WO2009157586A1 - Patch transdermique renfermant du fentanyl ou l’un de ses sels - Google Patents

Patch transdermique renfermant du fentanyl ou l’un de ses sels Download PDF

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Publication number
WO2009157586A1
WO2009157586A1 PCT/JP2009/061853 JP2009061853W WO2009157586A1 WO 2009157586 A1 WO2009157586 A1 WO 2009157586A1 JP 2009061853 W JP2009061853 W JP 2009061853W WO 2009157586 A1 WO2009157586 A1 WO 2009157586A1
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WIPO (PCT)
Prior art keywords
fentanyl
salt
patch
butyl
styrene
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PCT/JP2009/061853
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English (en)
Japanese (ja)
Inventor
信己 中村
孝行 小川
義和 辻本
勝志 池田
Original Assignee
祐徳薬品工業株式会社
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Priority claimed from JP2008169211A external-priority patent/JP4856125B2/ja
Priority claimed from JP2008191840A external-priority patent/JP2010030909A/ja
Application filed by 祐徳薬品工業株式会社 filed Critical 祐徳薬品工業株式会社
Priority to CN2009801246133A priority Critical patent/CN102076340B/zh
Publication of WO2009157586A1 publication Critical patent/WO2009157586A1/fr

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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to a transdermal absorption patch containing fentanyl (chemical name: N- (1-phenethylpiperidin-4-yl) -N-phenylpropionamide) or a salt thereof.
  • the transdermal absorption patch containing fentanyl or a salt thereof provided by the present invention is a preparation that is excellent in drug stability over time and does not precipitate fentanyl crystals, and is a long-acting anesthetic and analgesic. It is expected to be used as a lot.
  • Fentanyl and its citrate are synthetic opioid analgesics, and are mainly used as an injection for the treatment of acute postoperative pain and chronic cancer pain. Furthermore, in addition to the injection, a patch containing fentanyl (see Patent Document 1) has been developed and has already been highly effective in clinical settings.
  • This patch has a reservoir type, is excellent in sustained release of fentanyl, has a longer action time than an injection, and is suitable for treatment of cancer pain.
  • the formulation consists of a support, a drug storage layer, a controlled release layer, an adhesive layer and a liner, and the preparation of the formulation is complicated and requires high precision technology. is there. Therefore, the production cost is higher than that of a general patch, and improvement is required.
  • matrix-type fentanyl-containing patches have been developed and used in the medical field. Since the matrix type patch has a simple structure and a simple manufacturing method compared to the reservoir type patch, it can be manufactured at a low cost. However, since matrix-type patches do not have a controlled release layer, compared with reservoir-type patches, in general, the drug can be transferred to the skin more rapidly, but the drug absorption can be sustained. The drug content is low, the drug content is lowered, and further, drug crystals are precipitated in the adhesive base, and improvement on the preparation is required.
  • Matrix-type fentanyl patches that improve the above problems have also been developed.
  • a patch containing fentanyl in a silicone adhesive base see Patent Document 2
  • fentanyl, polyisobutylene, styrene-isoprene-styrene block copolymer, and alicyclic saturated hydrocarbon resin as a tackifying resin Patch see Patent Document 3 alone
  • fentanyl, polyisobutylene, patch containing mineral oil and absorption promoter see Patent Document 4
  • two types of polyisobutylene having different molecular weights tackifier (tackifying) Agent
  • a patch containing an organic liquid agent as absorption accelerator
  • the silicone adhesive base used in Patent Document 2 is generally poor in adhesiveness to the skin, causes peeling and turning at the time of application, and stable administration of drugs to cancer patients, that is, There is a possibility that the effective blood concentration of the drug cannot be maintained.
  • the patch of Patent Document 3 is a preparation excellent in adhesiveness to the skin, but the alicyclic saturated hydrocarbon resin used for the tackifying resin is more compatible with fentanyl than other tackifying resins. The fentanyl dissolved in the plaster layer may recrystallize and precipitate over time. Furthermore, the patches of Patent Documents 4 and 5 have good formulation stability and excellent skin permeability, but there are problems such as reduced adhesion to the skin and the occurrence of skin irritation during sweating and bathing. There is a possibility.
  • isopropyl myristate which is an organic liquid agent, saturated or unsaturated. Blending of isostearyl alcohol, octyldodecanol, etc., which are saturated long-chain branched alcohols, has been performed, but both reduce the original adhesiveness of the adhesive base, causing peeling and turning during application, The effective blood concentration cannot be maintained, and the adhesive residue on the skin is caused by reducing the cohesiveness of the adhesive base, resulting in a decrease in patient compliance.
  • JP 61-37725 A JP-T-2006-513160 WO 2004/024155 WO2004 / 035054 JP 2006-76994 A Japanese Patent Laid-Open No. 10-45570
  • the present invention suppresses the precipitation of crystals of fentanyl or a salt thereof over time without reducing skin adhesiveness, has excellent drug stability, has low skin irritation, and skin permeability of fentanyl or a salt thereof
  • An object of the present invention is to provide a fentanyl transdermal patch which is extremely good.
  • fentanyl-N-oxide form An oxide form (hereinafter sometimes referred to as “fentanyl-N-oxide form”) is formed, and this fentanyl-N-oxide form is decomposed when maintained at 60 ° C. for 24 hours, for example, to produce N-phenylpropionamide.
