WO2009120002A2 - Percutaneous preparation containing donepezil as active ingredient for treatment of dementia - Google Patents

Percutaneous preparation containing donepezil as active ingredient for treatment of dementia 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
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Prior art keywords
pyrrolidone
active ingredient
donepezil
dementia
rosin ester
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PCT/KR2009/001472
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French (fr)
Korean (ko)
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WO2009120002A3 (en
Inventor
최영권
이정식
김성수
구혜란
Original Assignee
아이큐어주식회사
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Publication of WO2009120002A2 publication Critical patent/WO2009120002A2/en
Publication of WO2009120002A3 publication Critical patent/WO2009120002A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053Transdermal 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

The present invention relates to a percutaneous preparation containing donepezil as an active ingredient for treatment of dementia. More specifically, the percutaneous preparation comprising donepezil as the active ingredient consists of a matrix layer containing drugs, a support layer for protecting the drugs, and a release layer. The matrix layer containing drugs comprises: donepezil or pharmaceutically acceptable salts thereof as the active ingredient; polyethylene vinyl acetate adhesives including rosin ester resin as a polymer substrate; and a penetration enhancer mixture of at least two kinds selected from the group consisting of pyrrolidone derivatives, C8-18 aliphatic derivatives, triacetin and triethyl citrate. The disclosed percutaneous preparation can increase dementia patient administration compliance and minimize side effects when compared with an oral preparation. Additionally, the percutaneous preparation is easily applied to skin and can release the drugs sustainably for a long time. Also, due to high skin-penetration properties, the preparation can replace conventional oral preparations for treatment of dementia.

Description

[규칙 제26조에 의한 보정 21.07.2009] 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제[Revision according to Rule 26.21.07.2009] Transdermal absorption preparation for the treatment of dementia containing donpezil as an active ingredient
본 발명은 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제에 관한 것이다.The present invention relates to a transdermal absorption preparation for treating dementia containing Donepezil as an active ingredient.
치매는 기억상실, 지능의 퇴보, 성격의 변화, 행동이상 등으로 특징되는 복합 인지장애가 특징인 증후군을 말한다. 이 증상은 중추신경계인 뇌와 관련이 있는 퇴행성 뇌신경질환으로서 중추신경계 퇴행성 질환을 유발시키는 서행적인 신경세포의 사멸에 의해 신경회로망에 비가역적인 기능장애가 초래하게 되고, 결국에는 해당 인체 기능의 영구적인 손실을 초래하게 된다. 퇴행성 뇌신경질환의 공통된 특징은 전반적인 혹은 특정한 세포의 사멸을 가져오는데, 분화된 신경세포는 재생 능력이 없어서 신경세포의 사멸은 결과적으로 비가역적인 뇌 기능의 손실로 나타나게 된다. 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.
치매가 어떻게 발생하는지에 대해서는 완전하게 규명하지 못한 상태이고, 다양한 병인학적, 병태생리학적 요소를 가지고 있으므로 단독으로 투여하는 치매치료제는 없는 실정이다. 그러나 간접적으로 치매환자들의 뇌에서 정상적인 사람보다 아세틸콜린(ACh)을 합성하는 콜린아세틸트랜스퍼라제(ChAT)가 20~30%로 감소된 것으로 알려졌으며, 또한 신경전달체인 아세틸콜린 농도가 16~30% 정도 감소하는 것으로 알려져있다. 그로인해, 간접적인 치료방법으로 신경전달체인 아세틸콜린을 가수분해하는 효소인 콜린에스테라제(ChE)를 억제하는 저해제를 이용하는 연구가 진행되어 오고 있다. 콜린에스테라제는 아세틸콜린에스테라제(AChE)와 부틸콜린에스테라제(BuChE)의 두 가지 형태를 갖는다. 상기의 아세틸콜린에스테라제는 체내 부교감 신경의 활성을 매개하는 신경전달물질들 중의 하나인 아세틸콜린을 콜린과 아세테이트로 가수분해하는 효소로서, 소포체 막에서 형성되어 세포막으로 이동하여 그 기능을 수행한다. 상기의 효소는 콜린 신경과 그 주위, 특히 근신경 접합부에 가장 많이 분포되어 있고, 혈장, 간 및 다른 조직에서도 발견되는 중요한 효소이다. It is not fully understood how dementia occurs, and because there are various etiological and pathophysiological factors, there is no treatment for dementia alone. However, indirectly, the brains of dementia patients are known to have reduced 20% to 30% of choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh), compared to normal humans, and the neurotransmitter concentration of acetylcholine is 16-30%. It is known to decrease in degree. Therefore, research has been conducted using an inhibitor that inhibits cholinesterase (ChE), an enzyme that hydrolyzes the neurotransmitter acetylcholine as an indirect treatment method. 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.
따라서, 현재 사용되고 있는 알츠하이머성 치매치료제는 아세틸콜린 분해효소인 아세틸콜린에스테라제 저해제가 대부분이며, 도네페질(Donepezil, 상품명:아리셉트), 타크린(Tacrine, 상품명:코크넥스), 리바스티그민(Rivastigmin, 상품명:엑셀론), 갈란타민(Galantamine, 상품명:레미닐) 등이 이에 속한다. Therefore, currently used 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.
상기 아세틸콜린에스테라제 저해제 중 도네페질은 1996년 미국 식품의약국(FDA)로부터 치매환자에 대한 사용허가를 받은 것으로 알츠하이머성 치매의 경증 및 중등증 이상의 치매 치료에 사용된다. Among the acetylcholinesterase inhibitors, 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.
상기 도네페질은 아세틸콜린에스테라제와 부틸콜린에스테라제라는 아세틸콜린 분해효소를 가역적으로 억제하는 효능을 지닌 약물로서, 상기의 억제 기능을 통해 신경전달 물질인 아세틸콜린이 정상인에 비해 저하되어 있는 알츠하이머 환자의 뇌 속에 아세틸콜린을 증가시켜 뇌 속의 콜린 작동성 신경을 활성화한다. 현재 사용되고 있는 도네페질 제제는 정제형태로서, 경구투여 경로를 통해 알츠하이머성 치매 환자에게 처방되고 있다. 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. Increasing acetylcholine in the brain of Alzheimer's patients activates cholinergic neurons in the brain. The donepezil preparations currently in use are in tablet form and are prescribed for Alzheimer's dementia patients via the oral route of administration.
