CN103830206B - The Percutaneously administrable preparation of the three-dimensional netted spatial configuration of agomelatine and preparation method - Google Patents
The Percutaneously administrable preparation of the three-dimensional netted spatial configuration of agomelatine and preparation method Download PDFInfo
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Abstract
The invention discloses Percutaneously administrable preparation and the preparation method of the three-dimensional netted spatial configuration of a kind of agomelatine, Percutaneously administrable preparation, the three-dimensional netted spatial configuration system of medicine carrying by back sheet, being coated on described back sheet and be compounded in adherent layer thereon and constitute.The three-dimensional netted spatial configuration system of medicine carrying, including the component of following percentage by weight: agomelatine 1～40%, nano-stephanoporate silicon dioxide 0～10%, pressure sensitive adhesive 40～90%, transdermal penetration enhancer 1～30%, dispersant 0～20%.The present invention can not effectively realize the sustained transdermal of medicine long period, maintains constant blood concentration, and preparation percutaneous absorption rate is fast, and Transdermal absorption amount is high, has stable, efficient feature.
Description
Technical field
The present invention relates to agomelatine and carry Percutaneously administrable preparation and preparation method.
Background technology
Depression is a hypotype of mood disorder, and patient is generally of depressed, interest or happy sense is lost, energy
The typical performance such as not good or tired and somatization (such as sleep-disorder).Can be caused by a variety of causes, with notable and lasting
Mental state low for main clinical characteristics, and mental state is low unbecoming with its situation, and severe patient may occur in which suicidal thought and row
For.Majority of cases has recurrent exerbation to be inclined to, and outbreak great majority can be alleviated every time, and part can have residual symptoms or transfer to slow
Property.
In patients with depression, at least the patient of 10% shows effect with manic symptoms, now should be diagnosed as two-way obstacle.Separately
The depression that we often say outward, in fact refers to major depression (major depression) clinically, has 16% in crowd
People all one's life certain period can be affected by.Suffer from depression in addition to paying serious emotion and social costs,
Economic cost is also huge.Adding up according to the World Health Organization, depression has become the fourth-largest illness in the world, it is contemplated that to 2020
Year, it is likely to become the second largest disease being only second to coronary heart disease.The illness rate of China's depression at present is about 3%～5%, presses down
Estimated 36,000,000 people of strongly fragrant disease patient, form distinct contrast with high incidence, and current national prefectural level is to go to the hospital
To the discrimination of depression less than 20%.And in existing patients with depression, the people only less than 10% receives Related Drug
Thing is treated.Depression, as " byproduct " of the modern economy of high speed development, affects people's the most more and more widely
Life.
Agomelatine, as global first epiphysin m receptor activator, is biological (electronics) isostere of naphthalene of epiphysin
Analog, it instead of indole ring with naphthalene core so that it is relatively epiphysin more metabolic stability.It is that a hypothalamus takes off black
The selectivity of element acceptor and specific agonist, have again weak 5-HT Receptor Competition antagonistic activity concurrently simultaneously, show
A kind of novel pharmacological characteristics of MASSA (melatonin agonist and selective 5-HT antagonist).It can simulate take off black
The effect of element, has again the mode of action of uniqueness, is treatment circadian rhythm disorders disease (such as sleep-disorder/depression)
The drug candidate of great future.Agomelatine is a kind of novel antidepressants, for melatonin receptor activator and five
Hydroxytryptamine 2C(5-HT2C) receptor antagonist, it is first epiphysin class antidepressants, it is in treating depression field
New breakthrough.
Agomelatine (Agomelatine) is white or off-white color crystalline powder, chemical entitled N-[2-(7-methoxyl group
Naphthalene-1-base) ethyl] acetamide, molecular formula is C15H17NO2, molecular weight: 243.3, structural formula is:
Agomelatine is readily soluble in ethanol, oxolane, aceticanhydride and methyl alcohol, glacial acetic acid, acetonitrile, ethyl acetate and
In acetone dissolve, slightly soluble in dichloromethane, soluble,very slightly in toluene, water, phosphate buffer (pH5.0,6.0,
6.8,7.4) in the most insoluble.The method of existing increase drug solubility has a lot, such as solid dispersion technology, nanometer
Technology, adds surfactant etc., or medicine is become salt etc..
