、コハク化ゼラチン、デンプン、プルラン、ポリビニルアルコール共重合体、マクロゴール等が挙げられる。
　可塑剤としては、濃グリセリン、糖アルコール等が挙げられる。 Here, as the solubilizer, for example, ethanol, propylene glycol, polyethylene glycol, sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl oleate, glyceryl myristate, polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl Examples include ether and glycerin.
Examples of the solubilizer include cyclodextrin and the like.
Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, and benzalkonium chloride.
Examples of the surfactant include polysorbate 80, polyoxyl 35 castor oil, and the like.
Examples of the colorant include titanium oxide, yellow ferric oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 3, edible red No. 102, edible red No. 105, edible red No. 106, and edible red No. 106. It is done.
Examples of the film base include gelatin, succinylated gelatin, starch, pullulan, polyvinyl alcohol copolymer, macrogol and the like.
Examples of the plasticizer include concentrated glycerin and sugar alcohol.
　本発明のソフトカプセル剤の内容物は、例えば、ナルフラフィン又はその酸付加塩、及び没食子酸プロピルを、エタノール等の可溶化剤に溶解し、これを疎水性の油性基剤に配合し、混合、撹拌することにより製造することができる。
　本発明のソフトカプセル剤の皮膜は、例えば、基剤、可塑剤及びチオ硫酸ナトリウムを水に分散させて、６０℃～９０℃で溶解させた後、真空脱泡することにより製造できる。
　本発明のソフトカプセル剤は、従来用いられているソフトカプセルの製法、例えばロータリー式全自動ソフトカプセル成型機を用いた打ち抜き法、二枚のゼラチンシート間に内容物を入れ金型で両面から圧縮して打ち抜く平板法或いは二重ノズルを用いた滴下法（シームレスカプセル等）等を用いて、内容物を皮膜に充填し、成型、乾燥することにより、製造することができる。
　斯くして得られた上記ソフトカプセル剤は、後記実施例に示すとおり、有効成分であるナルフラフィン又はその酸付加塩の含量安定性が極めて高く、特定の分解物の生成が抑制される。 The contents of the soft capsule of the present invention include, for example, nalfrafin or an acid addition salt thereof and propyl gallate dissolved in a solubilizing agent such as ethanol, and this is blended in a hydrophobic oily base, mixed and stirred. Can be manufactured.
The film of the soft capsule of the present invention can be produced, for example, by dispersing a base, a plasticizer, and sodium thiosulfate in water, dissolving at 60 ° C. to 90 ° C., and then vacuum degassing.
The soft capsule of the present invention is produced by a conventional soft capsule production method, for example, a punching method using a rotary type automatic soft capsule molding machine, a content is placed between two gelatin sheets, and the contents are compressed and punched from both sides with a mold. Using a flat plate method or a dropping method (seamless capsule or the like) using a double nozzle, the contents can be filled into a film, molded and dried.
The soft capsule thus obtained has a very high content stability of nalflaphine or an acid addition salt thereof as an active ingredient, as shown in Examples below, and the production of specific decomposition products is suppressed.
　本発明を以下の実施例により詳細に説明するが、本発明はこれに限定されるものではない。 The present invention will be described in detail with reference to the following examples, but the present invention is not limited thereto.
実施例１　ソフトカプセル剤の調製
　下記表１に示す所定量のナルフラフィン塩酸塩及び没食子酸プロピルを所定量のエタノールに溶解し、これを所定量の中鎖脂肪酸トリグリセリド［トリ（カプリル酸／カプリン酸）グリセリド（BASF社製）］に混合、撹拌してカプセル充填組成物を調製した。下記表１に示す所定量のゼラチン、コハク化ゼラチン、濃グリセリン、D-ソルビトール液、チオ硫酸ナトリウム及び酸化チタンを適量の精製水に撹拌・分散させて、６０℃で撹拌・溶解させた後、真空脱泡してゼラチン皮膜を調製した。上記のカプセル充填組成物及びゼラチン皮膜を用いて、ロータリー式全自動ソフトカプセル成型機を用いた打ち抜き法により、ソフトカプセル剤を調製した。
　また、比較品としてレミッチカプセル２．５μｇ［1カプセル中にナルフラフィン塩酸塩２．５μｇ配合（東レ社製）］を用いた。表２に比較品の配合成分を示す。 Example 1 Preparation of Soft Capsule Predetermined amounts of nalfurafine hydrochloride and propyl gallate shown in Table 1 below were dissolved in a predetermined amount of ethanol, and this was dissolved in a predetermined amount of medium chain fatty acid triglyceride [tri (caprylic acid / capric acid) glyceride. (BASF)] was mixed and stirred to prepare a capsule filling composition. A predetermined amount of gelatin, succinylated gelatin, concentrated glycerin, D-sorbitol solution, sodium thiosulfate and titanium oxide shown in Table 1 below were stirred and dispersed in an appropriate amount of purified water, and stirred and dissolved at 60 ° C. A gelatin film was prepared by vacuum defoaming. A soft capsule was prepared by a punching method using a rotary fully automatic soft capsule molding machine using the capsule filling composition and the gelatin film.