일반적으로, 경구제로서의 아세틸콜린에스테라제 저해제는 부작용이 심하고, 특히 간기능 장애, 소화기 장애 등의 문제점에 대한 보고가 있다. 상기 부작용이 일어나는 원인은 일반적으로 경구제는 간장으로의 일차 통과 효과를 회피하는 것이 불가능하고, 그 결과 간 기능에 영향을 주기 쉬우며, 소화관 내에서 고농도로 존재하기 때문에 소화관에서 부작용이 나타나기 쉽기 때문이다. In general, 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.
상기 저해제를 경구 투여할 경우, 투여 후 약물의 혈중농도변화에 있어서, 투여 후 도달하는 최대 혈중농도와 24시간 경과 후 혈중농도의 비가 크기 때문에 혈중농도를 부작용이 나타나는 농도까지 도달시키지 않으면서 장기간에 걸쳐 치료효과를 유지하는 것은 용이하지 않는 문제가 있다.In the case of oral administration of the inhibitor, 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.
또한, 일본 공개특허 제1999-315016호에는 치매 증상이 상당히 진전한 상태에서는 경구적으로 복용하는 것이 곤란해지는 경우가 있으므로 이를 해결하기위해 연고제 및 직장 투여를 위한 좌약제가 제안되었다. 그러나 이러한 제형들은 장시간에 걸쳐 유효성분을 지속적으로 투여하는 데에는 실용적이지 못하다는 문제가 있다.In addition, 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. However, these formulations have a problem that it is not practical to continuously administer the active ingredient over a long time.
또한, 미국 공개특허 제20040258741호 및 대한민국 공개특허 제2005-0037405호에는 SIS와 PIB 계열의 합성 고무계 고분자를 이용한 경피흡수제제를 제안하고 있다. 그러나 그 투과속도가 미흡하고 면적이 50 ㎠ 이상인 경피흡수제제를 1회에 1 내지 2일 동안 적용하는 방식이므로, 장기 투여의 경우, 피부에 많은 부담을 유발한다. 또한, 상기 경피흡수제제는 상당히 소수성인 매트릭스 내에 약물을 고농도로 함유하기 곤란하고 8% 이상의 농도일 경우 고체결정이 생성되기 때문에, 점착력의 감소, 피부투과 속도의 불균일 및 보관상의 문제가 있다. 또한, 요구되는 투여량을 만족하는 필요한 양의 약물을 매트릭스에 담지시키기는 매트릭스의 두께가 그에 비례하여 두꺼워지므로 초기에는 큰 차이가 없으나 시간이 지날수록 약물의 투과속도를 감소시키는 문제점이 있다.In addition, 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. However, since the permeation rate is insufficient and the transdermal absorption agent having an area of 50 cm 2 or more is applied at a time for 1 to 2 days, long-term administration causes a lot of burden on the skin. In addition, 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. In addition, since 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.
이에, 본 발명자들은 환자의 복약순응도를 높이기 위한 경피흡수제제에 관하여 연구하던 중, 소수성 매트릭스 내에서 약물의 결정 생성이 없이 고농도(10% 이상)의 약물을 함유하고, 장기간 동안 피부를 통해 약물을 지속적으로 투여하여 약물의 혈중농도를 부작용이 나타나는 농도까지 도달시키지 않으면서, 장기간에 걸쳐 치료 효과를 유지할 수 있는 경피흡수제제를 제조하고 본 발명을 완성하였다.Therefore, 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.
본 발명의 목적은 환자의 복약순응도를 높이기 위해 도네페질(donepezil)을 유효성분으로 함유하고, 소수성 매트릭스 내에서 10% 이상의 고농도 약물의 함유할 때에도 결정 생성이 없어 경피흡수제제의 점착력 감소 없이 장기간 동안 약물을 피부를 통해 체내로 전달할 수 있는 치매 치료용 경피흡수제제를 제공하는 데 있다.It is an object of the present invention to contain donepezil as an active ingredient in order to increase the patient's compliance with the drug, and even when a high concentration of drug in a hydrophobic matrix of 10% or more is contained, there is no crystallization for a long period of time without reducing the adhesion of the transdermal absorbent. It is to provide a transdermal absorption preparation for treating dementia that can deliver drugs into the body through the skin.
상기 목적을 달성하기 위하여, 본 발명은 유효성분으로서 도네페질 또는 이의 약학적으로 허용가능한 염, 기제로서 상기 유효성분의 결정화 방지를 위해 로진에스터 수지를 포함하는 EVA점착제 및 피부투과 증진제로서 피롤리돈 유도체, C8-18의 지방족 유도체, 트리아세틴 및 트리에틸시트레이트로 이루어지는 군으로부터 선택되는 2종 이상의 혼합물을 복합사용하는 약물함유 매트릭스층; 약물보호 지지층; 및 박리층으로 이루어지는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제를 제공한다.In order to achieve the above object, 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.
본 발명에 따른 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제는 피부 부착성이 우수하고, 소수성 매트릭스 내에서 10% 이상의 고농도 약물을 함유할 때에도 결정 생성을 방지함으로써 점착력의 감소를 방지하여 장기간 동안 약물을 지속적으로 방출할 수 있고, 약물의 피부투과도가 우수하여 종래의 치매 치료용 경구제를 대체하여 유용하게 사용될 수 있다. 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.
도 1은 본 발명에 따른 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제의 단면도이고(A: 약물보호 지지층, B: 약물함유 매트릭스층, C: 박리층),1 is a cross-sectional view of a transdermal absorption preparation for treating dementia containing Donepezil as an active ingredient according to the present invention (A: drug protection support layer, B: drug-containing matrix layer, C: release layer),
도 2는 본 발명에 따른 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제의 누적피부투과량을 나타낸 그래프이며,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,
도 3은 본 발명에 따른 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제의 평균피부투과속도를 나타낸 그래프이다.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.
본 발명은 The present invention
약물보호 지지층, 약물함유 매트릭스층 및 박리층으로 이루어지는 치매 치료용 경피흡수제제에 있어서, In the transdermal absorption preparation for treating dementia comprising a drug protective support layer, a drug-containing matrix layer and a peeling layer,
상기 약물함유 매트릭스층이 유효성분으로서 도네페질 또는 이의 약학적으로 허용가능한 염 2.0~25 중량%; 고분자 기제로서 로진에스터 수지를 함유하는 EVA점착제 50~80 중량%; 및 피부투과 증진제로서 피롤리돈 유도체, C8-18의 지방족 유도체, 트리아세틴 및 트리에틸시트레이트로 이루어지는 군으로부터 선택되는 어느 2종 이상의 혼합물 10~25 중량%을 포함하는 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제를 제공한다.2.0 to 25% by weight of the drug-containing matrix layer donepezil or a pharmaceutically acceptable salt thereof as an active ingredient; 50 to 80% by weight of an EVA adhesive containing a rosin ester resin as a polymer base; And 10-25 wt% of any two or more mixtures selected from the group consisting of pyrrolidone derivatives, aliphatic derivatives of C 8-18 , triacetin and triethyl citrate as skin permeation enhancers. Provided is a transdermal absorption preparation for treating dementia containing as an active ingredient.
