WO2008044336A1 - Préparation adhésive contenant un cristal - Google Patents

Préparation adhésive contenant un cristal Download PDF

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Publication number
WO2008044336A1
WO2008044336A1 PCT/JP2007/001104 JP2007001104W WO2008044336A1 WO 2008044336 A1 WO2008044336 A1 WO 2008044336A1 JP 2007001104 W JP2007001104 W JP 2007001104W WO 2008044336 A1 WO2008044336 A1 WO 2008044336A1
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WO
WIPO (PCT)
Prior art keywords
drug
adhesive layer
patch
pressure
sensitive adhesive
Prior art date
Application number
PCT/JP2007/001104
Other languages
English (en)
Japanese (ja)
Inventor
Takaaki Terahara
Kazunosuke Aida
Yasunari Michinaka
Akio Takeuchi
Naoyuki Uchida
Original Assignee
Hisamitsu Pharmaceutical Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hisamitsu Pharmaceutical Co., Inc. filed Critical Hisamitsu Pharmaceutical Co., Inc.
Priority to JP2008538566A priority Critical patent/JP5243254B2/ja
Publication of WO2008044336A1 publication Critical patent/WO2008044336A1/fr

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • 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
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a patch containing a drug in a dissolved state and a crystalline state in an adhesive layer. Furthermore, the present invention relates to a patch that has excellent adhesion to the skin and can be continuously absorbed from the skin at a high absorption rate even in the state where drug crystals are precipitated in the adhesive layer.
  • the technology of a transdermal absorption preparation that absorbs a drug contained in an adhesive layer through the skin is one of useful drug delivery systems for administering a drug for the treatment of a disease.
  • the formulation has been devised.
  • the drug supplied into the body from the preparation depends on the concentration gradient between the drug concentration dissolved in the adhesive layer and the drug concentration on the skin surface. If only a small amount of drug can be dissolved in the adhesive layer because it moves through the skin tissue, the absorption rate will decrease and it will be difficult to obtain a sufficient therapeutic effect. When the drug is consumed and the concentration gradient cannot be maintained, the absorption rate is lowered and the therapeutic effect is not sustained. For this reason, in order to maintain good percutaneous absorption of the drug over a long period of time and maintain the therapeutic effect of the absorbed drug, more drug is present in the adhesive layer in the dissolved state. However, it is necessary to maintain a sufficient concentration.
  • drugs with low saturation solubility in the adhesive layer limit the amount of drug that can be dissolved, thus increasing the absorption rate and increasing the drug concentration necessary to maintain absorption over a long period of time. It was difficult to maintain in the adhesive layer.
  • Patent Document 4 Percutaneous absorbability that is recrystallized and contains recrystallized particles of almost uniform size Formulation (refer to Patent Document 4), crystal mixed percutaneous absorption preparation that has been subjected to aging for a long time at low and high temperatures in order to deposit recrystallized particles in the adhesive uniformly and stably (Patent Document) (See 5).
  • the crystals are uniformly dispersed in the adhesive layer, and the crystals are deposited even on the surface of the adhesive layer, that is, the part that adheres to the skin and mucous membrane, so that the drug is completely dissolved in the adhesive layer.
  • the adhesive strength tends to decrease, and the applied state of the preparation to the skin surface tends to be insufficient, resulting in decreased adhesion to the skin and mucous membranes, and as a result, drug absorption does not continue for a long time. There was an inconvenience.
  • donepezil which is an acetylcholinesterase inhibitor
  • tandospirone which is a serotonin 5 HT 1 A receptor agonist
  • parenteral administration such as transdermal administration has been attracting attention as an administration form.
  • Patent Document 6 proposes a preparation for parenteral administration of donepezil hydrochloride as an ointment or suppository
  • Patent Document 7 discloses a transdermal substance contained in an adhesive composition in a dispersed state.
  • Absorption formulations have also been proposed. Although these drugs are expected to be effective as plasma preparations with plasma concentrations similar to those obtained by oral administration, they need to be replaced in order to continue treatment over a long period of time. There was a desire to provide a smaller area formulation.
  • Patent Document 1 Japanese Patent No. 2 6 9 7 1 9 1
  • Patent Document 2 Japanese Patent No. 2 7 5 3 8 0 0
  • Patent Document 3 Japanese Patent Application Laid-Open No. 6 3-30 0 8 8 18
  • Patent Document 4 JP-A-6 0-1 8 5 7 1 3
  • Patent Document 5 Japanese Unexamined Patent Publication No. 2 0 0 5 _ 3 5 0 3 7 3
  • Patent Document 6 Japanese Patent Laid-Open No. 11-3 1 5 0 1 6
  • Patent Document 7 WO 2 0 0 3/0 3 2 9 60
  • the present invention provides a patch in which a dissolved drug and a crystalline drug coexist in the adhesive layer, and suppresses a decrease in skin adhesive force caused by crystallization of the drug to a minimum. 2 It is an object to provide a patch capable of continuously supplying a drug from the skin for 4 hours or more.