The existing formulation of agomelatine is the oral tablet of Shi Weiya company of France research and development, the import of its product, commodity
Entitled dimension is new, but expensive, and every day, per os hora somni was administered once.It should be noted that and be administered by oral route
Agomelatine bioavilability in human body is low, and poor at same internal and between Different Individual biology
Out-phase is when big.And owing to agomelatine formulation is single, exist and significantly first pass effect of hepar and intestines and stomach eliminate, mouth
Take the final human bioavailability of tablet and be only 3%-4%.Further, mental patient is inconvenient for by oral administration, its patient
Compliance needs to be greatly improved, it is therefore necessary to existing formulation improves or selects suitable medication, preparation
Going out the form of administration that drug release rate is constant, bioavilability is high, toxic and side effect is little, this is accomplished by scientific research personnel by innovation
The research of property.
W02007116136A1 discloses a kind of pharmaceutical composition for treating GAD, this pharmaceutical composition
Comprise the one in the addition salts of agomelatine and hydrate, various crystal form and pharmaceutically acceptable acid or alkali, and can medicine
Use excipient.Patent CN101991559A discloses a kind of Agomelatine capsule medicine composite preparation and preparation side thereof
Method；The formula composition that it is characterized in that making 1000 is as follows: agomelatine 15-30g, mannitol 70-140g, micro-
Powder silica gel 0.5-1g, 10% pregelatinized starch solution are appropriate.CN102218050 discloses a kind of medicine group treating depression
Compound, this pharmaceutical composition is made up of raw material agomelatine and auxiliary material, wherein raw material agomelatine be micronized Ah
Ge Meilating.CN1287780C disclose comprise agomelatine can in mouth scattered pharmaceutical composition, its feature
It is to comprise agomelatine, and the particle being made up of the lactose granule shape starch being dried, the wherein ratio of lactose, starch
Be 90/10 to 25/75.CN1981752 discloses the solid coated preparation of agomelatine, and this can be in mouth for one
Scattered pharmaceutical composition, it is characterised in that agomelatine can be located at the excipient of pharmaceutical dispersions in mouth central core or
Centronucleus.Two above patent is all to use direct compression process to prepare oral disnitegration tablet, and this oral disnitegration tablet may improve
Agomelatine bioavilability in human body, but it is intended to the most directly be disintegrated release, it is possible to cause medicine
Bad mouthfeel, reduces the compliance of patient.
China CN101919800A, CN101836966A disclose oral disnitegration tablet and the dispersible tablet of agomelatine,
Above-mentioned patent document is the preparation carrying out preparation according to the quality requirement of oral disnitegration tablet or dispersible tablet, but depression is not belonging to
Acute disease, it is not necessary to use oral disnitegration tablet or this formulation involved great expense of dispersible tablet.Chinese patent CN101048791A
Disclose agomelatine medicinal composition and technique thereof, auxiliary with medicinal after agomelatine is crossed 100 mesh sieves by this patent
Material is mixed and made into oral formulations, shows the research by having related substance and dissolution rate, determine preparation prescription in specification, but
The detection method of the openest dissolution rate, this dissolution results remains to be discussed.
CN101206200A discloses a kind of HPLC method separating isolation analysis of agomelatine intermediate and finished product thereof,
Isolation analysis of agomelatine intermediate and products thereof can be separated fast and effectively by the method.Yaxuan Liu
et,Quantification and structural elucidation of potential impurities in agomelatine active
Pharmaceutical ingredient, " Journal of Pharmaceutical and Biomedical Analysis ", 81-82
(2013) 193-201.What is learnt military affairs, and RP-HPLC measures the content of agomelatine bulk drug, and " West China pharmacy is miscellaneous
Will ", 02 phase in 2010, the 204-205 page, disclose the detection method of agomelatine and its impurity.
Agomelatine is the most sensitive to acid, alkali, obtains seven kinds of impurity through strength degradation experiment.Formed impurity be mainly Ah
Ge Meilating N-(2-(7-methoxy-1-naphthyl) ethyl)-acetamide, 2-(7-methoxynaphthalene-1-base) acetonitrile, (7-methoxyl group
-3,4-dihydro-1-naphthyl) acetonitrile and 2-(7-methoxynaphthalene-1-base) ethylamine hydrochloride etc..Therefore, in pharmacy procedure
Should the stability of special concern agomelatine bulk drug, it is to avoid agomelatine forms impurity, and to reduce, its poison is secondary to be made
With.
