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WO2009120002A2 - Préparation percutanée contenant du donépézil comme principe actif, utilisée pour le traitement de la démence - Google Patents

Préparation percutanée contenant du donépézil comme principe actif, utilisée pour le traitement de la démence Download PDF

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Publication number
WO2009120002A2
WO2009120002A2 PCT/KR2009/001472 KR2009001472W WO2009120002A2 WO 2009120002 A2 WO2009120002 A2 WO 2009120002A2 KR 2009001472 W KR2009001472 W KR 2009001472W WO 2009120002 A2 WO2009120002 A2 WO 2009120002A2
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrolidone
active ingredient
donepezil
dementia
rosin ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2009/001472
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English (en)
Korean (ko)
Other versions
WO2009120002A3 (fr
Inventor
최영권
이정식
김성수
구혜란
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ICURE Pharmaceutical Inc
Original Assignee
ICURE Pharmaceutical 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 ICURE Pharmaceutical Inc filed Critical ICURE Pharmaceutical Inc
Publication of WO2009120002A2 publication Critical patent/WO2009120002A2/fr
Publication of WO2009120002A3 publication Critical patent/WO2009120002A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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

Definitions

  • the present invention relates to a transdermal absorption preparation for treating dementia containing Donepezil as an active ingredient.
  • Dementia is a syndrome characterized by complex cognitive impairments characterized by memory loss, loss of intelligence, personality changes, and behavioral problems.
  • This symptom is a degenerative neurological disorder associated with the brain, the central nervous system, resulting in irreversible dysfunction of the neural network by the death of slow neurons that cause central nervous system degenerative disease, and eventually permanent loss of the human body. Will result.
  • a common feature of degenerative neuropathy is the overall or specific cell death. Differentiated neurons are incapable of regenerative, resulting in the loss of irreversible brain function.
  • Cholinesterases come in two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE).
  • the acetylcholinesterase is an enzyme that hydrolyzes acetylcholine, one of the neurotransmitters that mediate the activity of parasympathetic nerves in the body, to choline and acetate, and is formed on the endoplasmic reticulum membrane and moves to the cell membrane to perform its function. .
  • the enzyme is most widely distributed in the choline nerve and its surroundings, especially in the muscle nerve junction, and is an important enzyme found in plasma, liver and other tissues.
  • Alzheimer's treatment for dementia is mainly an acetylcholinesterase inhibitor, an acetylcholine degrading enzyme, and is donepezil (Donepezil, trade name: Aricept), tacrine (Tacrine, Cokenex), rivastigmine ( Rivastigmin, trade name: Exelon), galantamine (Reminil), and the like.
  • donepezil was licensed for dementia patients from the US Food and Drug Administration (FDA) in 1996, and is used to treat dementia of mild and moderate dementia of Alzheimer's disease.
  • Donepezil is a drug having the effect of reversibly inhibiting acetylcholine degrading enzymes called acetylcholinesterase and butylcholinesterase, and acetylcholine, a neurotransmitter, is lowered than the normal person through the above inhibitory function.
  • acetylcholinesterase and butylcholinesterase acetylcholine degrading enzymes
  • acetylcholine a neurotransmitter
  • acetylcholinesterase inhibitors as oral agents have severe side effects, and there are reports of problems such as liver dysfunction and digestive disorders.
  • the cause of the side effects is generally because oral preparations are unable to avoid the first pass effect to the liver, and as a result it is easy to affect the liver function, because the high concentrations in the digestive tract is likely to cause side effects in the digestive tract. to be.
  • the ratio of the blood concentration after the administration of the drug is large, since the ratio of the maximum blood concentration reached after administration and the blood concentration after 24 hours has not been reached for a long time without reaching the concentration at which side effects occur. There is a problem that is not easy to maintain the therapeutic effect over.
  • Japanese Laid-Open Patent Publication No. 1999-315016 proposes an ointment and a suppository for rectal administration in order to solve this problem because it is sometimes difficult to take orally in a state in which dementia symptoms are quite advanced.
  • these formulations have a problem that it is not practical to continuously administer the active ingredient over a long time.
  • US Patent Publication No. 20040258741 and Korean Patent Publication No. 2005-0037405 propose a transdermal absorbent using a synthetic rubber-based polymer of the SIS and PIB series.