  • the present invention comprises a pressure-sensitive adhesive layer on one side of a support, and the pressure-sensitive adhesive layer is a five-layered material.
  • the present invention also relates to a patch that is less distributed on the surface of the pressure-sensitive adhesive layer that adheres to the skin.
  • the present invention also relates to a patch in which no crystalline drug exists on the surface of the pressure-sensitive adhesive layer that adheres to the skin.
  • the present invention relates to a patch characterized in that in the pressure-sensitive adhesive layer, there are more drugs present in a crystalline state than drugs present in a dissolved state.
  • the drug contained in the pressure-sensitive adhesive layer is selected from the group consisting of donevezil, tandspirone, amproxol, and risperidone, and pharmaceutically acceptable salts thereof.
  • the present invention relates to one or more types of patches, wherein the pressure-sensitive adhesive layer contains at least one tackifying resin selected from styrene-isoprene-styrene block copolymer and alicyclic saturated hydrocarbon or terpene resin. It relates to a patch to be used.
  • the present invention also relates to a patch wherein the blending ratio of the styrene-isoprene-styrene block copolymer and the tackifying resin contained in the pressure-sensitive adhesive layer is from 1: 1 to 1:10.
  • the pressure-sensitive adhesive layer contains 5 to 15% by mass of a drug in a dissolved state and a crystalline state with respect to the total weight of the adhesive layer.
  • the drug contained in the adhesive layer is at least one selected from the group consisting of donevezil, tandospirone, amproxol, and risperidone, and pharmaceutically acceptable salts thereof.
  • the patch according to any one of (1) to (5) above.
  • the pressure-sensitive adhesive layer further contains at least one selected from pressure-sensitive adhesives made of polyisobutylene or an acrylic polymer.
  • the pressure-sensitive adhesive layer further contains at least one plasticizer selected from the group consisting of liquid rubber, petroleum oil, and liquid fatty acid esters.
  • the pressure-sensitive adhesive layer further comprises at least one selected from the group consisting of fatty acids having 6 to 20 carbon atoms, esters of the fatty acids, amides of the fatty acids, pyrothiodecane, and propylene glycol fatty acid esters.
  • the adhesive strength measured with a peel measuring machine is 300 g / cm to 700 g / cm.
  • the crystalline drug in the adhesive layer adheres to the skin rather than the support side of the adhesive layer.
  • the density of the drug in the crystalline state in the pressure-sensitive adhesive layer is directed from the surface of the pressure-sensitive adhesive layer adhering to the skin to the surface adhering to the support (the surface opposite to the surface of the pressure-sensitive adhesive layer).
  • the density of the crystalline drug changes stepwise, continuously, discontinuously, or irregularly, and as a result, the crystalline drug in the adhesive layer adheres to the skin rather than the support side of the adhesive layer.
  • the drug in a crystalline state may be present in any distribution state inside the pressure-sensitive adhesive layer.
  • a conventional patch containing an excessive amount of drug even if no crystal deposition is observed immediately after production, it is stored at room temperature (25 ° C) for a long time (from 3 days to about 2 weeks) Crystals are intensively deposited on the surface of the pressure-sensitive adhesive layer on the release liner side, but such a phenomenon does not occur in the patch of the present invention.
  • the pressure-sensitive adhesive is 0% by mass.
  • drugs with saturation solubility or higher are included in the crystalline state in the drug layer, they have sufficient adhesive strength to adhere to the skin for 24 hours, and have excellent drug absorbability and drug efficacy. It can be used as a patch for imparting durability to the skin. Furthermore, it is possible to provide a patch that exhibits a stable therapeutic effect in the treatment of diseases and the like and can be used safely as a pharmaceutical product.
  • the configuration of the patch of the present invention is not particularly limited, but for example, a form including a single adhesive layer shown in FIG. 1 is preferable. That is, the support surface is provided with a drug-containing pressure-sensitive adhesive layer, and the pressure-sensitive adhesive layer surface is covered with a release liner layer that is peeled and removed when the preparation is used.
  • the drug contained in the adhesive layer of the patch of the present invention is blended in the base at a concentration equal to or higher than the saturation solubility, the drug in a dissolved state and a crystalline state exist together. That is, in the adhesive layer of the patch of the present invention, a drug that cannot be dissolved because it exceeds the saturation solubility exists in a crystalline state. Furthermore, the patch of the present invention can improve the drug absorption rate depending on the amount of the drug even in the concentration range exceeding the saturation solubility of the drug in the adhesive layer.
  • the drug in the crystalline state may be either a crystal that does not dissolve in the manufacturing process of the patch, or a crystal that is recrystallized after dissolving in the manufacturing process, and the effect of the present invention does not change in both cases.
