CN103830206A - Transdermal delivery preparation in three-dimensional netty spatial configuration of agomelatine and preparation method thereof - Google Patents
Transdermal delivery preparation in three-dimensional netty spatial configuration of agomelatine and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a transdermal delivery preparation in three-dimensional netty spatial configuration of agomelatine and a preparation method thereof. The transdermal delivery preparation consists of a backing layer, a medicine-loading system in a three-dimensional netty spatial configuration coated on the backing layer and an anti-sticking layer compounded on the system. The medicine-loading system in the three-dimensional netty spatial configuration comprises the following components in percentage by weight: 1-40% of agomelatine, 0-10% of nano-porous carbon dioxide, 40-90% of a pressure-sensitive adhesive, 1-30% of a transdermal penetration enhancer and 0-20% of a dispersant. The transdermal delivery preparation disclosed by the invention not only can continuously deliver the medicine in a transdermal manner for a longer time to maintain the constant blood concentration, but also is quick in transdermal absorption rate and high in transdermal absorptive amount, so that the preparation has the characteristics of stability and efficiency.
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 disorders, and that patient has is conventionally depressed, interest or happy sense is lost, energy is not good or tired and typical case's performance such as somatization (as sleep disorder).Can be caused by a variety of causes, low as main clinical characteristics taking remarkable and lasting mental state, and mental state is low unbecoming with its situation, and can there is suicidal thought and behavior in severe patient.Majority of cases has outbreak tendency repeatedly, and the great majority that at every turn show effect can be alleviated, and part can have residual symptoms or transfer to chronic.
In patients with depression, have at least 10% patient to show effect with manic symptoms, now should be diagnosed as two-way obstacle.The depression that we often say in addition, refers to major depression (major depression) clinically in fact, has 16% people affected by it in certain period in all one's life in crowd.Suffer from depression except serious emotion and social costs are paid in meeting, economic cost is also huge.According to World Health Organization's statistics, depression has become the fourth-largest illness in the world, expects the year two thousand twenty, may become the second largest disease that is only second to coronary heart disease.The China at present prevalence of depression is about 3%～5%, and patients with depression estimates at 3,600 ten thousand people, forms distinct contrast with high incidence, and national prefectural level is to go to the hospital to the discrimination of depression less than 20% at present.And in existing patients with depression, only accepted related drugs treatment less than 10% people.Depression, as " side-product " of the modern economy of high speed development, affects people's life more and more widely.
Agomelatine, as the whole world first melatonin m receptor agonist, is naphthalene biology (electronics) the isostere analog of melatonin, and it has replaced indole ring with naphthalene core, makes it have more metabolic stability compared with melatonin.It is selectivity and the specific agonist of a hypothalamus melatonin receptors, has again weak 5-HT receptor competitive antagonism activity simultaneously concurrently, shows the novel pharmacological characteristics of a kind of MASSA (melatonin agonist and selectivity 5-HT antagonist).It can simulate the effect of melatonin, has again unique model of action, is the drug candidate that has future for the treatment of physiological rhythm disorder disease (as sleep disorder/depression).Agomelatine is a kind of novel antidepressants, is melatonin receptor agonist and serotonin 2C(5-HT
2C) receptor antagonist, be first melatonin class antidepressants, it is the new breakthrough in treating depression field.
Agomelatine (Agomelatine) is white or off-white color crystalline powder, chemistry N-[2-(7-methoxynaphthalene-1-yl) ethyl by name] acetamide, molecular formula is C
15h
17nO
2, molecular weight: 243.3, structural formula is:
Agomelatine is easily molten in ethanol, oxolane, acetic anhydride and methanol, in glacial acetic acid, acetonitrile, ethyl acetate and acetone, dissolve, slightly soluble in dichloromethane, soluble,very slightly in toluene, almost insoluble in water, phosphate buffer (pH5.0,6.0,6.8,7.4).The method of existing increase drug solubility has a lot, and as solid dispersion technology, nanotechnology, adds surfactant etc., or by medicine salify etc.