  • the present inventors also suppressed the precipitation of crystals of fentanyl or a salt thereof over time without reducing skin adhesiveness, and had excellent drug stability and low skin irritation, and fentanyl or a salt thereof.
  • the adhesive base inherent in the production of a transdermal patch containing fentanyl or its salt Hindered phenol as a crystal precipitation inhibitor of fentanyl or a salt thereof, which is a bridge for improving the compatibility between fentanyl and an adhesive base, which is necessary for suppressing the crystallization of fentanyl over time without lowering the properties.
  • System antioxidants were found to be most suitable.
  • the present inventors added a hindered phenol-based antioxidant to the pressure-sensitive adhesive layer containing fentanyl or a salt thereof, and thereby the fentanyl crystals over time without reducing the original adhesiveness of the pressure-sensitive adhesive base. It has been found that a transdermal absorption patch can be obtained that suppresses precipitation, suppresses deterioration of the adhesive base with time, has good fentanyl skin permeability, and has low skin irritation. The invention has been completed.
  • one of the typical embodiments of the present invention is a transdermal patch containing fentanyl or a salt thereof characterized by containing 0.01 to 0.5% by mass of ascorbic acid ester.
  • transdermal patch containing fentanyl or a salt thereof ascorbic acid ester is 0.01 to 0 with respect to the total transdermal patch.
  • This is a method for stabilizing fentanyl or a salt thereof, characterized by containing 5% by mass.
  • the gist of another exemplary embodiment of the present invention is as follows. (1) A transdermal patch containing an effective amount of fentanyl or a salt thereof and a sufficient amount of a hindered phenol-based antioxidant to suppress precipitation of the fentanyl or a salt thereof.
  • a transdermal absorption type characterized in that the pressure-sensitive adhesive layer contains fentanyl or a salt thereof and a hindered phenol antioxidant, and the fentanyl or the salt thereof is present in a dissolved state in the pressure-sensitive adhesive layer. Patch.
  • a crystal precipitation inhibitor of fentanyl or a salt thereof containing a hindered phenol antioxidant as an active ingredient is a crystal precipitation inhibitor of fentanyl or a salt thereof containing a hindered phenol antioxidant as an active ingredient.
  • the present invention may include the following preferred embodiments.
  • transdermal patch comprising a support, fentanyl or a salt-containing pressure-sensitive adhesive layer, and a release liner
  • 0.01 to 0.5% by mass of ascorbic acid ester with respect to the total transdermal patch is fentanyl or Fentanyl contained in the salt-containing pressure-sensitive adhesive layer or a salt-containing transdermal patch.
  • Fentanyl or a salt thereof characterized in that 0.01 to 0.5% by mass of an ascorbic acid ester is incorporated in the transdermal patch containing fentanyl or a salt thereof with respect to the entire transdermal patch. Stabilization method.
  • the hindered phenolic antioxidant is 2,6-di-t-butyl-p-cresol or pentaerythrityl tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate]
  • a fentanyl or salt precipitation inhibitor composed of a hindered phenol-based antioxidant.
  • the hindered phenolic antioxidant is 2,6-di-t-butyl-p-cresol or pentaerythrityl tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate]
  • transdermal patch containing fentanyl or a salt thereof of the present invention By using the transdermal patch containing fentanyl or a salt thereof of the present invention, a preparation that can be stored for a long time and does not cause degradation of fentanyl or a salt thereof is obtained. The effect can be used effectively and continuously.
  • fentanyl or a salt thereof which is excellent in suppression of crystal precipitation of fentanyl or a salt thereof over time and excellent in drug stability without reducing the original adhesiveness of the adhesive base.
  • a transdermal patch is provided.
  • the fentanyl or salt-containing transdermal absorption patch obtained by the present invention can be an effective means for pain relief.
  • transdermal absorption patch containing fentanyl or a salt thereof of the present invention a method for stabilizing a transdermal absorption patch containing fentanyl or a salt thereof, and suppressing crystallization of fentanyl or a salt thereof over time.
  • the hindered phenolic antioxidant will be described in detail.
  • fentanyl-containing patch containing the fentanyl of the present invention or a salt thereof (hereinafter sometimes referred to as “fentanyl”) is as described above.
  • a synthetic opioid analgesic the chemical name of which is N- (1-phenethylpiperidin-4-yl) -N-phenylpropionamide.
  • the salt of fentanyl is not particularly limited as long as it is a pharmaceutically acceptable salt, and may be an inorganic salt or an organic salt.
  • Typical fentanyl salts include citrate, hydrochloride, fumarate and the like. Among these, fentanyl citrate is particularly preferable.
  • fentanyl or its salt may mix and use 2 or more types, it is usually good to use independently.
  • the effective amount of fentanyl is preferably in the range of 1 to 15% by mass, preferably 1 to 10% by mass in the pressure-sensitive adhesive composition.
  • fentanyl-containing patch of the present invention examples include dosage forms such as poultices and tapes, with tapes being preferred.
  • This tape basically comprises a support, an adhesive layer, and a release layer.