  • the transdermal absorbent preparation is difficult to contain a high concentration of the drug in a highly hydrophobic matrix, and when the concentration is 8% or more, solid crystals are produced, thereby reducing adhesion, nonuniformity of skin penetration rate, and storage problems.
  • the thickness of the matrix to support the required amount of the drug to meet the required dosage in the matrix becomes thicker in proportion, there is no big difference initially but there is a problem of decreasing the penetration rate of the drug over time.
  • the present inventors are studying a transdermal absorption agent for enhancing the patient's medication compliance, while containing a high concentration (10% or more) of the drug in the hydrophobic matrix without generating crystals of the drug, and the drug through the skin for a long time
  • a continuous transdermal absorption preparation that can maintain a therapeutic effect over a long period of time without reaching the concentration of the drug to the concentration of side effects is completed and completed the present invention.
  • the present invention is donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, pyrrolidone as an EVA adhesive and skin permeation enhancer comprising a rosin ester resin to prevent crystallization of the active ingredient as a base.
  • a drug-containing matrix layer comprising a combination of two or more kinds selected from the group consisting of derivatives, C 8-18 aliphatic derivatives, triacetin and triethyl citrate; Drug protection support layer; And it provides a transdermal absorption preparation for treating dementia containing Donepezil consisting of a release layer as an active ingredient.
  • the transdermal absorption agent for treating dementia containing Donepezil as an active ingredient according to the present invention has excellent skin adhesion and prevents a decrease in adhesion by preventing crystal formation even when a high concentration of drug is contained in a hydrophobic matrix of 10% or more.
  • the drug can be continuously released for a long time, and the skin permeability of the drug is excellent and can be usefully used in place of the conventional oral treatment for dementia.
  • A drug protection support layer
  • B drug-containing matrix layer
  • C release layer
  • Figure 2 is a graph showing the cumulative skin permeation amount of the transdermal absorption preparation for treating dementia containing donepezil as an active ingredient according to the present invention
  • Figure 3 is a graph showing the average skin permeation rate of the transdermal absorbent preparation for treating dementia containing donepezil as an active ingredient according to the present invention.
  • the present invention is a.
  • transdermal absorption preparation for treating dementia comprising a drug protective support layer, a drug-containing matrix layer and a peeling layer,
  • a transdermal absorption preparation for treating dementia containing as an active ingredient.
  • the drug-containing mattress layer of the transdermal absorption preparation according to the present invention contains donepezil or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the donepezil used in the present invention is preferably used as the acetylcholinesterase inhibitor of the donepezil or a pharmaceutically acceptable salt thereof in the free base (free base) form.
  • a pharmaceutically acceptable salt an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • Such pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate,
  • the active ingredient is dissolved or uniformly dispersed in the pressure-sensitive adhesive, it is preferably 2.0 to 25% by weight relative to the total weight of the drug-containing matrix. If the amount of donepezil or a pharmaceutically acceptable salt thereof is less than 2.0% by weight, the drug effect is inadequate, and at high concentrations exceeding 25% by weight, crystals of the drug are formed in the formulation, resulting in a decrease in adhesion. Can be.
  • the drug-containing matrix layer of the transdermal absorbent preparation according to the present invention preferably uses an EVA adhesive as the polymer substrate and the pressure-sensitive adhesive.
  • pressure-sensitive adhesives require adhesion to the skin, compatibility with drugs and other excipients, and as such adhesives, TRS (Sekisui Chemical Co., Osaka, Japan), Duro-Tec Acrylic pressure-sensitive adhesives such as (Duro-Tak; National Starch Chemical Co., bridgewater, NJ, USA) are commercially available.
  • TRS Sekisui Chemical Co., Osaka, Japan
  • Duro-Tec Acrylic pressure-sensitive adhesives such as (Duro-Tak; National Starch Chemical Co., bridgewater, NJ, USA) are commercially available.
  • the acrylic adhesive is used as a matrix of transdermal absorption agent for treating dementia, drug diffusion in the adhesive layer is slowed due to the interaction between the drug and the acrylic polymer in the adhesive layer, and the drug transition from the adhesive layer to the skin is also reduced. Therefore, it is difficult to deliver the required amount of drug.