Agomelatine preparation disclosed in above-mentioned patent document in terms of medicine stability, homogeneity and bioavilability lack
Point does not obtain improvement substantially.Thus, the present invention designs agomelatine Percutaneously administrable preparation and solves this type of with expectation
Problem.
, there is therapeutic action for a kind of active medicine enters systemic blood circulation by skin absorption in Percutaneously administrable preparation
Sustained-release preparation, Percutaneously administrable preparation is made up of active component and carrier, and the quality of its percutaneous abilities, except active component
Performance outside, depend mainly on the carrier for carrying active ingredients.
The carrier that agomelatine preparation capable of permeating skin is is medicine agomelatine with nano silicon, is formed three-dimensional netted vertical
Body structure, then this three-dimensional netted stereochemical structure system utilization Percutaneously administrable preparation technology of preparing is prepared agomelatine transdermal
Preparation.Slowly stably discharge medicine in this kind of preparation capable of permeating skin energy 96h of agomelatine, enter systemic blood by skin
Circulation, forms the whole body durative action preparation of cutaneous penetration.Transdermal patch can keep blood concentration stable in level of significance scope
In, not only there is more preferable biopotency, and it can be avoided that the blood concentration fluctuation that causes of oral administration, maintain blood medicine
Stablizing of concentration.Meanwhile, agomelatine cutaneous penetration can avoid Oral Gastrointestinal Tract first pass effect, improves biological utilisation
Degree, reduction individual difference, make patient medication safer, effective.The transdermal patch of the design is administered once, often for every four days
Secondary 1 patch, can maintain 96h to be administered continually and steadily；This transdermal patch can also improve drug safety, as there is bad reaction
Can wash away immediately, decrease the oral danger waiting administration.
Summary of the invention
It is an object of the invention to provide Percutaneously administrable preparation and the preparation of the three-dimensional netted spatial configuration of a kind of agomelatine
Method, with the defect overcoming prior art to exist.
Present invention firstly relates to the three-dimensional netted spatial configuration system of a kind of medicine carrying, including the component of following percentage by weight:
Described nano-stephanoporate silicon dioxide is selected from mesoporous silicon oxide, aerosil (aerogel) or xerogel
(xerogel) etc., its pore size is in the range of 2-200nm；
Described nano-stephanoporate silicon dioxide, is divided into 3 classes according to the size of hole: aperture is less than the referred to as micropore of 20nm,
Aperture is mesoporous between becoming of 2-50nm, the aperture referred to as macropore more than 50nm.
Described mesoporous silicon oxide includes ordered mesoporous silica dioxide, such as MCM-41, SBA-15 Emission in Cubic of hexagonal phase
MCM-48, the MCM-50 of lamellar phase, its characteristic feature includes: homogeneous and on nanoscale continuously adjustabe become
Aperture (2-50nm), bigger specific surface area (＞ 500m2/ g) and pore volume (0.5-1.5cm3/ g).Also include that other are situated between
Hole silica nano material, as three-dimensional meso-hole TUD-1, hollow mesoporous silicon oxide HMS and silica are received
The grain of rice MSN and VK-SP15, VK-SP20, VK-SP25 etc., preferably MCM-41, MCM-48, SBA-15,
TUD-1、VK-SP15、VK-SP20、VK-SP25。
Described meso-porous nano aerosil is controlled release meso-porous nano carrier, porosity 90%-99.8%；Aperture is
20～100nm；Three-dimensional manometer particle diameter is 2～70nm；Specific surface area 100-1000m2/g；Density 0.003g-30g/cm3；
Thermal conductivity factor 0.01-0.018w/m k.Described meso-porous nano aerosil, can use Germany and Britain Ai Lisheng Asia-Pacific electricity
The aerosil of hydrophobicity, hydrophily or both sexes that sub-Co., Ltd produces；Density 12.5-18kg/m3, compare table
Area 500-650m2/ g, porosity 95-98%, aperture 10-70nm, pore volume 3.5ml/g, thermal conductivity factor
0.01-0.018w/m·k。