이하, 본 발명에 따른 치매 치료용 경피흡수제제를 구성하는 상기 약물함유 매트릭스층을 설명한다. Hereinafter, the drug-containing matrix layer constituting the transdermal absorption preparation for treating dementia according to the present invention will be described.
먼저, 본 발명에 따른 경피흡수제제의 약물함유 매트리스층은 유효성분으로서 도네페질 또는 이의 약학적으로 허용가능한 염을 포함한다. First, 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.
본 발명에 사용되는 상기 도네페질은 아세틸콜린에스테라제 저해제로서 자유염기(free base) 형태인 도네페질 또는 이의 약학적으로 허용가능한 염을 사용하는 것이 바람직하다. 상기 약학적으로 허용가능한 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 사용할 수 있다.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. As the 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. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. 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, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate can be used.
또한, 상기 유효성분은 점착제 내에 용해되거나 균일하게 분산되어 있는 상태로서, 전체 약물함유 매트릭스 중량에 대해 2.0-25 중량%인 것이 바람직하다. 만약, 도네페질 또는 이의 약학적으로 허용가능한 염의 함량이 2.0 중량% 미만인 경우에는 약물효과가 미흡하며, 25 중량%를 초과하는 고농도의 경우에는 제제 내에서 약물의 결정이 생성되어 점착력의 감소가 생길 수 있다.In addition, 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.
다음으로, 본 발명에 따른 경피흡수제제의 약물함유 매트릭스층은 고분자 기재 및 감압성 점착제로서 EVA 점착제를 사용하는 것이 바람직하다.Next, 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.
일반적으로 감압성 점착제는 피부에 대한 점착성, 약물 및 기타 부형제와의 적합성 등이 요구되고, 이러한 특성을 가진 점착제로서 TRS(세키수이 케미칼 컴퍼니(Sekisui Chemical Co., Osaka, Japan)), 듀로-텍(Duro-Tak;내셔널 스타치 케미칼 컴퍼니(National Starch Chemical Co., bridgewater, N.J., USA))과 같은 아크릴계 점착제가 상용되고 있다. 그러나 이러한 아크릴계 점착제는 치매 치료용 경피흡수제제의 매트릭스로 사용될 경우, 점착층에서 약물과 아크릴계 고분자간의 상호작용으로 인하여 점착층 내에서의 약물 확산이 둔화되고 점착층으로부터 피부로의 약물 이행도 저하됨에 따라 필요량의 약물을 전달하기에 곤란하다. In general, 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. However, when 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.
따라서, 본 발명의 약물함유 매트리스층을 구성하는 점착제는 EVA 점착제를 사용하는 것이 바람직하다. 상기 EVA 점착제의 주원료인 폴리에틸렌 비닐아세테이트 공중합체는 비닐아세테이트 함량에 따라 그 용도가 다양할 뿐만 아니라, 내후성, 경시안정성, 인열강도, 내스트레스성 및 내오존성이 우수하고 고무에 비해 투명하고 무독한 열가소성 탄성수지이다. 이때, 바람직한 점착력을 나타내기 위하여 상기 EVA 점착제에 사용되는 EVA는 VA함량(비닐아세테이트 함량)이 4~50%인 것이 바람직하고, 33~41%인 것이 더욱 바람직하다.Therefore, it is preferable that 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. At this time, in order to exhibit a desirable adhesive force, 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%.
또한, 상기 EVA 점착제는 유효성분인 도네페질의 결정화 방지를 위해 로진에스터 수지를 포함한다. 아크릴을 제외한 대부분의 소수성 매트릭스 내에서 본 발명의 경피흡수제제의 유효성분으로서 도네페질은 기제에 대한 용해도 때문에 수일 또는 수 주 내에 결정이 생성됨으로 인하여 매트릭스 기제에 대한 약물의 용해도를 높이기 위해서 적당한 극성을 갖는 성분이 필요하다. 이러한 관점에서 본 발명에 따른 EVA 점착제에 사용되는 로진에스터 수지는 구조가 도네페질의 구조와 유사하고, 적당한 극성을 갖고 있음으로써 소수성 매트릭스 내에서 도네페질이 결정화되지 않고 안정하게 녹아 있거나 분산될 수 있게 한다. 이때 사용되는 로진에스터 수지는 펜타에리트리톨 로진에스터, 글리세롤 로진에스터, 펜타에리트리톨 수첨 로진에스터, 글리세롤 수첨 로진에스터 등이 바람직하고, 펜타에리트리톨 로진에스터인 것이 더욱 바람직하다. In addition, the EVA adhesive includes a rosin ester resin to prevent crystallization of donepezil, an active ingredient. As an active ingredient of the transdermal absorption preparation of the present invention in most hydrophobic matrices except acrylic, 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. In this respect, 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. In this case, 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.
상기 약물함유 매트리스층을 구성하는 고분자 기제로서 EVA 점착제의 함량은 전체 약물함유 매트릭스 중량에 대해 50-80 중량%인 것이 바람직하다. 만약, 상기 함량 범위를 벗어나는 경우에는 피부 적용성, 약물 및 다른 부형제와의 적합성의 관점에서 불리한 문제가 있다.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.
다음으로, 본 발명에 따른 경피흡수제제의 약물함유 매트릭스층은 피부투과 증진제로서 피롤리돈 유도체, C8-18 인 지방족 유도체, 트리아세틴 및 트리에틸시트레이트 중에서 선택되는 어느 2종 이상을 포함하는 것이 바람직하다. 약물의 피부투과율을 증진시키는 관점에서 상기 피부투과 증진제의 함유량은 전체 약물함유 매트릭스 중량에 대해 10-25 중량%인 것이 바람직하다.Next, the drug-containing matrix layer of the transdermal absorption preparation according to the present invention 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. In view of enhancing the skin permeability of the drug, the content of the skin permeation enhancer is preferably 10-25% by weight based on the total weight of the drug-containing matrix.