  • the adhesive which comprises the drug containing mattress layer of this invention uses EVA adhesive.
  • Polyethylene vinyl acetate copolymer which is the main raw material of the EVA adhesive, has various uses depending on the content of vinyl acetate, as well as weather resistance, seizure stability, tear strength, stress resistance and ozone resistance, and is transparent and non-toxic.
  • Thermoplastic elastomer is transparent and non-toxic.
  • the EVA content used in the EVA pressure-sensitive adhesive is preferably a VA content (vinyl acetate content) of 4 to 50%, more preferably 33 to 41%.
  • the EVA adhesive includes a rosin ester resin to prevent crystallization of donepezil, an active ingredient.
  • a rosin ester resin to prevent crystallization of donepezil, an active ingredient.
  • Donepezil has a suitable polarity to increase the solubility of the drug in the matrix base because crystals are formed within a few days or weeks because of the solubility in the base. It is necessary to have a component.
  • the rosin ester resin used in the EVA pressure-sensitive adhesive according to the present invention has a structure similar to that of donepezil and has an appropriate polarity so that the donepezil can be stably dissolved or dispersed in the hydrophobic matrix without crystallization. do.
  • the rosin ester resin used is preferably pentaerythritol rosin ester, glycerol rosin ester, pentaerythritol hydrogenated rosin ester, glycerol hydrogenated rosin ester, and more preferably pentaerythritol rosin ester.
  • the content of the EVA adhesive as the polymer base constituting the drug-containing mattress layer is preferably 50 to 80% by weight based on the total weight of the drug-containing matrix. If it is out of the content range, there are disadvantageous problems in terms of skin applicability, compatibility with drugs and other excipients.
  • the drug-containing matrix layer of the transdermal absorption preparation comprises any two or more selected from pyrrolidone derivatives, C 8-18 aliphatic derivatives, triacetin and triethyl citrate as skin penetration enhancers. It is preferable.
  • the content of the skin permeation enhancer is preferably 10-25% by weight based on the total weight of the drug-containing matrix.
  • the pyrrolidone derivative may be N-cyclohexyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone (1-butyl- 3-dodecyl-2-pyrrolidone), 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone , 1-hexyl-4-methyloxycarbonyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1-hexyl-4-methyloxycarbonyl-2-pyrrolidone (2-hydroxyethyl) pyrrolidone (1- (2-hydroxyethyl) pyrrolidone), 3-hydroxy-N-methyl-2-pyrrolidone, 1 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-methyl-2-pyrrolidone, N N-carprylyl-2-pyrrolidone, N-dodecyl-2
  • the aliphatic derivative of C 8-18 as the skin permeation enhancer is glycerol lauryl alcohol, oleyl alcohol, isopropyl myristrate, sorbitan monooleate -oleate, propylene monolaurate, propylene mono-oleate, oleyl macrogoglyceride, oleic acid, lauroyl macrogol glyceride macrogoglyceride, linoleoyl macrogoglyceride, propylene glycol caprylate / caprate, sorbitan monostearate mono-oleate, glycerol monolau Glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocap Propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / capric triglyceride, corn oil PEG-8 ester, corn oil Preference is given to PEG-6 esters, glycerol
  • triacetin or triethyl citrate can be used as the skin permeation enhancer.
  • the triacetin has been used as a dissolution aid, softener, skin permeation accelerator, etc.
  • Triethyl citrate is a softener of Eudragit-based polyacrylate polymer, and has been used as a softener for oral coating materials. Like cetin, it has a skin permeation enhancing effect on donepezil.
  • the above-mentioned skin permeation enhancer included in the drug-containing matrix layer of the transdermal absorbent preparation according to the present invention contains 10-25% by weight based on the total weight of the drug-containing matrix by mixing any two or more thereof.
  • the drug-protective support layer of the transdermal absorbent preparation for treating dementia according to the present invention is thin and flexible in order to prevent the loss of donepezil from the preparation during attachment or storage on the skin and does not cause an allergic reaction because it is not reactive with the skin. use.
  • the support layer according to the present invention is a plastic film such as polyethylene, polypropylene, ethylene vinyl acetate copolymer, vinylon, polyester, polyurethane, nylon, polyacrylonitrile, polyethylene terephthalate, polyolefin, and the like commonly used in transdermal absorbents.
  • film or nonwoven fabrics such as rayon and polyester having moisture absorption capability, woven fabrics such as polyester, acrylic, silk, cotton, or lamination thereof in order to prevent the transdermal absorption agent from falling off due to moisture emitted from the human body