The existing dosage form of agomelatine is the oral tablet of French Shi Weiya company research and development, and its product is import now, and commodity dimension by name is new, but expensive, every day, per os hora somni was administered once.It should be noted that agomelatine by the oral administration bioavailability in human body is low, and biological variability in same individuality and between Different Individual is quite large.And because agomelatine dosage form is single, exist and significant first pass effect of hepar and gastrointestinal tract elimination, the final human bioavailability of oral tablet is only 3%-4%.And, oral administration is very inconvenient to mental patient, its patient compliance sexual needs greatly improve, therefore be necessary existing dosage form to improve or select suitable medication, prepare the form of administration that drug release rate is constant, bioavailability is high, toxic and side effects is little, this just needs scientific research personnel to pass through the research of novelty.
W02007116136A1 discloses a kind of pharmaceutical composition that is used for the treatment of generalized anxiety disorder, the one in the addition salts that this pharmaceutical composition comprises agomelatine and hydrate, various crystal form and pharmaceutically acceptable acid or alkali, and pharmaceutically acceptable excipient.Patent CN101991559A discloses a kind of Agomelatine capsule medicine composite preparation and preparation method thereof; The formula that it is characterized in that making 1000 is composed as follows: agomelatine 15-30g, mannitol 70-140g, micropowder silica gel 0.5-1g, 10% pregelatinized Starch solution are appropriate.CN102218050 discloses a kind of pharmaceutical composition of Cure of depression, and this pharmaceutical composition is made up of raw material agomelatine and adjuvant, and its Raw agomelatine is micronized agomelatine.CN1287780C discloses the pharmaceutical composition that can disperse in mouth that comprises agomelatine, it is characterized in that comprising agomelatine, and the granule being made up of the lactose granule shape starch being dried, and wherein the ratio of lactose, starch is 90/10 to 25/75.CN1981752 discloses the solid coated preparation of agomelatine, and this is a kind of pharmaceutical composition that can disperse in mouth, it is characterized in that agomelatine can be arranged in central core or the centronucleus of the excipient of mouth dispersible preparation.Above two patents are all to adopt direct compression process to prepare oral cavity disintegration tablet, this oral cavity disintegration tablet may improve the bioavailability of agomelatine in human body, but in oral cavity, direct disintegrate discharge, likely cause the bad mouthfeel of medicine, reduce patient's compliance.
China CN101919800A, CN101836966A disclose oral cavity disintegration tablet and the dispersible tablet of agomelatine, above-mentioned patent documentation is the preparation of carrying out preparation according to the prescription of oral cavity disintegration tablet or dispersible tablet, but depression does not belong to emergency case, do not need to adopt this dosage form involving great expense of oral cavity disintegration tablet or dispersible tablet.Chinese patent CN101048791A discloses agomelatine medicinal composition and technique thereof, after agomelatine being crossed to 100 mesh sieves in this patent, be mixed and made into oral formulations with pharmaceutic adjuvant, in description, show by the research of related substance and dissolution, determine preparation prescription, but the detection method that does not disclose dissolution, this dissolution result remains to be discussed.
CN101206200A discloses a kind of HPLC method of compartment analysis agomelatine intermediate body and finished product thereof, with the method compartment analysis agomelatine intermediate body and products thereof fast and effectively.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 etc., RP-HPLC measures the content of agomelatine crude drug, West China Journal of Pharmaceutical Sciences, 02 phase in 2010,204-205 page, disclose agomelatine with and the detection method of impurity.
Agomelatine is all responsive to acid, alkali, obtains seven kinds of impurity through powerful degradation experiment.The impurity forming is mainly agomelatine N-(2-(7-methoxy-1-naphthyl) ethyl)-acetamide, 2-(7-methoxynaphthalene-1-yl) acetonitrile, (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile and 2-(7-methoxynaphthalene-1-yl) ethylamine hydrochloride etc.Therefore, stability that should special concern agomelatine crude drug in pharmacy procedure, avoids agomelatine to form impurity to reduce its toxic and side effects.
The disclosed agomelatine preparation of above-mentioned patent documentation does not obtain improvement substantially in the shortcoming aspect medicine stability, homogeneity and bioavailability.Thus, the present invention designs agomelatine Percutaneously administrable preparation to expect to solve problems.
Percutaneously administrable preparation, for a kind of active medicine absorbs the sustained-release preparation that enters systemic blood circulation and occur therapeutical effect by skin, Percutaneously administrable preparation is made up of active component and carrier, the quality of its percutaneous abilities, except the performance of active component, depend mainly on the carrier for supported active composition.