Described dispersant is selected from propane diols, glycerine, n-octyl alcohol, n-dodecanol, polyethylene glycol 200, PEG400
Or Macrogol 600；Preferably propane diols, glycerine, polyethylene glycol 200 or PEG400；
Described pressure sensitive adhesive is medicine carrying matrix, selected from natural rubber, polyisobutene, butene rubber, polyprene, silicon rubber,
Silicone copolymer, polyacrylate, methacrylate, acrylic acid/methacrylate copolymers, ethylene/acetic acid second
Enoate copolymer, ethene/acrylic ester copolymer, styrol copolymer or polyurethane etc., preferred acrylate pressure sensitive adhesive,
Available model can be but not limited to acrylate pressure-sensitive adhesive 87-2287, acrylate pressure-sensitive adhesive 87-4098, propylene
Acid esters pressure sensitive adhesive 87-2852, acrylate pressure-sensitive adhesive MG-0607 etc.；
Described transdermal penetration enhancer is selected from terpenes, amine, phosphide class, Laurocapram, poloxamer, laruyl alcohol sulfuric acid
Sodium, aliphatic acid or fatty acid ester；
Described terpenes includes cineole, citrene or flores aurantii tree alcohol；
Described amine includes urea, dodecyl-N or dimethylaminoethyl；Described phosphide class includes lecithin, Fabaceous Lecithin
Or phosphatidyl glycerol；
Described aliphatic acid includes oleic acid or laurate；Described fatty acid ester includes LA (LA), myristic acid
Isopropyl ester (IPM), propylene glycol dipelargonate or diethyl sebacate；
Most preferably, transdermal penetration enhancer is selected from isopropyl myristate (IPM), azone (Azone), laruyl alcohol lactic acid
Ester (LA) or glyceryl triacetate；
Preferably, the three-dimensional netted spatial configuration system of described medicine carrying, including the component of following percentage by weight:
The Percutaneously administrable preparation of the three-dimensional netted spatial configuration of agomelatine of the present invention, by back sheet, is coated in institute
State the three-dimensional netted spatial configuration system of the described medicine carrying on back sheet and be compounded in the three-dimensional netted vertical of described medicine carrying
The adherent layer that body configuration body is fastened is constituted；
The material of back sheet is polyester film, multiple containing aluminumpolyethylene composite membrane, polyester/polyethylene composite membrane, polyester/polypropylene
Close film, ethylene/vinyl acetate film, CAM, polyurethane film, non-woven fabrics or glass cloth.
Described adherent layer is the polycarbonate membrane that surface processes through organosilicon polymer or the alkyl polymer containing fluorination, as
The fluorine-treated polyester film of 3M company；
The preparation method of the Percutaneously administrable preparation of the described three-dimensional netted spatial configuration carrying agomelatine, including walking as follows
Rapid:
(1) agomelatine is dissolved in solvent, it is thus achieved that pastille solution A；
Described nano silicon is dispersed in dispersant, it is thus achieved that nano silicon dispersion liquid B；
Then A with B is mixed, ultrasonic disperse 0.5-1 hour, then soak 4-24 hour；
One or more than one in described solvent selected from ethanol, ethyl acetate, acetone.
(2) adding transdermal penetration enhancer and auxiliary agent in pressure sensitive adhesive, viscosity during addition ethyl acetate regulation glue 25 DEG C is extremely
350～2000cp, stir 0.5-2 hour with the speed of 2000-10000rpm；
(3) product of step (2) is added the product of step (1), stirs 10～30min with the speed of 500-1000rpm,
Obtain C；
Being mixed by the product of described B with step (2), the speed with 500～1000rpm stirs 10～30min, can obtain
The transdermal drug delivery system of the three-dimensional netted spatial configuration for medicine carrying described in.
(4) coating on adherent layer by the product of step (3), coating thickness is 0.10～0.5mm, and 60～90 DEG C are dried
0.5～1 hour, then cover upper back sheet, the cutaneous penetration system of the three-dimensional netted spatial configuration of described medicine carrying can be obtained
Agent.
When the transdermal patch of the present invention uses, can be attached on the intact skin of human body, each 1, with area
5-50cm2For suitably.