상기 피부투과 증진제로서 상기 피롤리돈 유도체는 N-사이클로헥실-2-피롤리돈(N-cyclohexyl-2-pyrrolidone), 1-부틸-3-도데실-2-피롤리돈(1-butyl-3-dodecyl-2-pyrrolidone), 1,5-디메틸-2-피롤리돈(1,5-dimethyl-2-pyrrolidone), 1-에틸-2-피롤리돈(1-ethyl-2-pyrrolidone), 1-헥실-4-메틸옥시카르보닐-2-피롤리돈(1-hexyl4-methyloxycarbonyl-2-pyrrolidone), 1-헥실-2-피롤리돈(1-hexyl-2-pyrrolidone), 1-(2-하이드록시에틸)피롤리돈(1-(2-hydroxyethyl)pyrrolidone), 3-하이드록시-N-메틸-2-피롤리돈(3-hydroxy-N-methyl-2-pyrrolidone), 1-라우릴-4-메틸옥시카르보닐-2-피롤리돈(1-lauryl-4-methyloxycarbonyl-2-pyrrolidone), N-메틸-2-피롤리돈(N-methyl-2-pyrrolidone), N-카프릴릴-2-피롤리돈(N-carprylyl-2-pyrrolidone), N-도데실-2-피롤리돈(N-dodecyl-2-pyrrolidone) 등이 바람직하고, N-도데실-2-피롤리돈(N-dodecyl-2-pyrrolidone)인 것이 더욱 바람직하다. As the skin permeation enhancer, 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-pyrrolidone, etc. are preferable, and N-dodecyl-2 is preferred. It is more preferable that it is -pyrrolidone (N-dodecyl-2-pyrrolidone).
또한, 상기 피부투과 증진제로서 C8-18의 지방족 유도체는 글리세롤 라우릴알코올(glycerol lauryl alcohol), 올레일알코올(oleyl alcohol), 이소프로필 미리스트레이트(isopropyl myristrate), 소르비탄 모노올레이트(sorbitan mono-oleate), 프로필렌 모노라우레이트(propylene monolaurate), 프로필렌 모노올레이트(propylene mono-oleate), 올레일 마크로골 글리세라이드(oleyl macrogoglyceride), 올레인산(oleic acid), 라우로일 마크로골 글리세라이드(lauroyl macrogoglyceride), 리놀레오일 마크로골 글리세라이드(linoleoyl macrogoglyceride), 프로필렌글리콜 카프릴레이트/카프레이트(Propylene glycol caprylate/caprate), 소르비탄 모노스테아레이트 모노올레이트(Sorbitan monostearate mono-oleate), 글리세롤 모노라우레이트(glycerol monolaurate), 프로필렌 글리콜 모노라우레이트(propylene glycol monolaurate), 프로필렌글리콜 모노카프릴레이트(propylene glycol monocaprylate), 소르비탄 모노라우레이트(sorbitan monolaurate), 라우릴 락테이트(lauryl lactate), 카프릴릭/카프릭 트리글리세라이드(caprylic/capric triglyceride), 옥수수유 PEG-8 에스터, 옥수수유 PEG-6 에스터 등이 바람직하고, 글리세롤 모노올레이트, 글리세롤 모노라우레이트, 프로필렌 글리콜 모노라우레이트, 프로필렌글리콜 모노카프릴레이트, 소르비탄 모노라우레이트, 라우릴 락테이트, 카프릴릭/카프릭 트리글리세라이드, 옥수수유 PEG-8 에스터, 옥수수유 PEG-6 에스터 등이 더욱 바람직하다.In addition, 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 monooleate, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / capric trigly More preferred are cerides, corn oil PEG-8 esters, corn oil PEG-6 esters, and the like.
나아가, 상기 피부투과 증진제로서 트리아세틴 또는 트리에틸시트레이트를 사용할 수 있다. 상기 트리아세틴은 용해보조제, 연화제, 피부투과 촉진제 등으로 사용되어 왔으며, 트리에틸시트레이트는 유드라짓(Eudragit) 계열의 폴리아크릴레이트 고분자의 연화제로서 경구제 코팅물질의 연화제로 많이 사용되어 왔으나 트리아세틴과 동일하게 도네페질에 대해서 피부투과 증진 효과가 있다.Furthermore, 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.
본 발명에 따른 경피흡수제제의 약물함유 매트릭스층에 포함되는 상술한 피부투과 증진제는 이들 중 어느 2종 이상을 혼합하여 전체 약물함유 매트릭스 중량에 대해 10-25 중량%를 포함하는 것이 바람직하다.It is preferable that 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.
다음으로, 본 발명에 따른 치매 치료용 경피흡수제제를 구성하는 약물보호 지지층 및 박리층을 설명한다. Next, the drug protection support layer and the release layer constituting the transdermal absorption preparation for treating dementia according to the present invention will be described.
본 발명에 따른 치매 치료용 경피흡수제제의 약물보호 지지층은 피부에 부착 또는 보관하는 동안 제제로부터 도네페질이 손실되는 것을 방지하기 위하여 얇고 유연성이 있으며 피부와의 반응성이 없어 알러지 반응을 야기시키지 않는 것을 사용한다. 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.
본 발명에 따른 상기 지지층은 경피흡수제제에서 통상적으로 사용되는 폴리에틸렌, 폴리프로필렌, 에틸렌 비닐아세테이트 공중합체, 비닐론, 폴리에스터, 폴리우레탄, 나일론, 폴리아크릴로니트릴, 폴리에틸렌테레프탈레이트, 폴리올레핀 등의 플라스틱 필름(film), 또는 인체로부터 발산되는 수분에 의해 경피흡수제제가 탈락되는 것을 방지하기 위하여 수분흡수 능력이 있는 레이온, 폴리에스터 등의 부직포, 폴리에스터, 아크릴, 실크, 면 등의 직포, 또는 이들의 적층 혼성물인 것을 사용할 수 있으며, 종래의 경피흡수제제에서 이용되고 있는 약물보호용 물질 중 어느 것을 사용하여도 무방하다.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.
또한, 본 발명에 따른 치매 치료용 경피흡수제제의 박리층은 경피흡수제제에 통상적으로 사용되는 이형필름이나 이의 적층물을 사용할 수 있다. 예를 들면, 실리콘 수지 또는 불소 수지를 도포한 폴리에틸렌, 폴리에스터, 폴리비닐 클로라이드, 폴리비닐리덴 클로라이드 등의 필름, 종이 또는 이들의 적층물을 사용할 수 있다.In addition, 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. For example, 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.