Further, as a comparative product, 2.5 μg of Remitch capsule [2.5 μg of nalfurafine hydrochloride in one capsule (manufactured by Toray Industries, Inc.)] was used. Table 2 shows the components of the comparative product.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
実施例２　安定性試験
　実施例１で調製したソフトカプセル剤をガラス瓶に入れ、密栓した状態で８０℃に１週間保存した。保存期間終了後に、各ソフトカプセル剤中のナルフラフィン塩酸塩の含量及び分解物をＨＰＬＣ法で測定した。測定結果を表３及び４に示す。 Example 2 Stability Test The soft capsule prepared in Example 1 was put in a glass bottle and stored at 80 ° C. for 1 week in a sealed state. After the storage period, the content and degradation products of nalflaphine hydrochloride in each soft capsule were measured by HPLC method. The measurement results are shown in Tables 3 and 4.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　表３から明らかなように、本発明品は、比較品と比べ、ナルフラフィン塩酸塩の残存率が高く、顕著な含量安定性を示した。また表４から明らかなように、本発明品は、比較品で認められた１０α－ＯＨ体の増加がなく、ナルフラフィンの分解物である１０α－ＯＨ体の顕著な抑制効果を示した。 As is apparent from Table 3, the product of the present invention had a high residual ratio of nalfurafine hydrochloride and a remarkable content stability compared to the comparative product. Further, as is clear from Table 4, the product of the present invention did not increase the 10α-OH form observed in the comparative product, and showed a remarkable inhibitory effect of the 10α-OH form, which is a decomposition product of nalfrafin.
　実施例３　ソフトカプセル剤の調製
　下記表５に示す所定量で実施例１と同様の方法によりソフトカプセル剤を調製した。
　また、実施例１と同様に比較品としてレミッチカプセル２．５μｇ［1カプセル中にナルフラフィン塩酸塩２．５μｇ配合（東レ社製）］を用いた。 Example 3 Preparation of Soft Capsule Soft capsules were prepared in the same manner as in Example 1 in the predetermined amounts shown in Table 5 below.
Further, in the same manner as in Example 1, 2.5 μg of Remitch capsules [2.5 μg of nalfurafine hydrochloride in one capsule (manufactured by Toray Industries, Inc.)] was used as a comparative product.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
実施例４　安定性試験
　実施例３で調製したソフトカプセル剤をＰＴＰ／ピロー包装し、４０℃７５％ＲＨ６箇月間保存した。１箇月後、３箇月後、保存期間終了後に、各ソフトカプセル剤中のナルフラフィン塩酸塩の含量及び分解物をＨＰＬＣ法で測定した。測定結果を表６及び７に示す。 Example 4 Stability Test The soft capsule prepared in Example 3 was PTP / pillow packed and stored for 6 months at 40 ° C. and 75% RH. After 1 month, 3 months, and the end of the storage period, the content and degradation products of nalflaphine hydrochloride in each soft capsule were measured by HPLC. The measurement results are shown in Tables 6 and 7.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　表６から明らかなように、本発明品は、比較品と比べ、ナルフラフィン塩酸塩の残存率が高く、顕著な含量安定性を示した。また表７から明らかなように、本発明品は、比較品で認められた分解物の増加がなく、ナルフラフィンの分解物の顕著な抑制効果を示した。 As is clear from Table 6, the product of the present invention had a high residual ratio of nalfurafine hydrochloride and a remarkable content stability compared to the comparative product. Further, as apparent from Table 7, the product of the present invention did not increase the decomposition products observed in the comparative product, and showed a remarkable inhibitory effect on the decomposition products of narfrafin.

Claims (3)

  1. 　カプセル内容物中にナルフラフィン又はその酸付加塩、疎水性の油性基剤及び没食子酸プロピルを含有し、カプセル皮膜中にチオ硫酸ナトリウムを含有するソフトカプセル剤。 A soft capsule containing nalfrafin or an acid addition salt thereof, a hydrophobic oily base and propyl gallate in the capsule contents, and sodium thiosulfate in the capsule film.
  2. 　ナルフラフィン又はその酸付加塩１質量部に対し、疎水性の油性基剤４００～２００，０００質量部、没食子酸プロピル１５０～２０，０００質量部を含有する請求項１記載のソフトカプセル剤。 The soft capsule according to claim 1, comprising 400 to 200,000 parts by weight of a hydrophobic oily base and 150 to 20,000 parts by weight of propyl gallate with respect to 1 part by weight of nalfurafine or an acid addition salt thereof.
  3. 　ナルフラフィン又はその塩１質量部に対し、チオ硫酸ナトリウム１５０～２０，０００質量部を含有する請求項１又は２記載のソフトカプセル剤。 The soft capsule according to claim 1 or 2, comprising 150 to 20,000 parts by mass of sodium thiosulfate with respect to 1 part by mass of nalfurafine or a salt thereof.
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