CN101455651A - Skin paste capable of improving dementia, delusion and myasthenia due to cholinergic - Google Patents
Skin paste capable of improving dementia, delusion and myasthenia due to cholinergic Download PDFInfo
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- CN101455651A CN101455651A CNA2009100448799A CN200910044879A CN101455651A CN 101455651 A CN101455651 A CN 101455651A CN A2009100448799 A CNA2009100448799 A CN A2009100448799A CN 200910044879 A CN200910044879 A CN 200910044879A CN 101455651 A CN101455651 A CN 101455651A
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Abstract
A skin patch which improves symptoms of ashronesia, delusion and myasthenia caused by cholinergic deficit is composed of an antiseizing layer, a medicine storing layer and a back lining layer, wherein the medicine storing layer comprises medicine, dissolvent and pressure-sensitive adhesive. The invention is characterized in that the medicine is galantamin or hydrobromate thereof. The galantamin or hydrobromate thereof is 0.007mg-10mg/cm<2>, and the medication area is 2.5-70cm<2>. The pressure-sensitive adhesive is selected from polyisobutene pressure-sensitive adhesive, emulsion and dissolvent type acrylate. When the pressure-sensitive adhesive is polyisobutene, the medicine storing layer is composed of medicine, dissolvent, pressure-sensitive adhesive, thickening agent, anti-oxidant and transdermal promoter. When the pressure-sensitive adhesive is emulsion type acrylate, the medicine storing layer is composed of medicine, dissolvent, pressure-sensitive adhesive, thickening agent and concentrated ammonia liquor. When the pressure-sensitive adhesive is dissolvent type acrylate, the medicine storing layer is composed of medicine, dissolvent, and pressure-sensitive adhesive. The skin patch of the invention can effectively treat the symptoms of ashronesia, delusion and myasthenia caused by cholinergic deficit, increase the life quality of patient and alleviate the burden of kin and society.
Description
Technical field
The present invention relates to medical technical field, is a kind of galantamine skin patch for the treatment of symptoms such as dementia that cholinergic disappearance causes, vain hope, myasthenia.
Background technology
Galantamine (Galanthamine) is a kind of phenanthridine alkaloid that extraction separation obtains from pale reddish brown amrallid, be reversible a, selectivity and competitive cholinesterase inhibitor, simultaneously can the allosteric activation nAChR, reduce the acetylcholine degraded by these two kinds of approach, activate cholinoceptor, improve symptoms such as dementia that the choline disappearance caused, vain hope, myasthenia.
(Alzheimer disease AD), is the common a kind of chronic progressive external neurodegenerative disease of old people to Alzheimer, is cardinal symptom with the dementia, and number of the infected is many, and it is wide to involve scope, has an appointment among the old people who exceedes 65 years old 10% to suffer from AD.Because of AD patient has memory more, orientation force and social activity ability obstacle do not have ability to abide by the progress of doctor's advice medication on time with mitigate the disease at all, bring the comparison white elephant for family members and society.So AD becomes in the geriatrics and needs to be resolved hurrily, and also is one of most thorny issue.AD removes and follows neurofibrillary tangle, also follows the neurotransmitter disappearance, especially basal forebrain cholinergic neuron disappearance.Galantamine can effectively improve levels of acetylcholine, mitigate the disease as maincenter type acetylcholinesteraseinhibitors inhibitors and the agent of cholinoceptor allosteric activation.At present, galanthamine hydrobromide is to use the medicine of more treatment Alzheimer, has obtained the FDA approval and has been used for the AD treatment.
Paranoea is the properest term of describing acute confusional state, about 10%～30% inpatient is subjected to the puzzlement of paranoea, paranoea is reversible, but bring some negative consequences, comprise and prolong the hospital stays, weaken patient's body constitution and reduce body function, also have potential cognitive function damage, this symptom needs the nursing of specialty also might cause death.Mechanism discovers that cholinergic disappearance is to cause the major reason of paranoea, so acetylcholinesteraseinhibitors inhibitors such as galantamine can effectively be treated paranoea.
Traditional galantamine form of administration that has gone on the market has oral formulations and ejection preparation, and drug administration by injection needs special technique, and for the dementia of symptom that needs long-term prescription such as AD initiation, it is very irrational adopting drug administration by injection.Peroral dosage form convenient drug administration, but the blood concentration fluctuation that traditional peroral dosage form causes, cause the gastrointestinal side effect as feel sick, vomiting etc.Exploitation can provide the controlled release form of constant relatively drug level, prolongs the administration cycle, for improving drug safety and alleviating family numbers of patients and burden on society all has very important significance.