Agomelatine preparation capable of permeating skin is the carrier taking nano silicon as medicine agomelatine, forms three-dimensional netted stereochemical structure, then this three-dimensional netted stereochemical structure system employs Percutaneously administrable preparation technology of preparing is made to agomelatine preparation capable of permeating skin.Slow Stable Release medicine in this of agomelatine kind of preparation capable of permeating skin energy 96h, enters systemic blood circulation by skin, forms the whole body durative action preparation of transdermal administration.Transdermal patch can keep blood drug level to be stabilized within the scope of effect level, not only has better biopotency, and the blood concentration fluctuation that can avoid oral administration to cause, maintains the stable of blood drug level.Meanwhile, agomelatine transdermal administration can be avoided Oral Gastrointestinal Tract first pass effect, improves bioavailability, reduces individual variation, makes patient's medication safer, effective.The design's transdermal patch administration in every four days 1 time, each 1 pastes, and can maintain the continual and steady administration of 96h; This transdermal patch can also improve drug safety, can wash away immediately as there is untoward reaction, has reduced the oral danger that waits administration.
Summary of the invention
The object of the present invention is to provide Percutaneously administrable preparation and the preparation method of the three-dimensional netted spatial configuration of a kind of agomelatine, the defect existing to overcome prior art.
First the present invention relates to a kind of three-dimensional netted spatial configuration system of medicine carrying, comprises the component of following percentage by weight:
Described nano-stephanoporate silicon dioxide is selected from mesoporous silicon oxide, aerosil (aerogel) or xerogel (xerogel) etc., and its pore size is within the scope of 2-200nm;
Described nano-stephanoporate silicon dioxide, is divided into 3 classes according to the size of hole: aperture is less than the micropore that is called of 20nm, and aperture is mesoporous between becoming of 2-50nm, and aperture is greater than the macropore that is called of 50nm.
Described mesoporous silicon oxide comprises ordered mesoporous silica dioxide, as the MCM-48 of the MCM-41 of six side's phases, SBA-15 Emission in Cubic, the MCM-50 of lamellar phase, its typical characteristic comprises: homogeneous and aperture (2-50nm) that continuously can modulation on nanoscale, larger specific surface area (> 500m
2/ g) and pore volume (0.5-1.5cm
3/ g).Also comprise other mesopore silicon dioxide nano materials, as three-dimensional meso-hole TUD-1, hollow mesoporous silicon oxide HMS and silica dioxide nano particle 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 100-1000m
2/ g; Density 0.003g-30g/cm
3; Heat conductivity 0.01-0.018w/mk.Described meso-porous nano aerosil, the aerosil of hydrophobicity, hydrophilic or both sexes that can adopt Germany and Britain's dust Lik-Sang Asia-Pacific Electronics Co., Ltd. to produce; Density 12.5-18kg/m
3, specific surface area 500-650m
2/ g, porosity 95-98%, aperture 10-70nm, pore volume 3.5ml/g, heat conductivity 0.01-0.018w/mk.
Described dispersant is selected from propylene glycol, glycerol, n-octyl alcohol, n-dodecanol, Macrogol 200, PEG400 or Macrogol 600; Preferably propylene glycol, glycerol, Macrogol 200 or PEG400;
Described pressure sensitive adhesive is medicine carrying substrate, be selected from natural rubber, polyisobutylene, butene rubber, polyprene, silicone rubber, silicone copolymer, polyacrylate, methacrylate, acrylic acid/methacrylate copolymers, ethylene/vinyl acetate, ethene/acrylic ester copolymer, styrol copolymer or polyurethane etc., preferred acrylate pressure sensitive adhesive, available model can be but be not limited to acrylate pressure-sensitive adhesive 87-2287, acrylate pressure-sensitive adhesive 87-4098, acrylate pressure-sensitive adhesive 87-2852, acrylate pressure-sensitive adhesive MG-0607 etc.;
Described transdermal penetrating agent is selected from terpenes, amine, phosphide class, laurocapram, poloxamer, sodium laurylsulfate, fatty acid or fatty acid ester;
Described terpenes comprises eucalyptole, limonene or orange blossom tree alcohol;
Described amine comprises carbamide, dodecyl-N or dimethylaminoethyl; Described phosphide class comprises lecithin, fabaceous lecithin or phosphatidyl glycerol;
Described fatty acid comprises oleic acid or lauric acid; Described fatty acid ester comprises LA (LA), isopropyl myristate (IPM), propylene glycol dipelargonate or ethyl sebacate;
Most preferred, transdermal penetrating agent is selected from myristic acid isopropyl ester (IPM), azone (Azone), LA (LA) or glyceryl triacetate;
Preferably, the three-dimensional netted spatial configuration system of described medicine carrying, comprises 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 backing layer, be coated in the three-dimensional netted spatial configuration system of the described medicine carrying on described backing layer and the adherent layer that is compounded in the three-dimensional netted spatial configuration system of described medicine carrying forms;
The material of backing layer is polyester film, containing aluminumpolyethylene composite membrane, polyester/polyethylene composite membrane, polyester/polypropylene composite membrane, ethylene/vinyl acetate film, cellulose acetate membrane, polyurethane film, non-woven fabrics or glass cloth.