  • the drug saturation solubility in the pressure-sensitive adhesive layer in the present invention is preferably from 0.1 to 5% by mass, and more preferably from 0.5 to 4.5% by mass. If the amount is less than 0.1% by mass, there are few drugs in the dissolved state, so that the drug is not sufficiently absorbed from the skin, or the dissolved drug tends to be consumed and the sustainability of absorption tends to be impaired.
  • the drug contained in the patch of the present invention is not particularly limited as long as it is effective for treatment.
  • it can be blended in an amount of 5 to 15% by mass with respect to the total mass of the pressure-sensitive adhesive, preferably an amount exceeding 5% by mass to an amount less than 15% by mass, more preferably 5.1 to 1 4. 9 mass 0 / o, 5. 5 ⁇ 1 4. 5 mass 0 / o, or 6-1 4 mass 0 / o, more preferably from 6 1 0% by weight or 8-1 0% by weight. If the amount of the drug is less than 5% by mass, the absorbed amount of the drug is insufficient and a sufficient therapeutic effect cannot be obtained continuously.
  • the drug concentration contained in the pressure-sensitive adhesive layer can be blended at 1 to 150 times the saturated solubility in the pressure-sensitive adhesive layer, but more preferably 2 to 25 times.
  • the drug crystals present in the pressure-sensitive adhesive layer are adhesively applied to the skin even though they are uniformly dispersed in the pressure-sensitive adhesive base composed mainly of a hydrophobic polymer. Almost no precipitation occurs on the surface of the agent layer. Further, the drug crystals existing in the pressure-sensitive adhesive layer of the present invention are concentrated on the surface of the pressure-sensitive adhesive layer even when they are dissolved or melted once and become supersaturated and then recrystallized and dispersed in the pressure-sensitive adhesive layer. Precipitation is suppressed.
  • the patch of the present invention has sufficient adhesive strength to the skin as in the case of a soluble preparation in which no crystals exist in the adhesive layer, and the preparation peels off from the skin during the application. It is possible to continuously administer the drug from the skin for a period of at least 24 hours.
  • the patch of the present invention there are fewer drug crystals distributed on the surface of the pressure-sensitive adhesive layer that adheres to the skin than the drug crystals distributed inside the pressure-sensitive adhesive layer (the support side of the pressure-sensitive adhesive layer). It is characterized by that.
  • the surface of the pressure-sensitive adhesive layer as used herein refers to the pressure-sensitive adhesive layer side of the solid / solid interface existing at the boundary where the pressure-sensitive adhesive is in contact with the skin when the patch is applied to the skin.
  • the adhesive strength of the pressure-sensitive adhesive decreases when it is precipitated.
  • the patch of the present invention should have few crystals to such an extent that the pressure-sensitive adhesive strength does not decrease, and more preferably, the adhesive layer surface on the side that adheres to the skin. There are no crystals. If there are no crystals on the surface of the pressure-sensitive adhesive layer that adheres to the skin, the surface of the pressure-sensitive adhesive layer that adheres to the skin is a smooth flat surface with no irregularities at the optical microscope level. As observed.
  • the distribution state of the drug crystals on the surface of the pressure-sensitive adhesive layer can be evaluated based on an index representing the crystal precipitation state by observing the state of the drug crystals deposited on a predetermined region of the surface of the pressure-sensitive adhesive base with the naked eye or an optical microscope. it can.
  • the adhesive strength of the patch decreases, and therefore, it can be evaluated by measuring the adhesive strength with a probe tack tester or a peel measuring instrument.
  • the adhesive strength measured with the probe tack tester of the patch of the present invention is 200 gf (gram weight) or more, preferably 200 gf to 500 gf.
  • the adhesive strength measured with a pill measuring machine is 300 gf.
  • the adhesive strength of the pressure-sensitive adhesive layer containing a drug at a concentration at which crystals do not precipitate in the pressure-sensitive adhesive layer preferably the adhesive strength of the pressure-sensitive adhesive layer when containing no drug is 100%, 40% or more, preferably 45% or more, more preferably 50% or more, more than 60%, 70% or more, 80% or more Those having an adhesive strength of 85% or higher, an adhesive strength of 90% or higher, and an adhesive strength of 95% or higher are preferable.
  • the drug crystals are distributed more than the surface on the side that adheres to the skin, and expressed as the concentration of the drug contained in the pressure-sensitive adhesive layer minus the saturation concentration, 2. 5 to 14.9% is contained as crystals, and more preferably 4.8 to 10%. 1 4. If it exceeds 9%, the cohesive strength of the adhesive base itself decreases, and there is a concern that it may cause cohesive failure after application to the skin. On the other hand, if it is less than 2.5%, when the patch is applied to the skin, the drug crystals are dissolved and absorbed, resulting in a shortage of drug in the preparation, and the absorption of the drug does not continue.
  • bronchodilators pro-powered terols, etc.
  • cardiotonic agents isoprenalin, dopamine, etc.
  • coronary vasodilators diiltiazem, verapamil, etc.