Transdermal delivery system (transdermal delivery system, TDS) be comparatively safe noninvasive administering mode, can reach the effect of slow release, medicine is steadily discharged by preparation controlled release and skin controlled release, the persistent stable blood concentration of keeping makes medication comparatively safe.From medicine-feeding technology, need not the special personnel special technique, the convenient application.In recent years, TDS becomes important component part in the field of medicaments with its special advantages.Such preparation can be the treatment and the prevention of some chronicity diseases and chronic disease and has created the effective again administering mode of a kind of convenience.The galantamine skin patch may become a kind of controlled release preparation that satisfies patient demand.
Summary of the invention
The purpose of this invention is to provide a kind of skin patch that can effectively treat symptoms such as dementia that cholinergic disappearance causes, vain hope, myasthenia, it is characterized in that containing galantamine or its hydrobromate.Effectively treat symptoms such as dementia, can improve patient's quality of life, alleviate family numbers of patients and social burden.
The present invention is a kind of, and to improve the technical scheme of skin patch of the symptoms such as dementia that the cholinergic disappearance causes as follows:
The present invention is a kind of skin patch that improves the symptoms such as dementia of cholinergic disappearance initiation, it is characterized in that medicine is galantamine or its hydrobromate, and galantamine or its hydrobromate are 0.007mg～10mg/cm
2, the administration area is 2.5～70cm
2
A kind of skin patch that improves the symptoms such as dementia of cholinergic disappearance initiation of the present invention, described skin patch is divided into adherent layer, drug storing layer and backing layer three parts.Drug storing layer comprises medicine and substrate, and medicine is dispersed in the substrate.Adherent layer and backing layer are with the ordinary skin patch, and the intermediate layer is Drug Storage and pressure sensitive adhesive amalgamation layer, is called drug storing layer, mainly are made up of medicine, solvent, pressure sensitive adhesive, and pressure sensitive adhesive is optional from polyisobutylene pressure sensitive adhesive and acrylate pressure-sensitive adhesive.Acrylate pressure-sensitive adhesive comprises solvent-borne type and emulsion-type.
When being substrate with the solvent-type acrylic ester pressure-sensitive, medicine is dissolved in appropriate solvent, solvent can be selected from dehydrated alcohol, alkaline dehydrated alcohol, propylene glycol, dimethyl pyrrolidone etc., consumption accounts for drug storing layer and forms 1～30% of percentage by weight, under the consoluet prerequisite of medicine, solvent load is few more good more; Residuals weight is replenished with pressure sensitive adhesive solution.
When being substrate with the emulsion acrylate pressure sensitive adhesive, medicine is dissolved in appropriate solvent, solvent can be selected from pure water, dehydrated alcohol, alkaline dehydrated alcohol, propylene glycol, dimethyl pyrrolidone etc., consumption accounts for drug storing layer and forms 1～20% of percentage by weight, under the consoluet prerequisite of medicine, solvent load is few more good more.Need add an amount of thickening agent when selecting emulsion-type pressure-sensitive for use, and it is closely neutral to regulate pH value with an amount of strong aqua ammonia.Thickening agent is selected from the Tangshan Hua Chang medical sanitary dressing YBJ-A11 of Industrial Co., Ltd. type and ROHM AND HAAS (China) MD-6000 of Investment Co., Ltd type, and consumption accounts for drug storing layer and forms 1～30% of weight, is meeting under the prerequisite that is coated with viscosity, and consumption is few more good more; Residuals weight is replenished with pressure sensitive adhesive solution.
When being substrate, add thickening agent, antioxidant and transdermal enhancer with the Polyisobutylene PSA.Polyisobutylene PSA mixes with high molecular and low-molecular-weight and uses, and with organic solvent swellings such as medical gasoline, adds plasticizer such as liquid paraffin and is beneficial to be coated with; Thickening agent is selected from carbon penta resin, Colophonium, esterase, hydrogenated fat etc., can select the same usefulness of one or more chemical compounds for use, and consumption accounts for drug storing layer and forms 1～60% of percentage by weight; Transdermal enhancer is selected from fatty acid, aliphatic alcohol, fatty acid ester, alkyl sulfoxide, azone, ketopyrrolidine, surfactant, urea compound, limonene etc., and other fat-soluble transdermal enhancers, can select one or more chemical compounds for use, consumption accounts for drug storing layer and forms 0.01～35% of percentage by weight; Oxidation for the aging and medicine that prevents drug storing layer can add antioxidant, and antioxidant is selected from one or more chemical compounds in 2,6-ditertbutylparacresol, antrancine 12 and the vitamin E, consumption account for that drug storing layer forms 0.01～2%.
The skin patch that the present invention is a kind of to improve the symptoms such as dementia that the cholinergic disappearance causes can provide constant relatively blood drug level relatively for a long time, is long-acting controlled release preparation in symptoms such as the dementia that causes of treatment cholinergic disappearance, vain hope, myasthenia good.For the quality of life of improving the patient, alleviate family numbers of patients and social burden, significant.