  • an effective amount of fentanyl and an amount of ascorbic acid sufficient to stabilize the fentanyl are contained. It is prepared by blending a sufficient amount of a hindered phenolic antioxidant to suppress crystal precipitation of ester and / or fentanyl and formulating it in accordance with a conventional method.
  • esters of ascorbic acid to be blended in the transdermal patch of the present invention include L-ascorbyl palmitate, L-ascorbate stearate, and L-ascorbate magnesium phosphate.
  • L-ascorbic acid palmitate is preferred because of its excellent compatibility with the soluble base.
  • the content of ascorbic acid ester is 0.01 to 0.5% with respect to the entire fentanyl-containing patch. If the blending amount is less than 0.01%, a sufficient stabilizing effect cannot be obtained, and if it exceeds 0.5%, there is no difference in stabilizing effect, and crystals of ascorbic acid ester itself precipitate. Therefore, the significance of increasing the amount cannot be found.
  • the ascorbic acid ester is preferably blended in a mass ratio (ascorbic acid ester / fentanyl or a salt thereof) in the range of 0.0015 to 0.5 with respect to the content of fentanyl or a salt thereof. If it is lower than 0.0015, a sufficient stabilizing effect may not be obtained, and even if it is higher than 0.5, further improvement of the effect may not be observed.
  • 2,6-di-t-butyl-p-cresol (trade name: Yoshinox) is used as a hindered phenol-based antioxidant that exhibits an effect of suppressing crystallization of fentanyl over time in a patch containing fentanyl.
  • the amount of hindered phenol-based antioxidant sufficient to suppress the precipitation of fentanyl crystals in the fentanyl-containing patch described above is 0.5 to 8% by mass, preferably 1.5 to 5% in the adhesive composition. %.
  • the amount of the hindered phenol-based antioxidant is less than 0.5%, sufficient fentanyl or a salt thereof is not obtained with the effect of suppressing crystal precipitation over time. There is no difference in the effect of suppressing typical crystal precipitation, and the significance of increasing the amount cannot be found.
  • the patch containing fentanyl that can be obtained by the present invention is suitable in that it has a long duration of medicinal effect and can maintain an analgesic effect for a long time.
  • the patch containing fentanyl which is an embodiment of the present invention, contains fentanyl or a salt thereof and an ester of ascorbic acid as a stabilizer in the pressure-sensitive adhesive layer, and more preferably hindered for suppressing crystal precipitation of fentanyl. Contains a phenolic antioxidant.
  • the adhesive base of the adhesive layer is preferably a hydrophobic adhesive base, and examples thereof include a rubber adhesive base, a hydrophobic acrylic adhesive base, and a silicone adhesive base.
  • the adhesive base is not particularly limited, but preferred examples include polyisobutylene (PIB), styrene-isoprene-styrene block copolymer (SIS) [for example, JSR Kraton elastomer; Kraton D-KX401CS, Kraton D-1107CP Manufactured by Shell Chemical Co., Ltd .; Califlex D-1111, Califlex TR-1107, manufactured by Nippon Synthetic Rubber; JSR5000, JSR-5002, SR5100, manufactured by Nippon Zeon Co., Ltd .; Quintac 3421, etc.], isoprene rubber [for example, Nippon Zeon NIPOL IR2200], styrene-butadiene-styrene block copolymer (SBS) [for example
  • the adhesive base is preferably blended in an amount of 0.1 to 98%, more preferably 0.1 to 70%, particularly 0.1 to 50% based on the mass of the entire adhesive layer of the fentanyl-containing patch.
  • the blending amount of the adhesive base is less than 0.1%, the physical properties of the preparation itself are deteriorated, and when it exceeds 98%, good adhesive strength to human skin may not be obtained.
  • a tackifier can be further blended in the adhesive layer in order to impart tackiness to the preparation.
  • tackifiers include rosin resins such as hydrogenated rosin glycerin esters, polyterpene resins, petroleum resins, and oil-soluble phenolic resin tackifiers. Specific examples of these include trade name, Clearon P-105, Foral 105, Archon P-100, KE-311, KE-100, Superester S-100, Tamorol 521, YS Resin 75, YS Resin PX1150N, KR -610 (all are trade names). These tackifiers are preferably blended in an amount of 10 to 70% by mass, particularly 20 to 60% by mass, based on the mass of the entire adhesive layer of the fentanyl-containing patch of the present invention.
  • fats and oils can be blended in the adhesive layer as a softening agent.
  • fats and oils for example, liquid paraffin, squalane, olive oil, camellia oil, persic oil, peanut oil and the like are preferable, and liquid paraffin is particularly preferable.
  • the fats and oils are preferably blended in an amount of 1 to 60% by mass, particularly 10 to 50% by mass based on the total mass of the adhesive layer of the fentanyl-containing patch of the present invention.
  • an absorption promoter can be blended in the plaster layer of the fentanyl-containing patch of the present invention as necessary.
  • the absorption enhancer may be any compound that has been recognized to promote absorption in the skin, such as fatty acids, fatty alcohols, fatty acid esters or ethers having 6 to 20 carbon chains, aromatic organic compounds, and the like. Mention may be made of acids, aromatic alcohols, aromatic organic acid esters or ethers.
  • lactic acid esters acetate esters, monoterpene compounds, sesquiterpene compounds, N-dodecylazacyclopentan-2-one (trade name: Azone) or derivatives thereof, glycerin fatty acid esters, sorbitan fatty acid esters, Examples thereof include polysorbate-based, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil-based, sucrose fatty acid esters.