In terms of improving drugloading rate and suppression drug crystallization, the present invention studies discovery, and nano silicon has three-dimensional netted
Structure, has huge specific surface area, shows great activity, the many meso-hole structures in surface and superpower adsorption capacity,
Medicine agomelatine can be adsorbed onto Nano-meter SiO_2 equably2Surface mesoporous in, therefore drugloading rate is greatly increased；Simultaneously
Nano-meter SiO_22Network structure can be formed when dry, therefore constitute the three-dimensional transdermal drug delivery system of tridimensional network.Should
The transdermal drug delivery system of form can not only improve agomelatine drugloading rate can suppress again medicine crystallization, and the most uniform
Medicine is dispersed in transdermal drug delivery system by ground, implements stable release.
In terms of improving the Adhesion property of transdermal drug delivery system, due to the gluing system of cutaneous penetration, it is desirable to product viscosity,
Mobility, curing rate reach optimum condition, nanometer silicon dioxide material are added in pressure sensitive adhesive and quickly form a kind of silica
Structure, i.e. Nano-meter SiO_22Little granuloplastic network structure, it is possible to suppression colloid flowing, Assimilation rate is accelerated, and improves
Adhesive effect；Simultaneously because SiO2Particle is tiny, further increases sealing and the barrier properties of glue.
In terms of preparation stability, due to Nano-meter SiO_22(VK-SP30F) be inorganic constituents, it is easy to in preparation prescription
Medicine and other component compatibility, nontoxic, tasteless；The most valuable is Nano-meter SiO_22Ultraviolet light within wavelength 400nm
Absorptivity is up to more than 70%, and the infrared reflectivity beyond wavelength 800nm is also reached more than 70%, and it reflects ultraviolet
Ability is strong, good stability, does not decomposes, nondiscolouring after being irradiated by ultraviolet, also will not play chemistry with other component in formula
Reaction, therefore adds it to be formed in transdermal drug delivery system shielding action, reaches anti-ultraviolet ageing and resistant to thermal aging
Purpose, adds medicine stability, also improves the anti-aging effect of pressure sensitive adhesive system.
The transdermal system of the present invention three-dimensional netted spatial configuration with nano-stephanoporate silicon dioxide as carrier, solves drugloading rate
The highest, medicine easily separates out crystallization affects that Transdermal absorption usefulness, pressure sensitive adhesive system Adhesion property be not ideal enough, pressure sensitive colloid
It it is the most aging, the defect such as medicine stability is poor.This transdermal drug delivery system can not only be continued above the insoluble drug release of 24 hours
And transdermal.In this delivery system Chinese traditional medicine is released into human body by skin, plays drug effect, is able to maintain that stable blood simultaneously
Concentration, reduces and takes frequency, increases compliance and the compliance of patient；Transdermal route avoids drug oral warp simultaneously
Intestines and stomach and the first pass effect of liver, have higher bioavilability, has clear superiority in medical applications.Can have
Effect realizes the sustained transdermal of medicine long period, maintains constant blood concentration, and preparation percutaneous absorption rate is fast, transdermal
Uptake is high, has stable, efficient feature.
Accompanying drawing explanation
Fig. 1 is the accumulation transport through skin rate diagram of the agomelatine transdermal patch of embodiment 1.
Fig. 2 is the accumulation transport through skin rate diagram of the agomelatine transdermal patch of embodiment 2.
Fig. 3 is the accumulation transport through skin rate diagram of the agomelatine transdermal patch of embodiment 3.
Fig. 4 is the accumulation transport through skin rate diagram of the agomelatine transdermal patch of embodiment 4.
Fig. 5 is the accumulation transport through skin rate diagram of the agomelatine transdermal patch of embodiment 5.
Detailed description of the invention is as follows:
Embodiment 1
Prescription:
The VK-SP15E type nano silicon that nano silicon produces selected from Xuancheng Jingrui New Material Co., Ltd. is flat
All particle diameter 15nm;
Dispersant is propane diols；
Pressure sensitive adhesive is acrylate pressure-sensitive adhesive 87-4098；
Transdermal penetration enhancer is Laurocapram (Azone)
(1) by the absolute ethyl alcohol of medicine dissolving medicine saturation solubility twice, nanometer silicon dioxide material is dispersed in
In dispersant, above two solution mixes, ultrasonic 0.5 hour, then soaks 4 hours, it is thus achieved that homodisperse three-dimensional netted
The medicine-carried system of spatial configuration；
(2) in pressure sensitive adhesive add transdermal penetration enhancer, add ethyl acetate regulation glue 25 DEG C time viscosity to 1500cp,
Stir 2 hours with the speed of 2000rpm, it is thus achieved that glue simultaneously, standby；
(3) in above-mentioned glue, add the product of step (1), stir 20min with the speed of 1000rpm；
(4) coating on back sheet by the product of step (3), coating thickness 0.25mm, 105 DEG C are dried 15 minutes
To volatilize organic solvent, then cover upper adherent layer, i.e. obtain product.