Description of drawings
Fig. 1 is " a blood pharmaceutical concentration-time curve (n=5) behind the transdermal administration of microdialysis sampling determination galantamine skin patch back "
The specific embodiment
Now in conjunction with the embodiments, the present invention is described in detail.
Prescription and proportioning:
Galanthamine hydrobromide 0.3g
Acrylic acid ester emulsion type pressure sensitive adhesive 36.9g
Thickening agent 1.2g
Strong aqua ammonia 1.5ml
Pure water 6.25ml
Preparation method is:
Galanthamine hydrobromide is dissolved in pure water, joins in the acrylic acid ester emulsion type pressure sensitive adhesive, the limit edged stirs, and adds thickening agent, strong aqua ammonia, stirs, and is laid on 1000cm
2On the separate paper, 80 ℃ were dried by the fire 30 minutes, covered backing layer, and room temperature is placed and spent the night, and cuts into 5 * 7cm
2, pack.
Prescription and proportioning:
Galanthamine hydrobromide 0.3g
Alkalescence dehydrated alcohol 2.0mL
Solvent-type acrylic ester pressure-sensitive (38%) 46.0g
Preparation method is:
Galanthamine hydrobromide is dissolved in alkaline dehydrated alcohol (regulating dehydrated alcohol to pH10 with the NaOH solution of 5mol/L), join solvent-type acrylic ester pressure-sensitive (DURO-TAK 87-2677, national of the United States's starch company) in, the limit edged stirs, and is laid on 1000cm
2On the separate paper, 80 ℃ were dried by the fire 30 minutes, covered backing layer, and room temperature is placed and spent the night, and cuts into 5 * 7cm
2, pack.
Prescription and proportioning:
Galantamine 3.1g
High molecular weight polyisobutylene 5.3g
Low-molecular-weight polyisobutylene 2.8g
Liquid paraffin 5.4g
Carbon penta resin 7.0g
2,6-ditertbutylparacresol 14mg
Azone 1.8g
Medical gasoline 100mL
Operating procedure:
By said ratio non-polar polymer high molecular weight polyisobutylene and low-molecular-weight polyisobutylene, plasticizer liquid paraffin and thickening agent carbon penta resin are added in the medical gasoline after the complete swelling, add medicine galantamine and transdermal enhancer azone and antioxidant 2,6-ditertbutylparacresol, stir, ultrasound wave is got rid of bubble, on coating machine, it is coated adherent layer routinely then, spreading area 1000cm
2, the limit is coated with the selvedge oven dry, 60 ℃ of oven dry, and the reuse backing layer covers and is transferred to backing layer.
Experimental example 1. adopts the microdialysis Sampling techniques to measure the blood substance concentration that the galantamine skin patch produces
Microdialysis (microdialysis, MD) be developed recently get up a kind of novel in the sampler body technology, loaded down with trivial details sample pretreatment before this technology has been avoided detecting, having realized that the microdialysis sample is directly used in high performance liquid chromatogram tandem mass spectrum (LC-MS/MS) and detects, is the effective ways in the body pharmacokinetic studies.The present invention uses this Sampling techniques and measures galantamine concentration in blood, the check skin patch at body transdermal penetration effect and controlled-release effect.
Adopt the microdialysis Sampling techniques to measure the blood substance concentration that the galantamine skin patch produces, method is as follows: male SD rat, body weight 200-220g, back depilation, natural feeding 24h, the anesthesia of 25% urethane is sampled in right internal jugular vein is inserted blood vessel with microdialysis probe to right atrium, after ligation is fixing, the ventricumbent position is mouse fixedly, (every 20min varies once phosphate buffer for PBS, pH7.4) 2 μ l/min perfusion probes.Behind the balance 1h, connect three parts of blank dialyzates, back depilation place gives the galantamine transdermal delivery system 5 * 7cm then
2, sampling 10h, sample adds the metronidazole solution of 1/4 volume as interior mark, and interior mark final concentration 10ng/ml, the high performance liquid chromatogram triple level Four bar mass spectrums (LC-MS/MS) of connecting are measured galantamine concentration.
1.5h blood drug level reaches peak value after recording the administration of a kind of galantamine skin patch of the present invention, and keeps more than the constant relatively blood drug level 10h, sees Fig. 1 blood substance concentration-time curve figure.Show that galantamine skin patch of the present invention can provide constant relatively blood drug level relatively for a long time, being a kind of skin patch that improves the symptoms such as dementia that cholinergic disappearance causes, is long-acting controlled release preparation in symptoms such as the dementia that causes of treatment cholinergic disappearance, vain hope, myasthenia good.