  • Such an absorption accelerator is 0.01 to 20% by mass, more preferably 0.1 to 10% by mass, and particularly 0.5 to 5% by mass based on the total mass of the pressure-sensitive adhesive layer of the fentanyl-containing patch of the present invention. It is preferable to mix
  • the blending amount of the absorption accelerator exceeds 20% by mass, irritation to the skin such as redness and edema may be observed, and when it is less than 0.01% by mass, the effect of blending the absorption promoter is obtained. It may not be present and is not preferred.
  • a hydrophilic polymer can be blended as necessary to absorb aqueous components such as sweat generated from the skin.
  • the hydrophilic polymer include light silicic acid anhydride, cellulose derivatives (carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMCNa), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), Hydroxyethylcellulose (HEC)), starch derivatives (pullulan), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), vinyl acetate (VA), carboxyvinyl polymer (CVP), ethylene vinyl acetate copolymer (EVA), acrylic polymer (Trade name: Eudragit), gelatin, polyacrylic acid, sodium polyacrylate, polyisobutylene maleic anhydride copolymer, alginic acid, sodium alginate, Raginan, gum arabic, tragacanth,
  • the pressure-sensitive adhesive layer of the fentanyl-containing patch of the present invention can be blended with other components such as a cross-linking agent, preservative, and ultraviolet absorber, if desired.
  • a cross-linking agent include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds.
  • the preservative ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate and the like are preferable.
  • UV absorbers examples include 4-tert-butyl-4′-methoxybenzoylmethane, 2- (4-diethylamino-2-hydroxybenzoyl) benzoic acid n-hexyl ester, 4-hydroxy-3-methoxycinnamic acid, Branched alkyl esters of 4-hydroxy-3-methoxycinnamic acid, terephthalylidene-3,3′-dicamphor-10,10′-disulfonic acid, 2- (2H-benzotriazol-2-yl) -4 -Methyl-6- [2-methyl-3- [1,3,3,3-tetramethyl-1-[(trimethylsilyl) oxydisiloxanyl] propyl] dioxoimidazolidinepropionic acid 2-ethylhexyl ester, 1 -(3,4-dimethoxyphenyl) -4,4-dimethyl-1,3-pentanedione, 2- (2-hydroxy-5-methoxyphen
  • the pressure-sensitive adhesive layer having the above composition can be produced by any known method.
  • fentanyl or a salt thereof, ascorbic acid ester as a stabilizer, more preferably a hindered phenol type as a crystallization inhibitor in an organic solvent solution of an adhesive base to be blended
  • the fentanyl-containing patch of the present invention can be obtained by coating on a support or release sheet, drying, and cutting into an arbitrary area.
  • a rosin resin is used as a tackifier, the stabilizing effect on fentanyl or a salt thereof is improved by treating the rosin resin with an ester of ascorbic acid in advance.
  • Examples of the treatment method using an ester of ascorbic acid include a method in which an ester of ascorbic acid and a rosin resin are dissolved in an appropriate solvent and left at 1 to 30 ° C. for 24 to 72 hours. More specifically, a solution in which a rosin resin is dissolved in a solvent such as benzene, toluene, xylene, and hexane is mixed with a solution in which an ester of ascorbic acid is dissolved in a solvent such as ethanol or isopropanol. Stabilization effect on fentanyl or a salt thereof is improved by adding fentanyl or a salt thereof after standing at 1 to 30 ° C. for 24 to 72 hours.
  • the coating on the support or release sheet is preferably performed so that the thickness of the pressure-sensitive adhesive layer when dried is 10 to 150 ⁇ m. If the thickness of the pressure-sensitive adhesive layer is less than 10 ⁇ m, sufficient adhesive strength to the skin may not be maintained, and if it exceeds 150 ⁇ m, the preparation may be peeled off or turned up due to rubbing against clothes, which is not preferable.
  • the area of the fentanyl-containing patch of the present invention when applied to the skin is preferably 2.5 to 60 cm 2 .
  • the area is less than 2.5 cm 2 , sufficient transdermal absorbability of fentanyl may not be obtained in treatment, and handling properties may be reduced. If the area exceeds 60 cm 2 , a sense of incongruity may occur during application, which may reduce the compliance of cancer patients.
  • the fentanyl-containing patch of the present invention can comprise a pressure-sensitive adhesive layer, a support layer for supporting the same, a release liner layer provided on the pressure-sensitive adhesive layer, and the like.
  • the support layer is, for example, cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, ethylene vinyl acetate copolymer (EVA), polyvinylidene chloride, polyethylene, polyethylene terephthalate (PET), polybutylene terephthalate, paper, aluminum sheet, etc. Or it can consist of those composite materials.
  • the release sheet is selected and used from, for example, a film made of a polymer material such as polyethylene terephthalate coated with silicone oil, or a sheet coated with silicone oil or the like on paper.
  • the laminated body thus manufactured may be cut into an arbitrary area as described above using a known cutting machine and enclosed in a packaging material such as an aluminum packaging material.
  • One of the characteristics of the fentanyl-containing patch of the present invention obtained as described above is that an effective amount of fentanyl is present in a dissolved state in the adhesive layer.