Described adherent layer is the polycarbonate membrane of surface through organosilicon polymer or the processing of fluorinated alkyl polymer, as the polyester film through fluorine processing of 3M company;
The preparation method of the Percutaneously administrable preparation of the described three-dimensional netted spatial configuration that carries agomelatine, comprises the steps:
(1) agomelatine is dissolved in solvent, obtains pastille solution A;
Described nano silicon is dispersed in dispersant, obtains nano silicon dispersion liquid B;
Then A is mixed with B, ultrasonic dispersion 0.5-1 hour, then soak 4-24 hour;
Described solvent is selected from a kind of in ethanol, ethyl acetate, acetone or more than one.
(2) in pressure sensitive adhesive, add transdermal penetrating agent and auxiliary agent, viscosity to the 350～2000cp while adding ethyl acetate to regulate 25 DEG C of glues, stirs 0.5-2 hour with the speed of 2000-10000rpm;
(3) product of step (2) is added to the product of step (1), stir 10～30min with the speed of 500-1000rpm, obtain C;
Described B is mixed with the product of step (2), stir 10～30min with the speed of 500～1000rpm, can obtain the transdermal drug delivery system of the described three-dimensional netted spatial configuration for medicine carrying.
(4) product of step (3) is coated on adherent layer, coating thickness is 0.10～0.5mm, and 60～90 DEG C are dried 0.5～1 hour, then covers upper backing layer, can obtain the Percutaneously administrable preparation of the three-dimensional netted spatial configuration of described medicine carrying.
When transdermal patch of the present invention uses, can be attached on the intact skin of human body, each 1, with area 5-50cm
2for suitable.
Aspect improving drug loading and suppressing drug crystallization, the present invention studies discovery, and nano silicon has tridimensional network, have huge specific surface area, show great activity, surperficial many meso-hole structures and superpower absorbability, can be adsorbed onto nanometer SiO equably by medicine agomelatine
2surface mesoporous in, therefore drug loading increases greatly; Nanometer SiO simultaneously
2when dry, can form network structure, therefore form the three-dimensional transdermal drug delivery system of tridimensional network.The transdermal drug delivery system of this form not only can improve agomelatine drug loading can suppress again medicine crystallize, and equably medicine is dispersed in transdermal drug delivery system in order, implements Stable Release.
Improving the aspect of performance that sticks of transdermal drug delivery system, due to the gluing system of transdermal administration, require product viscosity, mobility, curing rate to reach optimum condition, nano silicon Material Addition is formed very soon to a kind of masonry structure in pressure sensitive adhesive, i.e. nanometer SiO
2the network structure that granule forms, can suppress colloid and flow, and Assimilation rate is accelerated, and improves adhesive effect; Simultaneously due to SiO
2granule is tiny, has more increased sealing and the barrier properties of glue.
Aspect preparation stability, due to nanometer SiO
2(VK-SP30F) be inorganic constituents, be easy to preparation prescription in medicine and other component compatibility, nontoxic, tasteless; That especially valuable is nanometer SiO
2wavelength 400nm with interior uv absorption rate up to more than 70%, infrared reflectivity beyond wavelength 800nm is also reached more than 70%, its reflection ultraviolet ability is strong, good stability, after ultraviolet radiation, do not decomposed, invariant color, also not can with formula in other component chemically reactive, therefore it is added in transdermal drug delivery system and can form shielding action, the object that reaches anti-ultraviolet ageing and resistant to thermal aging, has increased medicine stability, has also improved the aging resistance effect of pressure sensitive adhesive system.