  • peripheral vasodilators dicamethate, trazoline, etc.
  • circulation Ring organ agents flunarizine, dicardipine, benidipine, efonidipine, etc.
  • arrhythmic agents propranolol, alprenolol, etc.
  • the pharmaceutically acceptable salt of the drug in the patch of the present invention is not particularly limited.
  • a basic drug it may be an inorganic salt or an organic salt, and may be an inorganic salt. Hydrochloric acid, odorous acid, kaiic acid, etc. It is used well.
  • organic salts include acetic acid, citrate, fumaric acid, maleic acid, etc. Among these, acetate is preferably used.
  • an acidic drug an alkali metal salt is exemplified, and among them, a sodium salt is preferably used.
  • the drug form when the drug form is a pharmaceutically acceptable acid addition salt, it is desirable to contain a basic compound in the adhesive layer, and the basic compound used is basic.
  • a basic compound used is basic.
  • Low molecular compounds containing nitrogen eg, triethanolamine, diisopropanolamine, diethanolamine, etc.
  • low molecular compounds containing basic nitrogen eg, aminoalkyl methacrylate copolymer _ E, polyvinylacetyl jetylamino
  • basic alkali metal salts sodium acetate, potassium acetate, sodium borate, sodium carbonate, trisodium citrate, sodium silicate, etc.
  • sodium hydroxide potassium hydroxide, etc.
  • triethanolamine, diisopropyl Panolamine, diethanolamine, aminoalkyl methacrylate copolymer_E, polyvinylacetate dimethylaminoacetate, sodium acetate, sodium silicate, sodium hydroxide, etc. are preferred, especially triethanolamine, amino Alkyl methacrylate copolymer_E, sodium acetate, and sodium hydroxide are preferred.
  • These compounds act on a chemically acceptable acid addition salt of a drug by a plasticizer in a solution or a pressure-sensitive adhesive layer in the manufacturing process of the drug product, thereby generating a drug molecular type and / or an ion-pair compound. It is also possible to improve skin permeability.
  • solvents used in this case include solvents used in the preparation of preparations such as lower alcohol, toluene, ethyl acetate, hexane, and cyclohexane, and plasticizers contained in the adhesive layer of the preparation.
  • solvents and plasticizers include methanol, ethanol, isopropanol, toluene, ethyl acetate, cyclohexane, liquid paraffin, liquid polybutene, and isopropyl myristate. Among these, methanol, ethanol, and myristate Propyl and liquid paraffin are preferred.
  • the pressure-sensitive adhesive layer of the present invention as described above, if the drug crystals on the surface of the pressure-sensitive adhesive layer that adheres to the skin are in a distribution state that is less than the drug crystals inside the pressure-sensitive adhesive layer, what kind of prescription is used?
  • a rubber polymer or an acrylate ester polymer can be used as the adhesive base.
  • Rubber polymers include styrene-isoprene-styrene block copolymer (hereinafter abbreviated as S I S), isoprene rubber, polyisobutylene (hereinafter abbreviated as P I B), styrene-butadiene-styrene block copolymer.
  • SBS styrene-butadiene rubber
  • SBR styrene-butadiene rubber
  • polysiloxane polysiloxane and the like.
  • S I S and P I B are preferable, and S I S is particularly preferable.
  • acrylate-based polymers examples include 2_ethyl hexyl acrylate, methyl acrylate, butyl acrylate, hydroxyethyl acrylate, 2_ethyl hexyl methacrylate, and the like.
  • the copolymer is not particularly limited as long as it contains at least one monomer of a (meth) acrylic acid derivative and is copolymerized, but preferably contains 50% or more of 2-ethylhexyl acrylate.
  • Specific examples of adhesives include acrylic acid listed as adhesives in the Pharmaceutical Additives Dictionary 2000 (edited by the Japan Pharmaceutical Additives Association).
  • Acrylic acid octyl ester copolymer acrylic acid 2_ethylhexyl ⁇ Vinylpyrrolidone copolymer solution, acrylic acid ester ⁇ Vinyl acetate copolymer, acrylic acid 2_ethylhexyl ⁇ Methacrylic acid 2_ethylhexyl ⁇ Copolymers of dodecyl methacrylate, methyl acrylate ⁇ acrylic acid 2_ethyl hexyl copolymer resin emulsion, acrylic polymer alkanolamine liquid and other adhesives, DURO- TAK acryl adhesive series _ (Such as 87-4098, 87-2194, 87-9301, 87-2979, 87-2074, etc.), Eudragit series (Higuchi Shokai), etc.
  • hydrophobic polymers Two or more of these hydrophobic polymers may be used in combination, and the blending amount based on the mass of the entire composition of these high molecules is determined in consideration of the formation of the pressure-sensitive adhesive layer and sufficient permeability. It is preferably 5 to 90% by mass, more preferably 10 to 70% by mass, and particularly preferably 10 to 50% by mass.