  • the presence of fentanyl in a dissolved state means that the fentanyl crystals are not observed when the pressure-sensitive adhesive layer is visually observed or observed with an optical microscope, and the pressure-sensitive adhesive layer is in a uniform state.
  • problems due to crystal formation in a conventional patch containing fentanyl are prevented, and the pharmacological effect of fentanyl is more effective. It is possible to use it.
  • fentanyl-containing patch of the present invention since fentanyl is continuously absorbed through the skin, it is an effective means of pain relief for patients who are difficult to administer narcotic analgesics. Become. Moreover, compared with the continuous subcutaneous administration method which is an invasive administration method, it can administer noninvasively and can also reduce a patient's burden. The dose can also be easily adjusted according to the patient's symptoms, age, weight, sex, etc., by cutting the preparation into an arbitrary size by a doctor.
  • fentanyl-N-oxide is, for example, an adhesive of a transdermal patch.
  • the fentanyl-containing patch of the present invention can be selected by containing an ester of ascorbic acid as a stabilizer, so that the primary decomposition product fentanyl-N-oxide, and further its thermal decomposition product, The production of certain four kinds of secondary decomposition products can be suppressed, and the drug stability over time is excellent.
  • Example 1-1 Patch containing fentanyl (1-1) A transdermal patch of the following formulation was prepared by the following production method. (How to) Fentanyl 1.0% Styrene-isoprene-styrene block copolymer * 18.2% Polyisoprene 9.8% Hydrogenated rosin glycerin ester ** 1.0% Polyterpene resin *** 41.99% Polybutene 14.0% Liquid paraffin 14.0% L-ascorbyl palmitate 0.01% Total 100% * : JSR Kraton elastomer, Kraton D-KX401CS ** : Arakawa Chemical Industries, Pine Crystal KE-311 *** : Arakawa Chemical Industries, Alcon P-100
  • Examples 1-2 Patch containing fentanyl (1-2) A transdermal patch of the following formulation was prepared by the following production method. (Prescription) Fentanyl 4.0% Styrene-isoprene-styrene block copolymer * 18.2% Polyisoprene 9.8% Hydrogenated rosin glycerin ester ** 5.0% Polyterpene resin *** 34.98% Polybutene 14.0% Liquid paraffin 14.0% L-ascorbyl palmitate 0.02% Total 100% * , ** and *** : Same as Example 1-1.
  • Examples 1-3 Patch containing fentanyl (1-3) A transdermal patch of the following formulation was prepared by the following production method. (Prescription) Fentanyl 6.0% Styrene-isoprene-styrene block copolymer * 18.2% Polyisoprene 9.8% Hydrogenated rosin glycerin ester ** 10.0% Polyterpene resin *** 27.5% Polybutene 14.0% Liquid paraffin 14.0% L-ascorbyl palmitate 0.5% Total 100% * , ** and *** : Same as Example 1-1.
  • Example 1-4 Fentanyl-containing patch (1-4) A transdermal patch of the following formulation was prepared by the following production method. (Prescription) Fentanyl 4.0% Styrene-isoprene-styrene block copolymer * 18.2% Polyisoprene 9.8% Hydrogenated rosin glycerin ester ** 5.0% Polyterpene resin *** 34.9% Polybutene 14.0% Liquid paraffin 14.0% L-ascorbyl palmitate 0.1% Total 100% * , ** and *** : Same as Example 1-1.
  • Example 1-5 Patch containing fentanyl (1-5) A transdermal patch of the following formulation was prepared by the following production method. (Prescription) Fentanyl 4.0% Styrene-isoprene-styrene block copolymer * 18.2% Polyisoprene 9.8% Hydrogenated rosin glycerin ester ** 5.0% Polyterpene resin *** 33.0% Polybutene 14.0% Liquid paraffin 14.0% L-ascorbyl palmitate 0.1% 3,5-di-tert-butyl-p-cresol 1.9% Total 100% * , ** and *** : Same as Example 1-1.
  • Example 1-6 Patch containing fentanyl (1-6) A transdermal patch of the following formulation was prepared by the following production method. (Prescription) Fentanyl 4.0% Styrene-isoprene-styrene block copolymer * 18.2% Polyisoprene 9.8% Hydrogenated rosin glycerin ester ** 5.0% Polyterpene resin *** 31.5% Polybutene 14.0% Liquid paraffin 14.0% L-ascorbyl palmitate 0.5% 3,5-di-tert-butyl-p-cresol 3.0% Total 100% * , ** and *** : Same as Example 1-1.
  • Example 1-7 Patch containing fentanyl (1-7) A transdermal patch of the following formulation was prepared by the following production method. (Prescription) Fentanyl 4.0% Styrene-isoprene-styrene block copolymer * 18.2% Polyisoprene 9.8% Hydrogenated rosin glycerin ester ** 5.0% Polyterpene resin *** 33.0% Polybutene 14.0% Liquid paraffin 14.0% L-ascorbyl palmitate 0.02% 3,5-di-tert-butyl-p-cresol 1.98% Total 100% * , ** and *** : Same as Example 1-1.