The transdermal system of the three-dimensional netted spatial configuration of the present invention taking nano-stephanoporate silicon dioxide as carrier, has solved that drug loading is not high, the easy crystallization of medicine affects Transdermal absorption usefulness, pressure sensitive adhesive system adhesion can be not ideal enough, the pressure sensitive adhesive system defects such as easily aging, medicine stability is poor.This transdermal drug delivery system not only can continue to exceed drug release and the transdermal of 24 hours.Be released in human body and bring into play drug effect by skin at this drug-supplying system Chinese medicine, can maintain stable blood drug level, reduce and take frequency, increase patient's compliance and compliance simultaneously; Transdermal route has been avoided the first pass effect of drug oral through gastrointestinal tract and liver simultaneously, has higher bioavailability, has clear superiority in medical applications.The lasting transdermal that can effectively realize the medicine long period, maintains constant blood drug level, and preparation percutaneous absorption rate is fast, and Transdermal absorption amount is high, has stable, efficient feature.
Brief description of the drawings
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:
Nano silicon is selected from the VK-SP15E type nano silicon that Xuancheng Jingrui New Material Co., Ltd. produces, mean diameter 15nm;
Dispersant is propylene glycol;
Pressure sensitive adhesive is acrylate pressure-sensitive adhesive 87-4098;
Transdermal penetrating agent is laurocapram (Azone)
(1) by the dehydrated alcohol of medicine dissolution medicine saturation solubility twice, by nano silicon dispersion of materials, in dispersant, above-mentioned two kinds of solution mix, ultrasonic 0.5 hour, soak again 4 hours, obtain the medicine-carried system of homodisperse three-dimensional netted spatial configuration;
(2) in pressure sensitive adhesive, add transdermal penetrating agent, the viscosity while adding ethyl acetate to regulate 25 DEG C of glues, to 1500cp, stirs 2 hours with the speed of 2000rpm simultaneously, obtains glue, for subsequent use;
(3), to the product that adds step (1) in above-mentioned glue, stir 20min with the speed of 1000rpm;
(4) product of step (3) is coated on backing layer, coating thickness 0.25mm, 105 DEG C are dried 15 minutes to volatilize organic solvent, then cover upper adherent layer, obtain product.
The material of described backing layer is non-woven fabrics;
Described adherent layer is that surface is through organosilicon polymer or containing the polycarbonate membrane of perfluorinated alkyl polymer treatment, 1022 polyester films through fluorine processing of 3M company.
Patch transdermal experiment:
Measure with improved Franz diffusion cell, with nude mice intact skin as see through skin, PEG400 aqueous solution using 30% is as receiver media, reception tank rotating speed is made as 200rpm, and 32 ± 0.5 DEG C of temperature, are affixed on skin keratin aspect by the patch preparing above, dermis of skin and receiver media close contact, spot sampling is measured, and every sub-sampling 0.3ml supplies 0.3ml receiver media immediately in Franz diffusion cell after sampling.By ten times of mobile phase for sample (PBS: acetonitrile=60:40) dilutions, by the agomelatine concentration in high performance liquid chromatography (HPLC) working sample.
Adopting agomelatine transdermal patch prepared by said method is 4.43ug/cm through the Mean Speed of nude mice skin
2.h. release 96h at the uniform velocity, illustrates that transdermal test in vitro process meets zero level dispose procedure at 96h, control discharge good.The accumulation transport through skin speed of agomelatine transdermal patch is shown in Fig. 1.
Adopt and prepare agomelatine transdermal patch with the method for embodiment 1.Its prescription is composed as follows:
Nano silicon is selected from the VK-SP20E type nano silicon that Xuancheng Jingrui New Material Co., Ltd. produces, mean diameter 20nm, and dispersant is PEG200; Pressure sensitive adhesive is silicone pressure-sensitive adhesive 4032; Transdermal penetrating agent is isopropyl myristate (IPM)
Adopt the method for embodiment 1 to prepare agomelatine transdermal patch, and use the method same with it to carry out transdermal test in vitro experiment, agomelatine transdermal patch is 4.95ug/cm through the Mean Speed of nude mice skin
2.h. release 96h at the uniform velocity, illustrates that transdermal test in vitro process meets zero level dispose procedure at 96h, control discharge good.The accumulation transport through skin speed of agomelatine transdermal patch is shown in Fig. 2.