본 발명에 따른 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제는 피부 부착성이 우수하고, 소수성 매트릭스 내에서 10% 이상의 고농도 약물을 함유할 때에도 결정 생성을 방지함으로써 점착력의 감소를 방지하여 장기간(1-7일) 동안 약물을 지속적으로 방출할 수 있고(도 2 참조), 적용기간이 길어지면서 피부투과 속도가 서서히 감소하나 최소 필요 투과 속도인 1.2 μg/㎠/hr보다 높은 피부투과속도를 유지하여 약물의 피부투과도가 우수하므로(도 3 참조) 종래의 치매 치료용 경구제를 대체하여 유용하게 사용될 수 있다. 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 μg / 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.
이하, 본 발명을 실시예 및 실험예를 통하여 상세하게 설명하고자 한다. 단, 하기의 실시예 및 실험예는 본 발명을 구체적으로 설명하기 위해 제공되는 것일 뿐, 본 발명의 범위가 이들 실시예 및 실험예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. However, the following Examples and Experimental Examples are provided only to specifically describe the present invention, but the scope of the present invention is not limited to these Examples and Experimental Examples.
<실시예 1> 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제의 제조Example 1 Preparation of Transdermal Absorbent for Treatment of Dementia Containing Donepezil as an Active Ingredient
도네페질 13 중량%, 글리세롤 모노라우레이트 5 중량%, 글리세롤 모노올레이트 5 중량%, EVA 점착제 77중량%에 톨루엔을 가하여 고형분 총량이 50%가 되게 하여 완전히 용해시킨 후, 약물이 함유된 점착용액을 도포기 위에 고정시킨 실리콘이 처리된 폴리에스터 이형필름 위에 도포하고 90 ℃에서 10 분간 1300 rpm의 속도의 풍속으로 건조시켜 두께가 85 μm인 점착층 시트를 제조한 뒤 폴리에스터 지지필름과 합지하고 이를 일정한 크기로 잘라 상기 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제를 제조하였다.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. Was applied on a silicone-treated polyester release film fixed on an applicator, and dried at a speed of 1300 rpm for 10 minutes at 90 ° C. to prepare an adhesive layer sheet having a thickness of 85 μm, and then laminated with a polyester support film. It was cut to a certain size to prepare a transdermal absorption preparation for treating dementia containing the donepezil as an active ingredient.
<실시예 2~20> 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제의 제조<Examples 2 to 20> Preparation of transdermal absorbent preparation for treating dementia containing Donepezil as an active ingredient
매트릭스 층을 구성하는 성분들의 조성을 하기 표 1에 나타낸 바와 같이 변화시키면서 실시예 1과 동일한 방법으로 수행하여 상기 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제를 제조하였다. 이때, 각 성분의 함량은 중량%이다.The 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.
표 1
성분(%)
도네페질 EVA점착제 GML GMO SML NP CCS CP8 LL TA TC CP6 PGML
실시예 1 13.0 77.0 5.0 5.0
2 13.0 77.0 5.0 5.0
3 13.0 77.0 5.0 5.0
4 13.0 77.0 5.0 5.0
5 13.0 77.0 5.0 5.0
6 13.0 77.0 5.0 5.0
7 13.0 72.0 10.0 5.0
8 13.0 72.0 10.0 5.0
9 13.0 72.0 10.0 5.0
10 13.0 72.0 10.0 5.0
11 13.0 72.0 10.0 5.0
12 13.0 72.0 10.0 5.0
13 13.0 72.0 10.0 5.0
14 13.0 72.0 10.0 5.0
15 11.5 73.5 10.0 5.0
16 10.0 75.0 10.0 5.0
17 13.0 62.0 10.0 10.0 5.0
18 13.0 62.0 10.0 5.0 10.0
19 13.0 62.0 10.0 10.0 5.0
20 13.0 62.0 10.0 5.0 10.0
EVA:폴리에틸렌 비닐아세테이트 점착제, GML:글리세롤 모노라우레이트, GMO:글리세롤 모노올레이트, SML:소르비탄 모노라우레이트, NP: N-도데실-2-피롤리돈, CCS:카프릴릭/카프릭 트리글리세라이드, CP8:옥수수유 PEG-8 에스터, LL:라우릴 락테이트, TA:트리아세틴, TC:트리에틸 시트레이트, CP6:옥수수유 PEG-6 에스터, PGML: 프로필렌글리콜 모노라우레이트
Table 1
ingredient(%)
Donepezil EVA adhesive GML GMO SML NP CCS CP8 LL TA TC CP6 PGML
Example One 13.0 77.0 5.0 5.0
2 13.0 77.0 5.0 5.0
3 13.0 77.0 5.0 5.0
4 13.0 77.0 5.0 5.0
5 13.0 77.0 5.0 5.0
6 13.0 77.0 5.0 5.0
7 13.0 72.0 10.0 5.0
8 13.0 72.0 10.0 5.0
9 13.0 72.0 10.0 5.0
10 13.0 72.0 10.0 5.0
11 13.0 72.0 10.0 5.0
12 13.0 72.0 10.0 5.0
13 13.0 72.0 10.0 5.0
14 13.0 72.0 10.0 5.0
15 11.5 73.5 10.0 5.0
16 10.0 75.0 10.0 5.0
17 13.0 62.0 10.0 10.0 5.0
18 13.0 62.0 10.0 5.0 10.0
19 13.0 62.0 10.0 10.0 5.0
20 13.0 62.0 10.0 5.0 10.0
EVA: polyethylene vinyl acetate adhesive, GML: glycerol monolaurate, GMO: glycerol monooleate, SML: sorbitan monolaurate, NP: N-dodecyl-2-pyrrolidone, CCS: caprylic / capric Triglyceride, CP8: corn PEG-8 ester, LL: lauryl lactate, TA: triacetin, TC: triethyl citrate, CP6: corn PEG PEG-6 ester, PGML: propylene glycol monolaurate
<비교예 1~31> <Comparative Examples 1-31>
매트릭스 층을 구성하는 성분들의 조성을 하기 표 2 및 표 3에 나타낸 바와 같이 변화시키면서 실시예 1과 동일한 방법으로 수행하여 상기 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제를 제조하였다. 이때, 각 성분의 함량은 중량%이다. The 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.