  • Example 1-8 Patch containing fentanyl (1-8) A transdermal patch of the following formulation was prepared by the following production method. (Prescription) Fentanyl 4.0% Styrene-isoprene-styrene block copolymer * 18.2% Polyisoprene 9.8% Hydrogenated rosin glycerin ester ** 10.0% Polyterpene resin *** 26.5% Polybutene 14.0% Liquid paraffin 14.0% L-ascorbyl palmitate 0.5% 3,5-di-tert-butyl-p-cresol 3.0% Total 100% * , ** and *** : Same as Example 1-1.
  • Test Example 1-1 Fentanyl-N-oxide production inhibitory action For the preparations obtained in Examples 1-2, 1-4, 1-6 and Comparative Examples 1-1, 1-2, fentanyl, fentanyl-N The amount of oxide and styrene produced was measured over time. The measuring method is as follows. Each test substance cut to 10.5 cm 2 was packaged one by one in an aluminum wrapping material, stored at room temperature, and measured over time for fentanyl, fentanyl-N-oxide and styrene. The release sheet of each test substance was peeled off, taken into a 50 mL centrifugal settling tube, added with 5 mL of tetrahydrofuran, and shaken for 20 minutes to completely dissolve the plaster.
  • the operation of high performance liquid chromatography consists of a column filled with a stainless tube with an inner diameter of 4.6 mm and a length of 10 cm (3 ⁇ m) octadecylsilylated silica gel for liquid chromatography (column temperature: constant temperature around 40 ° C.), detection wavelength Is 215 nm, the mobile phase is 2.72 g of potassium dihydrogen phosphate dissolved in 1000 mL of water, and a sodium hydroxide reagent solution is added to adjust the pH to 4.7 (mobile phase A) and acetonitrile for liquid chromatography (mobile phase B) The mobile phase was fed by mixing the mobile phase A and the mobile phase B under arbitrary conditions and controlling the concentration gradient. The results are summarized in Table 1.
  • FEN means fentanyl
  • N-oxide means fentanyl-N-oxide
  • styrene is the lowest molecular weight compound among the fentanyl degradation products.
  • Example 2-1 Patch containing fentanyl (2-1) A patch containing fentanyl was produced by the following composition and production method.
  • composition Fentanyl 1.0% Styrene-isoprene-styrene block copolymer * 15.8% Polyisoprene 8.5% Alicyclic saturated hydrocarbon resin ***** 15.5% Polyterpene resin *** 34.0% Liquid paraffin 24.2% 2,6-Di-tert-butyl-p-cresol 1.0% Total 100% * And *** : Same as Example 1-1. *** Yasuhara Chemical, YS Resin PX1150N
  • Styrene-isoprene-styrene block copolymer, polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and 2,6-di-t-butyl-p-cresol are added, mixed and stirred, and completely dissolved in toluene Dissolved in. Thereafter, fentanyl was added and further stirred and mixed to obtain a uniform dissolved product.
  • this dissolved material was coated on a release film (silicone-treated PET film, Fujimori Kogyo) using a doctor knife coating machine, then air-dried, and a support (PET / EVA laminated film, Fujimori on the coated surface). Industrial) was cut to a size of 42 cm 2 and packaged in an aluminum wrapping material to obtain a patch.
  • Example 2-2 Patch containing fentanyl (2-2) A patch containing fentanyl was produced by the following composition and production method.
  • composition Fentanyl 6.0% Styrene-isoprene-styrene block copolymer * 15.8% Polyisoprene 8.5% Alicyclic saturated hydrocarbon resin *** 10.5% Polyterpene resin *** 30.0% Liquid paraffin 24.2% 2,6-Di-tert-butyl-p-cresol 5.0% Total 100% * And *** : Same as Example 1-1. *** : Same as Example 2-1.
  • Styrene-isoprene-styrene block copolymer, polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and 2,6-di-t-butyl-p-cresol are added, mixed and stirred, and completely dissolved in toluene Dissolved in. Thereafter, fentanyl was added and further stirred and mixed to obtain a uniform dissolved product.
  • this dissolved material was coated on a release film (silicone-treated PET film, Fujimori Kogyo) using a doctor knife coating machine, then air-dried, and a support (PET / EVA laminated film, Fujimori on the coated surface). Industrial) was cut to a size of 42 cm 2 and packaged in an aluminum wrapping material to obtain a patch.
  • Example 2-3 Fentanyl-containing patch (2-3) A patch containing fentanyl was produced by the following composition and production method.
  • composition Fentanyl 3.0% Styrene-isoprene-styrene block copolymer * 15.8% Polyisoprene 8.5% Alicyclic saturated hydrocarbon resin *** 12.5% Polyterpene resin *** 34.0% Liquid paraffin 24.2% 4,4'-butylidenebis- (6-t-butyl- 2.0% 3-methylphenol) Total 100% * And *** : Same as Example 1-1. *** : Same as Example 2-1.
  • Example 2-4 Patch containing fentanyl (2-4) A patch containing fentanyl was produced by the following composition and production method.
  • composition Fentanyl 1.0% Styrene-isoprene-styrene block copolymer * 15.8% Polyisoprene 8.5% Alicyclic saturated hydrocarbon resin *** 14.5% Polyterpene resin *** 34.0% Liquid paraffin 24.2% 2,2'-methylenebis- (4-ethyl- 2.0% 6-t-butylphenol) Total 100% * And *** : Same as Example 1-1. *** : Same as Example 2-1.