The material of described back sheet is non-woven fabrics；
Described adherent layer is surface through organosilicon polymer or the polycarbonate membrane containing perfluorinated alkyl polymer treatment,
1022 fluorine-treated polyester films of 3M company.
Patch transdermal experiment:
It is measured, with nude mice intact skin as through skin, with the PEG400 of 30% with the Franz diffusion cell improved
The aqueous solution is as receiving medium, and reception tank rotating speed is set to 200rpm, and temperature 32 ± 0.5 DEG C, by good patch patch made above
In skin keratin aspect, dermis of skin contacts with receiving medium-tight, and spot sampling measures, every sub-sampling 0.3ml, sampling
After supply in Franz diffusion cell immediately 0.3ml receive medium.By sample flowing phase (PBS: acetonitrile=60:40)
Dilute ten times, measure the agomelatine concentration in sample by high performance liquid chromatography (HPLC).
It is 4.43ug/cm that the agomelatine transdermal patch using said method to prepare passes through the Mean Speed of nude mice skin2.h.
At the uniform velocity release 96h, illustrates that transdermal test in vitro process meets Zero order release process at 96h, controls release good.Algebraic oriented language U.S.A draws
The accumulation transport through skin speed of spit of fland transdermal patch is shown in Fig. 1.
Embodiment 2
Use and prepare agomelatine transdermal patch with the method for embodiment 1.Its prescription composition is as follows:
The VK-SP20E type nano silicon that nano silicon produces selected from Xuancheng Jingrui New Material Co., Ltd. is flat
All particle diameter 20nm, dispersant is PEG200；Pressure sensitive adhesive is silicone pressure-sensitive adhesive 4032；Transdermal penetration enhancer is myristic acid
Isopropyl ester (IPM)
The method using embodiment 1 prepares agomelatine transdermal patch, and use carries out external with the method as it
Transdermal experiment, then agomelatine transdermal patch is 4.95ug/cm through the Mean Speed of nude mice skin2The most at the uniform velocity release
96h, illustrates that transdermal test in vitro process meets Zero order release process at 96h, controls release good.Agomelatine transdermal patch
The accumulation transport through skin speed of agent is shown in Fig. 2.
Embodiment 3
Use and prepare agomelatine transdermal patch with the method for embodiment 1.Its prescription composition is as follows:
The VK-SP25E type nano silicon that nano silicon produces selected from Xuancheng Jingrui New Material Co., Ltd. is flat
All particle diameter 25nm, dispersant is propane diols；Pressure sensitive adhesive is acrylate pressure-sensitive adhesive 87-2287；Transdermal penetration enhancer is three second
Acid glyceride uses the method for embodiment 1 to prepare agomelatine transdermal patch, and use is carried out with the method as it
Percutaneous penetration, then agomelatine transdermal patch is 3.52ug/cm through the Mean Speed of nude mice skin2The most at the uniform velocity release
Medicine 96h, illustrates that transdermal test in vitro process meets Zero order release process at 96h, controls release good.Agomelatine transdermal
The accumulation transport through skin speed of patch is shown in Fig. 3.
Embodiment 4
Use and prepare agomelatine transdermal patch with the method for embodiment 1.Its prescription composition is as follows:
The MCM-48 type nano silicon that nano silicon produces selected from Xuancheng Jingrui New Material Co., Ltd., averagely
Particle diameter 30nm；Dispersant is PEG400；Pressure sensitive adhesive is acrylate pressure-sensitive adhesive 87-2852；Transdermal penetration enhancer is bay
Alcohol lactate (LA)；The method using embodiment 1 prepares agomelatine transdermal patch, and use with as it
Method carries out percutaneous penetration, then agomelatine transdermal patch through the Mean Speed of nude mice skin is
4.94ug/cm2The most at the uniform velocity release 96h, illustrates that transdermal test in vitro process meets Zero order release process at 96h, controls release good
Good.The accumulation transport through skin speed of agomelatine transdermal patch is shown in Fig. 4.