  • the pressure-sensitive adhesive layer of the patch of the present invention may contain a tackifying resin in order to supplement the adhesive strength to the skin.
  • tackifying resins include rosin derivatives (eg, rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, pentaerythryl! Rosin ester of rosin), alicyclic saturated hydrocarbon resins ( For example, Alcon P 100, Arakawa Chemical Industries), aliphatic hydrocarbon resin (for example, Quinton B 1700, Nippon Zeon), terpene resin (for example, Clearon P-1 125 Yashara Chemical), resin maleate, etc. Can be mentioned.
  • glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and terpene resin are preferable, and the use of alicyclic saturated hydrocarbon resin and terpene resin constitutes an adhesive base. It is easy to obtain a patch having such a structure because it dissolves in the amorphous part of the amorphous polymer or semi-crystalline polymer and raises the glass transition temperature to induce drug crystallization inside the adhesive layer. .
  • the blending amount of the tackifying resin based on the entire composition of the pressure-sensitive adhesive layer is 5 to 70% by mass, preferably 5% in consideration of sufficient adhesive strength as a patch and irritation to the skin at the time of peeling. ⁇ 60 mass%, more preferably 10 to 50 mass%.
  • a styrene-isoprene-styrene block copolymer is preferably used as the adhesive base, and an alicyclic saturated hydrocarbon (eg, Alcon P100) or a combination of terpene resins is preferably used as the tackifier resin.
  • an alicyclic saturated hydrocarbon eg, Alcon P100
  • a combination of terpene resins is preferably used as the tackifier resin.
  • the ratio of SIS in the pressure-sensitive adhesive layer to the tackifier resin is 1: 1 to 1:10, preferably 1: 3 to 1: 9
  • a preparation having a crystal distribution as described above can be suitably constructed, and has a sufficient adhesive force to the skin and is a patch preparation with excellent skin permeability of the drug. Can do.
  • the pressure-sensitive adhesive layer of the present invention may contain a plasticizer as necessary.
  • Plasticizers that can be used include petroleum oils (eg, paraffinic process oil, liquid paraffin, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, vegetable oils (eg, olive oil) Oil, camellia oil, castor oil, tall oil, laccase oil), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, liquid polybutene, liquid isoprene rubber), Liquid fatty acid esters (eg, isopropyl myristate, hexyl laurate, jetyl sebacate, diisopropyl sebacate), diethylene glycol, polyethylene glycol, salicylate glycol, propylene glycol, dipropylene glycol Toriasechin, Kuen acid triethyl, Kurotami tons, etc.
  • petroleum oils
  • liquid paraffin liquid polybutene, isopropyl myristate, decyl sebacate, and hexyl laurate are preferable, and liquid polybutene, isopropyl myristate, or liquid baraffine is particularly preferable.
  • Two or more of these components may be used in combination, and the blending amount based on the entire composition of the adhesive layer of such a plasticizer will maintain sufficient permeability and sufficient cohesive strength as a patch preparation. In consideration of the total, it can be blended in an amount of 10 to 70% by mass, preferably 10 to 60% by mass, and more preferably 10 to 50% by mass.
  • the pressure-sensitive adhesive layer of the present invention may further contain an absorption enhancer.
  • an absorption enhancer that can be used, any of the compounds that have been conventionally recognized to absorb absorption in the skin.
  • a saturated or unsaturated fatty acid having 6 to 20 carbon atoms a saturated or unsaturated fatty alcohol having 2 to 10 carbon atoms, or an ester of a saturated or unsaturated fatty acid having 6 to 20 carbon atoms.
  • Amides of saturated or unsaturated fatty acids having 6 to 20 carbon atoms, ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers (above saturated or unsaturated Either Well, it can be either cyclic or straight-chain branched), lactic acid esters, acetate esters, monoterpene compounds, sesquiterpene compounds, Azone, Azone Derivatives, Pyrothiodecane, Glycerin fatty acid esters, Propylene glycol fatty acid esters, Sorbitan fatty acid esters (Span series) Polysorbate series (Tween series), Polyethylene glycol fatty acid esters, Polyoxyethylene hardened castor oil series (HCO) Type), polyoxyethylene alkyl ethers, sucrose fatty acid esters, vegetable oils and the like.
  • oleic acid oleyl alcohol, lauryl alcohol, isostearyl alcohol, lauric acid diethanol amide, glycerin mono force prelate, glycerin mono force Rate, glycerin Monooree Ichito, sorbitan monolaurate, propylene glycol one Rumonora Ureates, polyoxyethylene lauryl ether, and pyrothiodecane are preferred.
  • the entire composition of the adhesive layer Is preferably 0.1 to 20% by mass, more preferably 0.05 to 10% by mass, and particularly preferably 0.1 to 5% by mass. be able to.
  • the support layer of the patch of the present invention is not particularly limited as long as it is suitable for supporting the pressure-sensitive adhesive layer, but a stretchable or non-stretchable layer can be used.