Embodiment 3
Adopt and prepare agomelatine transdermal patch with the method for embodiment 1.Its prescription is composed as follows:
Nano silicon is selected from the VK-SP25E type nano silicon that Xuancheng Jingrui New Material Co., Ltd. produces, mean diameter 25nm, and dispersant is propylene glycol; Pressure sensitive adhesive is acrylate pressure-sensitive adhesive 87-2287; Transdermal penetrating agent is that glyceryl triacetate adopts the method for embodiment 1 to prepare agomelatine transdermal patch, and uses the method same with it to carry out transdermal test in vitro experiment, and agomelatine transdermal patch is 3.52ug/cm through the Mean Speed of nude mice skin
2.h. release 96h at the uniform velocity, illustrates that transdermal test in vitro process meets zero level dispose procedure at 96h, control discharge good.The accumulation transport through skin speed of agomelatine transdermal patch is shown in Fig. 3.
Embodiment 4
Adopt and prepare agomelatine transdermal patch with the method for embodiment 1.Its prescription is composed as follows:
Nano silicon is selected from the MCM-48 type nano silicon that Xuancheng Jingrui New Material Co., Ltd. produces, mean diameter 30nm; Dispersant is PEG400; Pressure sensitive adhesive is acrylate pressure-sensitive adhesive 87-2852; Transdermal penetrating agent is LA (LA); Adopt the method for embodiment 1 to prepare agomelatine transdermal patch, and use the method same with it to carry out transdermal test in vitro experiment, agomelatine transdermal patch is 4.94ug/cm through the Mean Speed of nude mice skin
2.h. release 96h at the uniform velocity, illustrates that transdermal test in vitro process meets zero level dispose procedure at 96h, control discharge good.The accumulation transport through skin speed of agomelatine transdermal patch is shown in Fig. 4.
Embodiment 5
Prepare agomelatine transdermal patch by the method for same embodiment 1.Its prescription is composed as follows:
Nano silicon is selected from the VK-SP15E type nano silicon that Xuancheng Jingrui New Material Co., Ltd. produces, mean diameter 15nm; Dispersant is glycerol; Pressure sensitive adhesive is acrylate pressure-sensitive adhesive 87-2287; Transdermal penetrating agent is laurocapram (Azone); Adopt the method for embodiment 1 to prepare agomelatine transdermal patch, and use the method same with it to carry out transdermal test in vitro experiment, agomelatine transdermal patch is 4.41ug/cm through the Mean Speed of nude mice skin
2.h. release 96h at the uniform velocity, illustrates that transdermal test in vitro process meets zero level dispose procedure at 96h, control discharge good.The accumulation transport through skin speed of agomelatine transdermal patch is shown in Fig. 5.
Claims (7)
1. the three-dimensional netted spatial configuration system of medicine carrying, is characterized in that, comprises the component of following percentage by weight:
2. the three-dimensional netted spatial configuration system of medicine carrying according to claim 1, is characterized in that, described nano-stephanoporate silicon dioxide is selected from mesoporous silicon oxide, aerosil or xerogel, and its pore size is within the scope of 2-200nm.
3. the three-dimensional netted spatial configuration system of medicine carrying according to claim 1, is characterized in that, described dispersant is selected from propylene glycol, glycerol, n-octyl alcohol, n-dodecanol, Macrogol 200, PEG400 or Macrogol 600;
Described pressure sensitive adhesive is selected from natural rubber, polyisobutylene, butene rubber, polyprene, silicone rubber, silicone copolymer, polyacrylate, methacrylate, acrylic acid/methacrylate copolymers, ethylene/vinyl acetate, ethene/acrylic ester copolymer, styrol copolymer or polyurethane;
Described transdermal penetrating agent is selected from terpenes, amine, phosphide class, laurocapram, poloxamer, sodium laurylsulfate, fatty acid or fatty acid ester;
Described terpenes comprises eucalyptole, limonene or orange blossom tree alcohol;
Described amine comprises carbamide, dodecyl-N or dimethylaminoethyl; Described phosphide class comprises lecithin, fabaceous lecithin or phosphatidyl glycerol;
Described fatty acid comprises oleic acid or lauric acid; Described fatty acid ester comprises LA (LA), isopropyl myristate (IPM), propylene glycol dipelargonate or ethyl sebacate.