Embodiment 5
Agomelatine transdermal patch is prepared by the method for same embodiment 1.Its prescription composition is as follows:
The VK-SP15E type nano silicon that nano silicon produces selected from Xuancheng Jingrui New Material Co., Ltd. is flat
All particle diameter 15nm；Dispersant is glycerine；Pressure sensitive adhesive is acrylate pressure-sensitive adhesive 87-2287；Transdermal penetration enhancer is bay
Azone (Azone)；The method using embodiment 1 prepares agomelatine transdermal patch, and uses same with it
The method of sample carries out percutaneous penetration, then agomelatine transdermal patch is 4. through the Mean Speed of nude mice skin
41ug/cm2The most at the uniform velocity release 96h, illustrates that transdermal test in vitro process meets Zero order release process at 96h, controls release good.
The accumulation transport through skin speed of agomelatine transdermal patch is shown in Fig. 5.
Claims (4)
1. the three-dimensional netted spatial configuration system of medicine carrying, it is characterised in that include the component of following percentage by weight:
Described transdermal penetration enhancer selected from Laurocapram, LA (LA), isopropyl myristate (IPM),
Propylene glycol dipelargonate or diethyl sebacate；
Described nano-stephanoporate silicon dioxide is selected from mesoporous silicon oxide, its pore size in the range of 2-50nm.
The three-dimensional netted spatial configuration system of medicine carrying the most according to claim 1, it is characterised in that described dispersant
Selected from propane diols, glycerine, n-octyl alcohol, n-dodecanol, polyethylene glycol 200, PEG400 or Macrogol 600.
3. the Percutaneously administrable preparation of the three-dimensional netted spatial configuration of agomelatine, by back sheet, is coated on described back sheet
The three-dimensional netted spatial configuration system of the medicine carrying described in any one of claim 1～2 and be compounded in adherent layer structure thereon
Become.
The preparation of the Percutaneously administrable preparation of the three-dimensional netted spatial configuration of agomelatine the most according to claim 3
Method, it is characterised in that comprise the steps:
(1) agomelatine is dissolved in solvent, it is thus achieved that pastille solution A；
Described nano-stephanoporate silicon dioxide is dispersed in dispersant, it is thus achieved that nano silicon dispersion liquid B；
Then A with B is mixed, ultrasonic disperse 0.5-1 hour, then soak 4-24 hour；
One or more than one in described solvent selected from ethanol, ethyl acetate, acetone；
(2) in pressure sensitive adhesive, add transdermal penetration enhancer and auxiliary agent, add ethyl acetate, viscosity during regulation glue 25 DEG C
To 350～2000cp, stir 0.5-2 hour with the speed of 2000-10000rpm；
(3) product of step (2) is added the product of step (1), stirs 10～30min with the speed of 500-1000rpm,
Obtain C；
(4) coating on adherent layer by the product of step (3), coating thickness is 0.10～0.50mm, does for 60～90 DEG C
Dry 0.5～1 hour, then cover upper back sheet, the cutaneous penetration of the three-dimensional netted spatial configuration of described medicine carrying can be obtained
Preparation.
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| US20160184246A1 (en) * | 2014-12-30 | 2016-06-30 | Noven Pharmaceuticals, Inc. | Transdermal drug delivery systems for agomelatine |
| CN108939142A (en) * | 2018-07-05 | 2018-12-07 | 安徽玉然经编科技有限公司 | A kind of dressing of the microballoon containing composite antibacterial |
| CN110151735B (en) * | 2019-06-06 | 2021-07-06 | 深圳市泛谷药业股份有限公司 | Agomelatine transdermal patch and preparation method thereof |
| CN110787152B (en) * | 2019-12-10 | 2023-11-21 | 宁夏医科大学 | Transdermal gel patch for promoting skin absorption capacity of low medicine and preparation method thereof |
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| WO2013191187A1 (en) * | 2012-06-20 | 2013-12-27 | 株式会社メドレックス | Adhesive preparation composition obtained by blending drug, organic solvent, lipophilic ointment base, and powder |
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| WO2013191187A1 (en) * | 2012-06-20 | 2013-12-27 | 株式会社メドレックス | Adhesive preparation composition obtained by blending drug, organic solvent, lipophilic ointment base, and powder |
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