표 2
구분 비교예
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
성분(%) 도네페질 13 13 13 13 13 13 13 13 13 13 13 13 13 13 12
SIS 점착제 77 67
SEP 점착제 77
SBS 점착제 77
아크릴 점착제 77
EVA 점착제 77 67 77 77 77 77 77 77 77 77
NP 10 10 10 20 10 20 10
SML 10
SMO 10
PMO 10
PML 10
GMO 10
GML 10
IPM 10
PGML 10
SIS:스티렌-이소프렌-스티렌, SEP:스티렌-에틸렌-프로필렌, SBS:스티렌-부타디엔-스티렌, 아크릴 점착제:폴리아크릴레이트 점착제, EVA:폴리에틸렌 비닐아세테이트, NP: N-도데실-2-피롤리돈, SML:소르비탄 모노라우레이트, SMO: 소르비탄 모노올레이트, PMO: 폴리옥시에틸렌 모노올레이트, PML:폴리옥시에틸렌 모노라우레이트, GMO:글리세롤 모노올레이트, GML:글리세롤 모노라우레이트, IPM:이소프로필 미리스트레이트, PGML: 프로필렌글리콜 모노라우레이트
TABLE 2
division Comparative example
One 2 3 4 5 6 7 8 9 10 11 12 13 14 15
ingredient(%) Donepezil 13 13 13 13 13 13 13 13 13 13 13 13 13 13 12
SIS adhesive 77 67
SEP adhesive 77
SBS adhesive 77
Acrylic adhesive 77
EVA adhesive 77 67 77 77 77 77 77 77 77 77
NP 10 10 10 20 10 20 10
SML 10
SMO 10
PMO 10
PML 10
GMO 10
GML 10
IPM 10
PGML 10
SIS: styrene-isoprene-styrene, SEP: styrene-ethylene-propylene, SBS: styrene-butadiene-styrene, acrylic adhesive: polyacrylate adhesive, EVA: polyethylene vinyl acetate, NP: N-dodecyl-2-pyrrolidone , SML: sorbitan monolaurate, SMO: sorbitan monooleate, PMO: polyoxyethylene monooleate, PML: polyoxyethylene monolaurate, GMO: glycerol monooleate, GML: glycerol monolaurate, IPM Isopropyl myristate, PGML: Propylene glycol monolaurate
표 3
구분 비교예
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
성분(%) 도네페질 10 13 13 13 13 13 13 13 13 13 13 13 13 13 13
EVA 점착제 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77
OMG 10
LL 10
OA 10
TA 10
CP8 10
GMLi 10
CP6 10
LM6G 10
LiM6G 10
PGCC 10
TC 10
SMS 10
DGME 10
PGML 10
PGMC 10
EVA:폴리에틸렌 비닐아세테이트, OMG:올레일 마크로골 글리세라이드, LL:라우릴 락테이트, OA:올레인산, TA:트리아세틴, CP8:옥수수유 PEG-8 에스터, GMLi:글리세롤 모노리놀레이트, CP6:옥수수유 PEG-6 에스터, LM6G:라우로일 마크로골-6 글리세라이드, LiM6G:리놀레일 마크로골-6 글리세라이드, PGCC:프로필렌 글리콜 카프릴레이트/카프레이트, TC:트리에틸 시트레이트, SMS:소르비탄 모노스테아레이트, DGME:디에틸렌 글리콜 모노에틸 에테르(트란스큐톨 P), PGML:프로필렌글리콜 모노라우레이트, PGMC:프로필렌글리콜 모노카프릴레이트
TABLE 3
division Comparative example
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
ingredient(%) Donepezil 10 13 13 13 13 13 13 13 13 13 13 13 13 13 13
EVA adhesive 77 77 77 77 77 77 77 77 77 77 77 77 77 77 77
OMG 10
LL 10
OA 10
TA 10
CP8 10
GMLi 10
CP6 10
LM6G 10
LiM6G 10
PGCC 10
TC 10
SMS 10
DGME 10
PGML 10
PGMC 10
EVA: polyethylene vinyl acetate, OMG: oleyl macrogol glyceride, LL: lauryl lactate, OA: oleic acid, TA: triacetin, CP8: corn oil PEG-8 ester, GMLi: glycerol monolinoleate, CP6: corn Oil PEG-6 ester, LM6G: lauroyl macrogol-6 glyceride, LiM6G: linoleyl macrogol-6 glyceride, PGCC: propylene glycol caprylate / caprate, TC: triethyl citrate, SMS: sorb Non-elastic monostearate, DGME: diethylene glycol monoethyl ether (transcutol P), PGML: propylene glycol monolaurate, PGMC: propylene glycol monocaprylate
상기에서 제조된 실시예 1~20 및 비교예 1~30에서 제조된 경피흡수제제에 대한 도네페질 약물의 피부투과 실험을 하기와 같이 실시하였다.Skin permeation experiment of the donepezil drug for the transdermal absorption preparations prepared in Examples 1 to 20 and Comparative Examples 1 to 30 were prepared as described above.
<실험예 1> Experimental Example 1
약물투과 실험용 확산장치(프란쯔셀)는 수용상의 pH가 7.4인 인산 완충액에 피부의 부패방지를 위해 소듐 아자이드 0.5 중량%를 첨가하여 제조하였다. 실험용 확산장치에 수용상을 채워 온도를 32±0.5 ℃로 유지시키고, 피부는 사체비부(Human cadaver skin)를 사용하여 상기 실시예 1~20 및 비교예 1~30에서 제조된 각각의 매트릭스를 공여셀 크기에 맞게 절단하여 적용시켰다. 시간이 경과함에 따라, 시간별로 상기 약물이 확산된 완충용액 250 μL씩을 취하여 액체크로마토그래피법으로 투과된 약물을 정량하였다. 실시예 1~20 및 비교예 1~30에서 제조된 패치에 약물을 투과한 후 7일간 경과시의 약물 평균 피부투과속도를 하기의 표 4 및 표 5에 나타내었다.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. As time passed, 250 μL 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.