  • a stretchable or non-stretchable layer can be used.
  • cloth, nonwoven fabric, polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, polyethylene terephthalate, aluminum sheet, or a composite material thereof can be used.
  • the adhesive layer When the adhesive layer is laminated on the support, it may or may not have water vapor permeability. In the present invention, even a closed patch (having almost no water vapor permeability) does not decrease the skin permeability of the drug.
  • the thickness of the support of the patch of the present invention is preferably 20 m to 80 m.
  • the preparation area of the patch of the present invention is preferably 5 to 40 cm 2 . If it is less than 5 cm 2 , the absorbed amount of the drug will be insufficient and a sufficient therapeutic effect will not be obtained, and if it exceeds 40 cm 2 , the end of the patch will easily peel off when applied for a long time, or the support This is because there is a tendency that wrinkles are likely to occur.
  • the patch of the present invention can be produced, for example, by the following method.
  • an adhesive base containing a drug is melted by heat, applied to a release liner or support, and then bonded to a support or release paper to obtain this agent.
  • the adhesive base component containing the drug is dissolved in an organic solvent such as toluene, hexane, ethyl acetate, lower alcohol, cyclohexane, etc., and is spread on a release liner or support to remove the solvent. After drying and removing at a predetermined temperature, it is possible to obtain this agent by laminating it with a support or a release liner.
  • the adhesive component having a drug saturation solubility of 0.1 to 5% by mass is mixed with a lower alcohol or toluene so that the concentration of the drug with respect to the total mass of the adhesive is 5 to 15% by mass.
  • the thickness of the pressure-sensitive adhesive layer containing the drug thus obtained is preferably 20 m to 150 Um, more preferably about 50 m to 120 m, but is not particularly limited as long as it is not extremely ⁇ There is no.
  • Fig. 1 illustrates a cross section of the patch of the present invention.
  • FIG. 2 is a graph showing the results of measuring the skin permeation rate at 24 hours after applying the patches of Examples 2 and 3 of the present invention and the patch of Comparative Example 7.
  • a patch having the following composition containing 9.0% of donepezil as a drug was produced.
  • a patch with the following composition containing 9.0% of donepezil hydrochloride as a drug was produced.
  • a patch having the following composition containing 9.0% of donepezil as a drug was manufactured.
  • a patch having the following composition containing 10% of tandospirone as a drug was produced.
  • DURO-TAK 87-4098 1 0. 0% Alicyclic saturated hydrocarbon resin (Arcon P _ 1 00) 48. 6% Liquid paraffin 1 2.0% Propylene glycol monolaurate 5.0%
  • a patch containing the following composition containing donepezil 10.0% as a drug was produced.
  • a patch having the following composition was produced in the same manner as in Example 1.
  • a patch having the following composition was produced in the same manner as in Example 1.
  • a patch having the following composition was produced in the same manner as in Example 1.
  • a patch having the following composition was produced in the same manner as in Example 1.
  • a patch having the following composition was produced in the same manner as in Example 1.
  • a patch having the following composition was produced in the same manner as in Example 1.
  • Donepezil hydrochloride 5.0% SIS 1 6.0% Polyisoptylene 6.8% Alicyclic saturated hydrocarbon resin (Alcon P_ 1 00) 38.8% Liquid paraffin 27.4% Sodium acetate 3.0% Sorbitan monolaurate 3.0%
  • the back skin of the hairless mouse was peeled off, and the dermis side was placed on the receptor layer side, and attached to a flow-through cell (5 cm 2 ) in which 37 ° C hot water was circulated around the outer periphery.
  • the patches obtained in Examples 1 to 6 and Comparative Examples 1 to 7 were affixed to the stratum corneum side, and physiological saline was used for the receptor layer every 5 hours at a rate of 5 ml / hr (hr). Sampling was performed for up to 24 hours.
  • the receptor solution obtained every hour is measured accurately and the drug concentration is measured by high performance liquid chromatography.
  • the permeation rate per hour was calculated, and the skin permeation rate per unit area in a steady state was determined. The results are shown in Table 1 below.
  • Comparative Example 5 shows the adhesive strength when no drug is blended.
  • the adhesive strength of the adhesives of the present invention shown in Examples 1 to 6 is somewhat reduced by the blending of the drugs. It was shown that it still retains sufficient adhesive strength.
  • Comparative Example 6 is an example in which the amount of the drug is too small, and it can be seen that sufficient results cannot be obtained at the maximum skin permeation rate.
  • Comparative Example 7 the adhesive strength slightly decreased with the addition of the drug, and crystal precipitation was observed inside the adhesive layer. However, when the amount of the drug was 5% by mass, the maximum skin permeation rate was sufficient. A good value was obtained.
  • crystals that were not observed immediately after production were observed on the surface of the release liner side of the adhesive layer.