  • Hybrid materials may be used, and any of drug-protecting substances used in conventional transdermal absorption preparations may be used.
  • the release layer of the transdermal absorbent preparation for treating dementia according to the present invention may be a release film or a laminate thereof commonly used in the transdermal absorbent preparation.
  • a film such as polyethylene, polyester, polyvinyl chloride, polyvinylidene chloride or the like coated with silicone resin or fluorine resin, paper or a laminate thereof can be used.
  • the transdermal absorption agent for treating dementia containing Donepezil as an active ingredient according to the present invention has excellent skin adhesion and prevents a decrease in adhesion by preventing crystal formation even when a high concentration of drug is contained in a hydrophobic matrix of 10% or more.
  • the drug can be released continuously for a long period of time (1-7 days) (see FIG. 2), and the skin penetration rate gradually decreases as the application period becomes longer, but the skin penetration rate is higher than the minimum required penetration rate of 1.2 ⁇ g / cm 2 / hr.
  • By maintaining the excellent skin permeability of the drug see Fig. 3) can be useful to replace the conventional oral treatment for dementia.
  • Toluene was added to 13% by weight of donepezil, 5% by weight of glycerol monolaurate, 5% by weight of glycerol monooleate, and 77% by weight of EVA pressure-sensitive adhesive so that the total amount of solid content was 50%, completely dissolved, and then the adhesive solution containing the drug.
  • composition of the matrix layer was changed in the same manner as in Example 1 while changing the composition as shown in Table 1 to prepare a transdermal absorption preparation for treating dementia containing the donepezil as an active ingredient. At this time, the content of each component is weight percent.
  • composition of the components constituting the matrix layer was changed as shown in Table 2 and Table 3, and was carried out in the same manner as in Example 1 to prepare a transdermal absorption preparation for treating dementia containing the donepezil as an active ingredient. At this time, the content of each component is weight percent.
  • Drug permeation experiment diffusion device (Franzcel) was prepared by adding 0.5% by weight of sodium azide to prevent rot of the skin to the phosphate buffer pH 7.4 of the aqueous phase.
  • the experimental diffusion device was filled with an aqueous phase to maintain a temperature of 32 ⁇ 0.5 ° C., and the skin was donated with each matrix prepared in Examples 1 to 20 and Comparative Examples 1 to 30 using a human cadaver skin. Cut to cell size and applied.
  • 250 ⁇ L of the buffer solution in which the drug was diffused was taken for each hour, and the drug permeated by liquid chromatography was quantified. After the drug permeated through the patches prepared in Examples 1 to 20 and Comparative Examples 1 to 30, the average drug permeation rate of the skin after 7 days was shown in Tables 4 and 5 below.
  • Example 1 4.85 ⁇ 1.22
  • Example 11 4.94 ⁇ 1.30
  • Example 2 4.39 ⁇ 0.86
  • Example 12 5.40 ⁇ 1.40
  • Example 3 4.36 ⁇ 1.10
  • Example 13 7.74 ⁇ 0.85
  • Example 4 4.90 ⁇ 0.64
  • Example 14 5.56 ⁇ 0.62
  • Example 5 5.68 ⁇ 0.68
  • Example 15 7.25 ⁇ 0.91
  • Example 6 5.34 ⁇ 0.35
  • Example 16 6.07 ⁇ 0.93
  • Example 7 5.81 ⁇ 0.21
  • Example 17 7.62 ⁇ 0.05
  • Example 8 6.05 ⁇ 0.44
  • Example 18 6.88 ⁇ 2.15
  • Example 9 6.50 ⁇ 0.74
  • Example 19 7.40 ⁇ 2.40
  • Example 10 5.34 ⁇ 0.58
  • Example 20 7.72 ⁇ 0.97
  • FIGS. 2 and 3 The cumulative penetration rate and skin penetration rate change for Examples 13 to 19, which are relatively good in skin permeation test results, are shown in FIGS. 2 and 3, respectively. It can be seen from FIG. 2 that the drug is continuously released during the experimental period, and through FIG. 3, the initial release rate is high, so that the drug is administered at the initial stage of attachment of the transdermal absorbent, thereby maximizing the therapeutic effect.
  • Donepezil is more specific for acetylcholinesterase (AChE) in the brain than plasma butylcholinesterase (BChE) and has a half-life of 58-90 hours, a bioavailability of 100%, and a protein binding rate of 96%. Excellent inhibitory effect on therapase.
  • AChE acetylcholinesterase
  • BChE plasma butylcholinesterase
  • the maximum blood concentration was 9.8 ⁇ 1.1 ng / mL in a single oral administration, and when administered repeatedly, the steady-state was reached within 15 days and the average plasma concentration was 26.5 ⁇ in the steady state. It is 3.9 ng / mL and the average plasma cleaning rate is constant at 0.13 L / hr / kg.
  • the calculated skin penetration rate is approximately 3.455 ⁇ 3.9 ⁇ g / hr.
  • the prepared transdermal absorption preparations can be seen that the required level of skin penetration rate or maintained at a slightly higher rate during the experimental period.