표 4
피부투과속도(μg/cm2/hr) 피부투과속도(μg/cm2/hr)
실시예 1 4.85±1.22 실시예 11 4.94±1.30
실시예 2 4.39±0.86 실시예 12 5.40±1.40
실시예 3 4.36±1.10 실시예 13 7.74±0.85
실시예 4 4.90±0.64 실시예 14 5.56±0.62
실시예 5 5.68±0.68 실시예 15 7.25±0.91
실시예 6 5.34±0.35 실시예 16 6.07±0.93
실시예 7 5.81±0.21 실시예 17 7.62±0.05
실시예 8 6.05±0.44 실시예 18 6.88±2.15
실시예 9 6.50±0.74 실시예 19 7.40±2.40
실시예 10 5.34±0.58 실시예 20 7.72±0.97
Table 4
Skin penetration rate (μg / cm 2 / hr) Skin penetration rate (μg / cm 2 / hr)
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
표 5
피부투과속도(μg/cm2/hr) 피부투과속도(μg/cm2/hr)
비교예 1 3.58±0.87 비교예 16 3.33±0.86
비교예 2 3.89±0.13 비교예 17 2.53±0.62
비교예 3 3.82±0.58 비교예 18 2.87±0.01
비교예 4 3.88±0.52 비교예 19 2.10±0.05
비교예 5 2.39±0.34 비교예 20 2.90±0.32
비교예 6 3.21±0.62 비교예 21 1.94±0.36
비교예 7 1.46±0.10 비교예 22 2.89±0.96
비교예 8 2.68±0.40 비교예 23 2.30±0.20
비교예 9 1.73±0.20 비교예 24 0.79±0.02
비교예 10 1.64±0.50 비교예 25 1.67±0.06
비교예 11 0.98±0.03 비교예 26 3.20±0.31
비교예 12 1.84±0.80 비교예 27 2.43±0.04
비교예 13 3.83±0.22 비교예 28 2.68±0.31
비교예 14 2.67±0.96 비교예 29 2.32±0.08
비교예 15 1.60±1.13 비교예 30 1.35±0.04
Table 5
Skin penetration rate (μg / cm 2 / hr) Skin penetration rate (μg / cm 2 / hr)
Comparative Example 1 3.58 ± 0.87 Comparative Example 16 3.33 ± 0.86
Comparative Example 2 3.89 ± 0.13 Comparative Example 17 2.53 ± 0.62
Comparative Example 3 3.82 ± 0.58 Comparative Example 18 2.87 ± 0.01
Comparative Example 4 3.88 ± 0.52 Comparative Example 19 2.10 ± 0.05
Comparative Example 5 2.39 ± 0.34 Comparative Example 20 2.90 ± 0.32
Comparative Example 6 3.21 ± 0.62 Comparative Example 21 1.94 ± 0.36
Comparative Example 7 1.46 ± 0.10 Comparative Example 22 2.89 ± 0.96
Comparative Example 8 2.68 ± 0.40 Comparative Example 23 2.30 ± 0.20
Comparative Example 9 1.73 ± 0.20 Comparative Example 24 0.79 ± 0.02
Comparative Example 10 1.64 ± 0.50 Comparative Example 25 1.67 ± 0.06
Comparative Example 11 0.98 ± 0.03 Comparative Example 26 3.20 ± 0.31
Comparative Example 12 1.84 ± 0.80 Comparative Example 27 2.43 ± 0.04
Comparative Example 13 3.83 ± 0.22 Comparative Example 28 2.68 ± 0.31
Comparative Example 14 2.67 ± 0.96 Comparative Example 29 2.32 ± 0.08
Comparative Example 15 1.60 ± 1.13 Comparative Example 30 1.35 ± 0.04
상기 표 4 및 표 5를 비교해 볼 때, 도네페질은 특정 피부투과 증진제의 단독사용보다는 복합사용이 효과적이라는 것을 알 수 있고, 또한 지방족 유도체의 둘 이상의 복합사용, N-도데실-2-피롤리돈 및 지방족 유도체의 복합사용, 지방족 유도체, N-도데실-2-피롤리돈, 트리아세틴 및 트리에틸시트레이트의 복합사용이 효과적이라는 것도 알 수 있다. When comparing Table 4 and Table 5, it can be seen that donepezil is more effective than the combined use of a specific skin permeation enhancer alone, and also combined use of two or more aliphatic derivatives, N-dodecyl-2-pyrroli It can also be seen that the combined use of the don and aliphatic derivatives, the combined use of the aliphatic derivatives, N-dodecyl-2-pyrrolidone, triacetin and triethyl citrate are effective.
비교적 피부투과실험 결과가 양호한 실시예 13 내지 19에 대한 누적투과량과 피부투과속도변화를 각각 도 2 및 도 3에 나타내었다. 도 2를 통해 약물이 실험기간동안 지속적으로 방출됨을 알 수 있으며, 도 3을 통해 초기 방출 속도가 높아 경피흡수제제의 부착 초기에 약물이 제거되는 것 이상으로 투여되므로 치료 효과를 극대화 할 수 있다. 또한 도네페질은 혈장 부틸콜린에스테라제(BChE) 보다 뇌의 아세틸콜린에스테라제(AChE)에 더 특이성이 있으며 반감기가 58~90시간, 생체이용율 100% 및 단백결합율 96%로 아세틸콜린에스테라제에 대한 억제효과가 우수하다.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.
또한 5 mg 경구제의 경우 1회 경구투여 시 최대혈중농도는 9.8 ± 1.1 ng/mL이며 반복적으로 투여했을 때 15일 이내에 항정상태(steady-state)에 도달하고 항정상태에서 평균혈장농도는 26.5 ± 3.9 ng/mL이며 평균혈장청소율은 0.13 L/hr/kg으로 일정하다. 이를 통해 필요한 피부투과속도를 계산하면 대략 3.455 ± 3.9 ㎍/hr 정도이다. 도 3에서 알 수 있듯이 제조된 경피흡수제제는 실험기간 동안 필요한 피부투과속도 수준이거나 조금 높은 속도로 유지됨을 알 수 있다.In the case of 5 mg oral administration, 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 μg / hr. As can be seen in Figure 3, 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.

Claims (10)

  1. 약물보호 지지층, 약물함유 매트릭스층 및 박리층으로 이루어지는 치매 치료용 경피흡수제제에 있어서, In the transdermal absorption preparation for treating dementia comprising a drug protective support layer, a drug-containing matrix layer and a peeling layer,
    상기 약물함유 매트릭스층은 유효성분으로서 도네페질 또는 이의 약학적으로 허용가능한 염 2.0~25 중량%, 고분자 기제로서 로진에스터 수지를 함유하는 EVA 점착제 50~80 중량%, 및 피부투과 증진제로서 피롤리돈 유도체, C8-18의 지방족 유도체, 트리아세틴 및 트리에틸시트레이트로 이루어지는 군으로부터 선택되는 2종 이상의 혼합물 10~25 중량%를 포함하는 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The drug-containing matrix layer is 2.0-25% by weight of donepezil or a pharmaceutically acceptable salt thereof as an active ingredient, 50-80% by weight of an EVA adhesive containing a rosin ester resin as a polymer base, and pyrrolidone as a skin permeation enhancer. For treating dementia containing donepezil as an active ingredient, comprising 10-25 wt% of a mixture of two or more kinds selected from the group consisting of derivatives, C 8-18 aliphatic derivatives, triacetin and triethyl citrate Percutaneous Absorption.