  • the horizontal axis represents time (hour) and the vertical axis indicates skin permeation speed of (g / cm 2 / hr) .
  • the black circle mark (book) indicates the case of the patch of Example 2
  • the black square mark (country) indicates the case of the patch of Example 3
  • the white circle mark ( ⁇ ) indicates the patch of Comparative Example 7. Each case of the agent is shown.
  • the patches of Examples 2 and 3 of the present invention can keep the skin permeation rate substantially constant from about 12 hours to 23 hours after the start of the test.
  • the patch of Comparative Example 7 reached the maximum in about 9 — 11 hours after the start of the test, and then the skin permeation rate decreased, indicating that it was not persistent.
  • the present invention provides a patch that has sufficient adhesive strength to adhere to the skin for 24 hours, is excellent in skin absorbability of a drug, and has sustained drug efficacy. It exhibits a stable therapeutic effect by, is safe and useful as a pharmaceutical, and has industrial applicability.

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  • Veterinary Medicine (AREA)
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  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Neurosurgery (AREA)
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  • Botany (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une préparation adhésive qui permet de fournir un médicament par voie transdermique de manière prolongée durant au moins 24 heures. L'invention concerne plus particulièrement une préparation adhésive présentant une couche adhésive sensible à la pression sur une surface d'un support, ladite couche adhésive sensible à la pression contenant plus de 5 % en masse, et de préférence plus de 5 % en masse mais moins de 15 % en masse, d'un médicament à l'état fondu et à l'état cristallin. Le médicament à l'état cristallin contenu dans la couche adhésive sensible à la pression est réparti en une plus petite quantité sur la surface de la couche adhésive sensible à la pression devant adhérer à la peau que sur le côté du support de la couche adhésive sensible à la pression.
PCT/JP2007/001104 2006-10-11 2007-10-11 Préparation adhésive contenant un cristal WO2008044336A1 (fr)

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WO2009145269A1 (fr) * 2008-05-30 2009-12-03 エーザイ・アール・アンド・ディー・マネジメント株式会社 Préparation transdermique
WO2009145177A1 (fr) * 2008-05-30 2009-12-03 日東電工株式会社 Préparation de patch contenant du donézépil et conditionnement
JP2011522019A (ja) * 2008-06-02 2011-07-28 イギリス国 経皮薬物送達装置
WO2011136283A1 (fr) * 2010-04-28 2011-11-03 久光製薬株式会社 Suppresseur d'irritation cutanée et préparation transdermique
WO2012016569A1 (fr) 2010-08-05 2012-02-09 Conrig Pharma Aps Dérivés deutérés de tandospirone convenant comme agonistes du récepteur 5-ht1a
WO2012043801A1 (fr) * 2010-09-30 2012-04-05 積水メディカル株式会社 Patch
EP2491931A1 (fr) * 2009-10-21 2012-08-29 Teikoku Seiyaku Co., Ltd. Préparation transdermiquement absorbable contenant du donépézile
JP2014502639A (ja) * 2011-01-12 2014-02-03 タイワン バイオテック カンパニー リミテッド ドネペジル経皮吸収型パッチ及びアルツハイマー病の治療方法
JP5415645B1 (ja) * 2013-06-28 2014-02-12 久光製薬株式会社 貼付剤の製造方法、貼付剤及び包装体
JP2014508728A (ja) * 2010-12-24 2014-04-10 サムヤン バイオファーマシューティカルズ コーポレイション リバスティグミンを含有する経皮吸収製剤
WO2014181840A1 (fr) * 2013-05-08 2014-11-13 株式会社 ケイ・エム トランスダーム Timbre adhésif
JP2015522012A (ja) * 2012-07-05 2015-08-03 エスケー ケミカルス カンパニー リミテッド ロチゴチンを含有した経皮吸収製剤（Ｔｒａｎｓｄｅｒｍａｌｃｏｍｐｏｓｉｔｉｏｎｃｏｍｐｒｉｓｉｎｇｒｏｔｉｇｏｔｉｎｅ）
WO2016103999A1 (fr) * 2014-12-26 2016-06-30 ニチバン株式会社 Emballage pour timbre et procédé d'emballage