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Abstract

L'invention concerne une préparation percutanée contenant du donépézil comme principe actif, utilisée pour le traitement de la démence. De manière plus spécifique, la préparation percutanée contenant du donépézil comme principe actif comprend une couche matricielle contenant le médicament, une couche de support pour protéger le médicament, et une couche de libération. La couche matricielle renfermant le médicament contient : du donépézil ou ses sels pharmaceutiquement acceptables comme principe actif; des adhésifs de poyléthylène/acétate de vinyle contenant une résine d'ester de colophane comme substrat polymère; et un mélange facilitant la pénétration, constitué d'au moins deux substances sélectionnées dans le groupe comprenant les dérivés de pyrrolidone, les dérivés aliphatiques C8-18, la triacétine et le citrate de triéthyle. La préparation percutanée selon l'invention permet d'accroître l'adhésion du patient atteint de démence à l'administration du traitement et réduit au minimum les effets secondaires par rapport à une préparation orale. En outre, la préparation percutanée s'applique facilement sur la peau et permet la libération soutenenue du médicament pendant une longue durée. De plus, en raison de ses bonnes propriétés de pénétration dans la peau, cette préparation peut remplacer les préparations orales classiques pour le traitement de la démence.
PCT/KR2009/001472 2008-03-24 2009-03-23 Préparation percutanée contenant du donépézil comme principe actif, utilisée pour le traitement de la démence Ceased WO2009120002A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2008-0026952 2008-03-24
KR1020080026952A KR101454362B1 (ko) 2008-03-24 2008-03-24 도네페질을 유효성분으로 함유하는 치매 치료용경피흡수제제

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WO2009120002A3 WO2009120002A3 (fr) 2009-12-23

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Cited By (5)

* Cited by examiner, † Cited by third party
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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
US9155711B2 (en) 2010-06-30 2015-10-13 Nal Pharmaceuticals, Ltd. Transdermal drug delivery system containing donepezil
US20170290780A1 (en) * 2014-12-18 2017-10-12 Icure Pharmaceutical Inc. Transdermal composition containing donepezil as active ingredient
US10195408B2 (en) 2014-02-20 2019-02-05 Nal Pharmaceutical Group Limited Transdermal drug delivery system containing donepezil
JP2021508713A (ja) * 2017-12-27 2021-03-11 ドン−ア エスティ カンパニー リミテッド ドネペジルを含有する認知症治療用経皮吸収製剤

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ES2652491T3 (es) * 2009-10-21 2018-02-02 Teikoku Seiyaku Co., Ltd. Preparación que contiene donepecilo de absorción transdérmica
JP5766475B2 (ja) * 2010-03-30 2015-08-19 日東電工株式会社 貼付製剤およびその製造方法
KR101054317B1 (ko) * 2011-01-28 2011-08-08 신신제약 주식회사 리바스티그민을 함유하는 경피흡수제제
KR101964295B1 (ko) * 2012-09-05 2019-04-01 주식회사 한독 피부 자극이 감소된 메만틴 경피전달 시스템
KR101485822B1 (ko) 2014-01-22 2015-01-23 주식회사 대웅제약 도네페질 또는 그의 염을 함유하는 경피흡수제제
US10966936B2 (en) 2015-12-30 2021-04-06 Corium, Inc. Systems comprising a composite backing and methods for long term transdermal administration
CA3028436A1 (fr) 2016-06-23 2017-12-28 Corium International, Inc. Matrice adhesive a un domaine hydrophile, un domaine hydrophobes et un agent therapeutique
US9993466B2 (en) 2016-07-27 2018-06-12 Corium International, Inc. Donepezil transdermal delivery system
MX2019001104A (es) 2016-07-27 2019-10-02 Corium Int Inc Sistemas de suministro transdermico de memantina.
CN111132669A (zh) * 2017-07-26 2020-05-08 考里安公司 具有带溶剂填充孔的微孔膜的透皮递送系统
US11173132B2 (en) 2017-12-20 2021-11-16 Corium, Inc. Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point
KR102115102B1 (ko) 2018-12-21 2020-05-26 동아에스티 주식회사 안정화된 도네페질 함유 경피 흡수제제
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JP7170728B2 (ja) 2017-12-27 2022-11-14 ドン－ア エスティ カンパニー リミテッド ドネペジルを含有する認知症治療用経皮吸収製剤

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