  • Example 2-5 Patch containing fentanyl (2-5) A patch containing fentanyl was produced by the following composition and production method.
  • composition Fentanyl 2.0% Styrene-isoprene-styrene block copolymer * 15.8% Polyisoprene 8.5% Alicyclic saturated hydrocarbon resin *** 12.5% Polyterpene resin *** 34.0% Liquid paraffin 24.2% Pentaerythrityl tetrakis [3- (3,5-di-tert-butyl-4-hydro 3.0% Xiphenyl) propionate] Total 100% * And *** : Same as Example 1-1. *** : Same as Example 2-1.
  • Styrene-isoprene-styrene block copolymer Styrene-isoprene-styrene block copolymer, polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and pentaerythrityl tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl ) Propionate] was added and stirred, and completely dissolved in toluene. Thereafter, fentanyl was added and further stirred and mixed to obtain a uniform dissolved product.
  • this dissolved material was coated on a release film (silicone-treated PET film, Fujimori Kogyo) using a doctor knife coating machine, then air-dried, and a support (PET / EVA laminated film, Fujimori on the coated surface). Industrial) was cut to a size of 42 cm 2 and packaged in an aluminum wrapping material to obtain a patch.
  • Example 2-6 Fentanyl-containing patch (2-6) A patch containing fentanyl was produced by the following composition and production method.
  • Example 2-7 Patch containing fentanyl (2-7) A patch containing fentanyl was produced by the following composition and production method.
  • composition Fentanyl 3.0% Styrene-isoprene-styrene block copolymer * 15.8% Polyisoprene 8.5% Alicyclic saturated hydrocarbon resin *** 14.5% Polyterpene resin *** 34.0% Liquid paraffin 22.7% Pentaerythrityl tetrakis [3- (3,5-di-tert-butyl-4-hydro 1.5% Xiphenyl) propionate] Total 100% * And *** : Same as Example 1-1. *** : Same as Example 2-1.
  • Styrene-isoprene-styrene block copolymer Styrene-isoprene-styrene block copolymer, polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and pentaerythrityl tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl ) Propionate] was added and stirred, and completely dissolved in toluene. Thereafter, fentanyl was added and further stirred and mixed to obtain a uniform dissolved product.
  • this dissolved material was coated on a release film (silicone-treated PET film, Fujimori Kogyo) using a doctor knife coating machine, then air-dried, and a support (PET / EVA laminated film, Fujimori on the coated surface). Industrial) was cut to a size of 42 cm 2 and packaged in an aluminum wrapping material to obtain a patch.
  • Example 2-8 Patch containing fentanyl (2-8) A patch containing fentanyl was produced by the following composition and production method.
  • composition Fentanyl 2.0% Styrene-isoprene-styrene block copolymer * 15.8% Polyisoprene 8.5% Alicyclic saturated hydrocarbon resin ***** 15.5% Polyterpene resin *** 34.0% Liquid paraffin 22.7% 2,6-Di-tert-butyl-p-cresol 1.5% Total 100% * And *** : Same as Example 1-1. *** : Same as Example 2-1.
  • Styrene-isoprene-styrene block copolymer, polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and 2,6-di-t-butyl-p-cresol are added, mixed and stirred, and completely dissolved in toluene Dissolved in. Thereafter, fentanyl was added and further stirred and mixed to obtain a uniform dissolved product.
  • this dissolved material was coated on a release film (silicone-treated PET film, Fujimori Kogyo) using a doctor knife coating machine, then air-dried, and a support (PET / EVA laminated film, Fujimori on the coated surface). Industrial) was cut to a size of 42 cm 2 and packaged in an aluminum wrapping material to obtain a patch.
  • Example 2-9 Patch containing fentanyl (2-9) A patch containing fentanyl was produced by the following composition and production method.
  • composition Fentanyl 6.0% Styrene-isoprene-styrene block copolymer * 15.8% Polyisoprene 8.5% Alicyclic saturated hydrocarbon resin *** 9.5% Polyterpene resin *** 30.0% Liquid paraffin 24.2% 2,6-Di-tert-butyl-p-cresol 5.0% Oleyl alcohol 1.0% Total 100% * And *** : Same as Example 1-1. *** : Same as Example 2-1.
  • Example 2-10 Patch containing fentanyl (2-10) A patch containing fentanyl was produced by the following composition and production method.
  • Comparative Example 2-1 Comparative patch containing fentanyl (2-1) A fentanyl-containing comparative patch was produced by the following composition and production method.
  • Comparative Example 2-2 Comparative patch containing fentanyl (2-2) A fentanyl-containing comparative patch was produced by the following composition and production method.
  • Comparative Example 2-3 Comparative patch containing fentanyl (2-3) A fentanyl-containing comparative patch was produced by the following composition and production method.
  • Comparative Example 2-4 Comparative patch containing fentanyl (2-4) A fentanyl-containing comparative patch was produced by the following composition and production method.
  • composition Fentanyl 10.0% Acrylic polymer + 90.0% Total 100% + : Same as Example 2-6.
  • Comparative Example 2-5 Comparative patch containing fentanyl (2-5) A fentanyl-containing comparative patch was produced by the following composition and production method.