JPWO2016167345A1 (ja) * 2015-04-15 2017-11-16 久光製薬株式会社 ロピニロール含有貼付剤
US9987361B1 (en) 2014-12-29 2018-06-05 Noven Pharmaceuticals, Inc. Compositions and method for sustained drug delivery by active transdermal technology
US10758535B1 (en) 2019-04-26 2020-09-01 Sumitomo Dainippon Pharma Co., Ltd. Therapeutic drug for dyskinesia
WO2021166987A1 (fr) * 2020-02-19 2021-08-26 大日本住友製薬株式会社 Préparation à absorption transdermique
US11559525B2 (en) 2019-04-26 2023-01-24 Sumitomo Pharma Co., Ltd. Therapeutic drug for dyskinesia
US11628169B2 (en) 2020-08-31 2023-04-18 Sumitomo Pharma Co., Ltd. Therapeutic drug for motor complications in Parkinson's disease

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JP5421252B2 (ja) * 2008-05-30 2014-02-19 エーザイ・アール・アンド・ディー・マネジメント株式会社 経皮吸収製剤
WO2009145177A1 (fr) * 2008-05-30 2009-12-03 日東電工株式会社 Préparation de patch contenant du donézépil et conditionnement
JP5208209B2 (ja) * 2008-05-30 2013-06-12 日東電工株式会社 ドネペジル含有貼付製剤およびその包装体
CN102046171B (zh) * 2008-05-30 2013-06-19 日东电工株式会社 经皮吸收制剂
WO2009145269A1 (fr) * 2008-05-30 2009-12-03 エーザイ・アール・アンド・ディー・マネジメント株式会社 Préparation transdermique
JP2011522019A (ja) * 2008-06-02 2011-07-28 イギリス国 経皮薬物送達装置
EP2491931A1 (fr) * 2009-10-21 2012-08-29 Teikoku Seiyaku Co., Ltd. Préparation transdermiquement absorbable contenant du donépézile
EP2491931A4 (fr) * 2009-10-21 2013-06-12 Teikoku Seiyaku Kk Préparation transdermiquement absorbable contenant du donépézile
WO2011136283A1 (fr) * 2010-04-28 2011-11-03 久光製薬株式会社 Suppresseur d'irritation cutanée et préparation transdermique
JP5654006B2 (ja) * 2010-04-28 2015-01-14 久光製薬株式会社 皮膚刺激抑制剤及び経皮吸収製剤
CN102858372A (zh) * 2010-04-28 2013-01-02 久光制药株式会社 皮肤刺激抑制剂和经皮吸收制剂
WO2012016569A1 (fr) 2010-08-05 2012-02-09 Conrig Pharma Aps Dérivés deutérés de tandospirone convenant comme agonistes du récepteur 5-ht1a
JPWO2012043801A1 (ja) * 2010-09-30 2014-02-24 積水メディカル株式会社 貼付剤
WO2012043801A1 (fr) * 2010-09-30 2012-04-05 積水メディカル株式会社 Patch
JP5850371B2 (ja) * 2010-09-30 2016-02-03 積水メディカル株式会社 貼付剤
JP2014508728A (ja) * 2010-12-24 2014-04-10 サムヤン バイオファーマシューティカルズ コーポレイション リバスティグミンを含有する経皮吸収製剤
JP2014502639A (ja) * 2011-01-12 2014-02-03 タイワン バイオテック カンパニー リミテッド ドネペジル経皮吸収型パッチ及びアルツハイマー病の治療方法
JP2015522012A (ja) * 2012-07-05 2015-08-03 エスケー ケミカルス カンパニー リミテッド ロチゴチンを含有した経皮吸収製剤（Ｔｒａｎｓｄｅｒｍａｌｃｏｍｐｏｓｉｔｉｏｎｃｏｍｐｒｉｓｉｎｇｒｏｔｉｇｏｔｉｎｅ）
WO2014181840A1 (fr) * 2013-05-08 2014-11-13 株式会社 ケイ・エム トランスダーム Timbre adhésif
JP5415645B1 (ja) * 2013-06-28 2014-02-12 久光製薬株式会社 貼付剤の製造方法、貼付剤及び包装体
JPWO2016103999A1 (ja) * 2014-12-26 2017-10-05 ニチバン株式会社 貼付剤のための包装体および包装方法
WO2016103999A1 (fr) * 2014-12-26 2016-06-30 ニチバン株式会社 Emballage pour timbre et procédé d'emballage
US9987361B1 (en) 2014-12-29 2018-06-05 Noven Pharmaceuticals, Inc. Compositions and method for sustained drug delivery by active transdermal technology
JPWO2016167345A1 (ja) * 2015-04-15 2017-11-16 久光製薬株式会社 ロピニロール含有貼付剤
US10716763B2 (en) 2015-04-15 2020-07-21 Hisamitsu Pharmaceutical Co., Inc. Transdermal patch containing ropinirole
US10758535B1 (en) 2019-04-26 2020-09-01 Sumitomo Dainippon Pharma Co., Ltd. Therapeutic drug for dyskinesia
US11559525B2 (en) 2019-04-26 2023-01-24 Sumitomo Pharma Co., Ltd. Therapeutic drug for dyskinesia
WO2021166987A1 (fr) * 2020-02-19 2021-08-26 大日本住友製薬株式会社 Préparation à absorption transdermique
KR20220143065A (ko) 2020-02-19 2022-10-24 스미토모 파마 가부시키가이샤 경피 흡수 제제
US11628169B2 (en) 2020-08-31 2023-04-18 Sumitomo Pharma Co., Ltd. Therapeutic drug for motor complications in Parkinson's disease

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