Classifications

• • 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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• Health & Medical Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Cited By (3)

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• 2016
  • 2016-06-02 TW TW105117439A patent/TW201707703A/zh unknown
  • 2016-06-03 WO PCT/JP2016/066537 patent/WO2016195057A1/ja active Application Filing
  • 2016-06-03 CN CN201680032582.9A patent/CN107613982A/zh active Pending
  • 2016-06-03 JP JP2016550820A patent/JP6082503B1/ja active Active
  • 2016-06-03 KR KR1020177034467A patent/KR20180013934A/ko not_active Application Discontinuation

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