4. the three-dimensional netted spatial configuration system of medicine carrying according to claim 2, is characterized in that, described dispersant is selected from propylene glycol, glycerol, n-octyl alcohol, n-dodecanol, Macrogol 200, PEG400 or Macrogol 600;
Described pressure sensitive adhesive is selected from natural rubber, polyisobutylene, butene rubber, polyprene, silicone rubber, silicone copolymer, polyacrylate, methacrylate, acrylic acid/methacrylate copolymers, ethylene/vinyl acetate, ethene/acrylic ester copolymer, styrol copolymer or polyurethane;
Described transdermal penetrating agent is selected from terpenes, amine, phosphide class, laurocapram, poloxamer, sodium laurylsulfate, fatty acid or fatty acid ester;
Described terpenes comprises eucalyptole, limonene or orange blossom tree alcohol;
Described amine comprises carbamide, dodecyl-N or dimethylaminoethyl; Described phosphide class comprises lecithin, fabaceous lecithin or phosphatidyl glycerol;
Described fatty acid comprises oleic acid or lauric acid; Described fatty acid ester comprises LA (LA), isopropyl myristate (IPM), propylene glycol dipelargonate or ethyl sebacate.
5. according to the three-dimensional netted spatial configuration system of the medicine carrying described in claim 1～4 any one, it is characterized in that, comprise the component of following percentage by weight:
6. the Percutaneously administrable preparation of the three-dimensional netted spatial configuration of agomelatine, is made up of backing layer, the three-dimensional netted spatial configuration system that is coated in the medicine carrying described in claim 1～5 any one on described backing layer and compound adherent layer thereon.
7. the preparation method of the Percutaneously administrable preparation of the three-dimensional netted spatial configuration of according to claim 6 year agomelatine, is characterized in that, comprises the steps:
(1) agomelatine is dissolved in solvent, obtains pastille solution A;
Described nano silicon is dispersed in dispersant, obtains nano silicon dispersion liquid B;
Then A is mixed with B, ultrasonic dispersion 0.5-1 hour, then soak 4-24 hour;
Described solvent is selected from a kind of in ethanol, ethyl acetate, acetone or more than one.
(2) in pressure sensitive adhesive, add transdermal penetrating agent and auxiliary agent, add ethyl acetate, viscosity to the 350～2000cp while regulating 25 DEG C of glues, stirs 0.5-2 hour with the speed of 2000-10000rpm;
(3) product of step (2) is added to the product of step (1), stir 10～30min with the speed of 500-1000rpm, obtain C; Described B is mixed with the product of step (2), stir 10～30min with the speed of 500～1000rpm;
(4) product of step (3) is coated on adherent layer, coating thickness is 0.10～0.50mm, and 60～90 DEG C are dried 0.5～1 hour, then covers upper backing layer, can obtain the Percutaneously administrable preparation of the three-dimensional netted spatial configuration of described medicine carrying.
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| CN201410067721.4A Active CN103830206B (en) | 2014-02-26 | 2014-02-26 | The Percutaneously administrable preparation of the three-dimensional netted spatial configuration of agomelatine and preparation method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016109483A1 (en) * | 2014-12-30 | 2016-07-07 | 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 |
| CN110151735A (en) * | 2019-06-06 | 2019-08-23 | 深圳市泛谷药业股份有限公司 | A kind of agomelatine transdermal patch and preparation method thereof |
| CN110787152A (en) * | 2019-12-10 | 2020-02-14 | 宁夏医科大学 | Transdermal gel patch for promoting low-absorption-capacity medicine of skin and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2014
- 2014-02-26 CN CN201410067721.4A patent/CN103830206B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016109483A1 (en) * | 2014-12-30 | 2016-07-07 | 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 |
| CN110151735A (en) * | 2019-06-06 | 2019-08-23 | 深圳市泛谷药业股份有限公司 | A kind of agomelatine transdermal patch and preparation method thereof |
| 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 |
| CN110787152A (en) * | 2019-12-10 | 2020-02-14 | 宁夏医科大学 | Transdermal gel patch for promoting low-absorption-capacity medicine of skin 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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| Publication number | Publication date |
|---|---|
| CN103830206B (en) | 2016-08-31 |
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