  2. 제1항에 있어서, 피부투과 증진제로서 상기 피롤리돈 유도체는 N-사이클로헥실-2-피롤리돈, 1-부틸-3-도데실-2-피롤리돈, 1,5-디메틸-2-피롤리돈, 1-에틸-2-피롤리돈, 1-헥실-4-메틸옥시카르보닐-2-피롤리돈, 1-헥실-2-피롤리돈, 1-(2-하이드록시에틸)피롤리돈, 3-하이드록시-N-메틸-2-피롤리돈, 1-라우릴-4-메틸옥시카르보닐-2-피롤리돈, N-메틸-2-피롤리돈, N-카프릴릴-2-피롤리돈 및 N-도데실-2-피롤리돈으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The method of claim 1, wherein the pyrrolidone derivatives as skin permeation enhancers are N-cyclohexyl-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- (2-hydroxyethyl) Pyrrolidone, 3-hydroxy-N-methyl-2-pyrrolidone, 1-lauryl-4-methyloxycarbonyl-2-pyrrolidone, N-methyl-2-pyrrolidone, N-car A transdermal absorption preparation for treating dementia, comprising donepezil as an active ingredient, which is selected from the group consisting of prillyl-2-pyrrolidone and N-dodecyl-2-pyrrolidone.
  3. 제2항에 있어서, 상기 피롤리돈 유도체는 N-도데실-2-피롤리돈인 것을 특징으로 하는 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The method of claim 2, wherein the pyrrolidone derivative is N-dodecyl-2-pyrrolidone, characterized in that the transdermal absorption preparation for the treatment of dementia, containing donepezil as an active ingredient, characterized in that.
  4. 제1항에 있어서, 피부투과 증진제로서 상기 C8-18의 지방족 유도체는 글리세롤 라우릴알코올, 올레일알코올, 이소프로필 미리스트레이트, 소르비탄 모노올레이트, 프로필렌 모노라우레이트, 프로필렌 모노올레이트, 올레일 마크로골 글리세라이드, 올레인산, 라우로일 마크로골 글리세라이드, 리놀레오일 마크로골 글리세라이드, 프로필렌글리콜 카프릴레이트/카프레이트, 소르비탄 모노스테아레이트모노올레이트, 글리세롤 모노라우레이트, 프로필렌 글리콜 모노라우레이트, 프로필렌글리콜 모노카프릴레이트, 소르비탄 모노라우레이트, 라우릴 락테이트, 카프릴릭/카프릭 트리글리세라이드, 옥수수유 PEG-8 에스터 및 옥수수유 PEG-6 에스터로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The aliphatic derivative of C 8-18 as a skin permeation enhancer is glycerol lauryl alcohol, oleyl alcohol, isopropyl myrilate, sorbitan monooleate, propylene monolaurate, propylene monooleate, oleic acid. Il macrogol glyceride, oleic acid, lauroyl macrogol glyceride, linoleyl macrogol glyceride, propylene glycol caprylate / caprate, sorbitan monostearate monooleate, glycerol monolaurate, propylene glycol monolaurate Selected from the group consisting of laurate, propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate, caprylic / capric triglycerides, corn oil PEG-8 esters and corn oil PEG-6 esters Percutaneous for the treatment of dementia containing Donepezil as an active ingredient Absorbents.
  5. 제4항에 있어서, 상기 C8-18의 지방족 유도체는 글리세롤 모노올레이트, 글리세롤 모노라우레이트, 프로필렌 글릴콜 모노라우레이트, 프로필렌글리콜 모노카프릴레이트, 소르비탄 모노라우레이트, 라우릴 락테이트, 카프릴릭/카프릭 트리글리세라이드, 옥수수유 PEG-8 에스터 및 옥수수유 PEG-6 에스터로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The method of claim 4, wherein the C 8 - aliphatic derivatives of 18 glycerol monooleate, glycerol monolaurate, propylene articles rilkol monolaurate, propylene glycol caprylate, sorbitan laurate, lauryl lactate, A transdermal absorption agent for treating dementia comprising Donepezil as an active ingredient, which is selected from the group consisting of caprylic / capric triglycerides, corn oil PEG-8 esters and corn oil PEG-6 esters.
  6. 제1항에 있어서, 상기 로진에스터 수지는 유효성분의 결정화를 방지하기 위해 사용되는 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The transdermal absorption preparation for treating dementia according to claim 1, wherein the rosin ester resin is used to prevent crystallization of the active ingredient.
  7. 제1항에 있어서, 상기 로진에스터 수지는 글리세롤 로진에스터, 펜타에리트리톨 로진에스터, 글리세롤 수첨로진에스터 및 펜타에리트리톨 수첨로진에스터로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The rosin ester resin according to claim 1, wherein the rosin ester resin is selected from the group consisting of glycerol rosin ester, pentaerythritol rosin ester, glycerol hydrogenated rosin ester, and pentaerythritol hydrogenated rosin ester. Percutaneous absorption preparations for treating dementia.
  8. 제7항에 있어서, 상기 로진에스터 수지는 펜타에리트리톨 로진에스터인 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The method of claim 7, wherein the rosin ester resin is pentaerythritol rosin ester, characterized in that the percutaneous absorption preparation for the treatment of dementia containing donepezil as an active ingredient.
  9. 제1항에 있어서, 상기 EVA 점착제에 사용되는 EVA는 VA함량(비닐아세테이트 함량)이 4~50%인 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The transdermal absorption agent for treating dementia according to claim 1, wherein the EVA used in the EVA pressure-sensitive adhesive contains donepezil as an active ingredient, wherein the VA content (vinyl acetate content) is 4 to 50%.
  10. 제1항에 있어서, 상기 EVA 점착제에 사용되는 EVA는 VA함량(비닐아세테이트 함량)이 33~41%인 것을 특징으로 하는 도네페질을 유효성분으로 함유하는 치매 치료용 경피흡수제제.The transdermal absorption agent for treating dementia according to claim 1, wherein the EVA used in the EVA pressure-sensitive adhesive has donepezil as an active ingredient, wherein the VA content (vinylacetate content) is 33 to 41%.
PCT/KR2009/001472 2008-03-24 2009-03-23 Percutaneous preparation containing donepezil as active ingredient for treatment of dementia WO2009120002A2 (en)

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