  • Styrene-isoprene-styrene block copolymer, polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and octyldodecanol were taken, mixed and stirred, and completely dissolved in toluene. Thereafter, fentanyl was added, and further stirred and mixed to obtain a uniform dissolved product. Next, this dissolved material was coated on a release film (silicone-treated PET film, Fujimori Kogyo) using a doctor knife coating machine, then air-dried, and a support (PET / EVA laminated film, Fujimori on the coated surface). Industrial) was cut to a size of 42 cm 2 and packaged in an aluminum wrapping material to obtain a comparative patch.
  • Test Example 2-1 Inhibition of Crystal Precipitation of Fentanyl
  • the evaluation method is as follows.
  • each test preparation cut to 42 cm 2 was packaged one by one in an aluminum wrapping material and stored at 4 ° C., and the fentanyl crystal precipitation state over time was visually evaluated.
  • ⁇ was given when there was very little crystal precipitation
  • x was given when considerable crystal precipitation was observed
  • ⁇ was given when there was no crystal precipitation at all.
  • Test example 2-2 Adhesion test: For the patches prepared in Example 2-2 and Comparative Example 2-5, a placebo patch (a patch excluding fentanyl alone) was prepared, and the feeling of use was tested. In the test, the test preparation was applied to the breasts of 12 healthy adult males for 3 days, and the adhesive condition at that time and the adhesive residue of the paste on the skin at the time of peeling were evaluated according to the following criteria. The results are shown in Table 3.
  • hindered phenol-based antioxidants particularly 2,6-di-t-butyl-p-, as fentanyl crystallization inhibitor, which suppresses crystallization of fentanyl over time.
  • the fentanyl-containing patch of the present invention containing an ester of ascorbic acid as a stabilizer can be stored for a long time and does not cause degradation of fentanyl or a salt thereof.
  • the effect can be used effectively and continuously.
  • a hindered phenolic antioxidant is added as a crystal precipitation inhibitor, it suppresses the crystallization of fentanyl or its salt over time, exhibits low irritation, and exhibits excellent adhesion and skin permeability. Is done.

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Abstract

La présente invention a pour objet un patch renfermant du fentanyl ou l’un de ses dérivés qui ne provoque aucune diminution de l’adhésivité à la peau, présente une stabilité élevée du médicament, peut inhiber le dépôt dépendant du temps des cristaux de fentanyl, irrite cependant peu la peau et affiche une perméabilité cutanée extrêmement élevée du fentanyl. Ce patch renfermant du fentanyl ou l’un de ses dérivés est constitué d’un support, d’une couche adhésive sensible à la pression renfermant le fentanyl ou l’un de ses dérivés et d’une membrane de libération, la couche adhésive sensible à la pression renfermant le fentanyl ou l’un de ses dérivés contenant 0,01 à 0,5 % en masse d’un ascorbate tel qu’un L-ascorbate palmitate. Ce patch renfermant du fentanyl ou l’un de ses dérivés contient en outre un antioxydant du type phénol encombré dans une quantité suffisante pour l’inhibition du dépôt de fentanyl ou de l’un de ses sels.
PCT/JP2009/061853 2008-06-27 2009-06-29 Patch transdermique renfermant du fentanyl ou l’un de ses sels WO2009157586A1 (fr)

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JP2008169211A JP4856125B2 (ja) 2008-06-27 2008-06-27 安定化されたフェンタニルまたはその塩含有組成物及びこれを用いた医薬製剤並びにフェンタニルまたはその塩の安定化方法
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JP2008191840A JP2010030909A (ja) 2008-07-25 2008-07-25 フェンタニル類を含む経皮吸収型貼付剤およびその製造方法ならびにフェンタニル類の結晶析出抑制方法および結晶析出抑制剤

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Cited By (4)

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WO2011010645A1 (fr) * 2009-07-24 2011-01-27 帝國製薬株式会社 Préparation adhésive contenant du fentanyl destinée à un usage externe
EP2462927A1 (fr) * 2010-12-03 2012-06-13 Hexal AG Système thérapeutique transdermique comportant du fentanyl
WO2017073516A1 (fr) * 2015-10-26 2017-05-04 久光製薬株式会社 Timbre cutané adhésif
US9650338B1 (en) 2016-07-29 2017-05-16 VDM Biochemicals, Inc. Opioid antagonist compounds and methods of making and using

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WO2011010645A1 (fr) * 2009-07-24 2011-01-27 帝國製薬株式会社 Préparation adhésive contenant du fentanyl destinée à un usage externe
US9375422B2 (en) 2009-07-24 2016-06-28 Teikoku Seiyaku Co., Ltd. Fentanyl-containing adhesive preparation for external use
US10143662B2 (en) 2009-07-24 2018-12-04 Teikoku Seiyaku Co., Ltd. Fentanyl-containing adhesive preparation for external use
EP2462927A1 (fr) * 2010-12-03 2012-06-13 Hexal AG Système thérapeutique transdermique comportant du fentanyl
WO2017073516A1 (fr) * 2015-10-26 2017-05-04 久光製薬株式会社 Timbre cutané adhésif
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US9650338B1 (en) 2016-07-29 2017-05-16 VDM Biochemicals, Inc. Opioid antagonist compounds and methods of making and using

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