Claims (7)
1. one kind is improved the skin patch that the cholinergic disappearance causes dementia, vain hope, myasthenia symptom, form by adherent layer, drug storing layer and backing layer three parts, wherein drug storing layer comprises medicine, solvent, pressure sensitive adhesive, it is characterized in that medicine is galantamine or its hydrobromate, galantamine or its hydrobromate are 0.007mg～10mg/cm
2, the administration area is 2.5～70cm
2
Described pressure sensitive adhesive is selected from Polyisobutylene PSA and acrylate pressure-sensitive adhesive, and wherein acrylate pressure-sensitive adhesive is selected from solvent-borne type and emulsion-type;
When described pressure sensitive adhesive was polyisobutylene, drug storing layer was made up of medicine, solvent, pressure sensitive adhesive, thickening agent, antioxidant and transdermal enhancer;
When described pressure sensitive adhesive was emulsion acrylate, drug storing layer was made up of medicine, solvent, pressure sensitive adhesive, thickening agent, strong aqua ammonia;
When described pressure sensitive adhesive was the solvent-type acrylic ester, drug storing layer was made up of medicine, solvent, pressure sensitive adhesive.
2. a kind of skin patch that the cholinergic disappearance causes dementia, vain hope, myasthenia symptom that improves according to claim 1, solvent is selected from dehydrated alcohol, alkaline dehydrated alcohol, propylene glycol, dimethyl pyrrolidone when it is characterized in that described pressure sensitive adhesive is the solvent-type acrylic ester, the percentage by weight that consumption accounts for the drug storing layer composition is 1～30%, and residuals weight is replenished with pressure sensitive adhesive solution.
3. a kind of skin patch that the cholinergic disappearance causes dementia, vain hope, myasthenia symptom that improves according to claim 2, solvent is selected from alkaline dehydrated alcohol when it is characterized in that described pressure sensitive adhesive is the solvent-type acrylic ester, the percentage by weight that consumption accounts for the drug storing layer composition is 1～30%, and residuals weight is replenished with pressure sensitive adhesive solution.
4. a kind of cholinergic disappearance of improving according to claim 1 causes dull-witted, vain hope, the skin patch of myasthenia symptom, solvent is selected from pure water when it is characterized in that described pressure sensitive adhesive is emulsion acrylate, dehydrated alcohol, the alkalescence dehydrated alcohol, propylene glycol, dimethyl pyrrolidone, the percentage by weight that consumption accounts for the drug storing layer composition is 1～20%, thickening agent is selected from the Tangshan Hua Chang medical sanitary dressing YBJ-A11 of Industrial Co., Ltd. type and ROHM AND HAAS (China) MD-6000 of Investment Co., Ltd type, the percentage by weight that consumption accounts for the drug storing layer composition is 1～30%, and residuals weight is replenished with pressure sensitive adhesive solution.
5. a kind of skin patch that cholinergic disappearance causes dementia, vain hope, myasthenia symptom that improves according to claim 4, solvent is selected from pure water when it is characterized in that described pressure sensitive adhesive is emulsion acrylate.
6. a kind of skin patch that the cholinergic disappearance causes dementia, vain hope, myasthenia symptom that improves according to claim 1, when it is characterized in that described pressure sensitive adhesive is Polyisobutylene PSA, Polyisobutylene PSA is that high molecular and low-molecular-weight are mixed use; Solvent is medical gasoline; Plasticizer is a liquid paraffin; Thickening agent is selected from one or more the same usefulness in carbon penta resin, Colophonium, esterase, the hydrogenated fat, and the percentage by weight that consumption accounts for the drug storing layer composition is 1～60%; Transdermal enhancer is selected from one or more the same usefulness in fatty acid, aliphatic alcohol, fatty acid ester, alkyl sulfoxide, azone, ketopyrrolidine, surfactant, the urea compound, limonene, and the percentage by weight that consumption accounts for the drug storing layer composition is 0.01～35%; Antioxidant is selected from one or more the same usefulness in 2,6-ditertbutylparacresol, antrancine 12 and the vitamin E, and the percentage by weight that consumption accounts for the drug storing layer composition is 0.01～2%.
7. a kind of skin patch that the cholinergic disappearance causes dementia, vain hope, myasthenia symptom that improves according to claim 6, when it is characterized in that described pressure sensitive adhesive is Polyisobutylene PSA, Polyisobutylene PSA is that high molecular and low-molecular-weight are mixed use; Solvent is medical gasoline; Plasticizer is a liquid paraffin; Thickening agent is selected from carbon penta resin, and the percentage by weight that consumption accounts for the drug storing layer composition is 1～60%; Transdermal enhancer is selected from azone, and the percentage by weight that consumption accounts for the drug storing layer composition is 0.01～35%; Antioxidant is selected from 2,6-ditertbutylparacresol, and the percentage by weight that consumption accounts for the drug storing layer composition is 0.01～2%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100448799A CN101455651A (en) | 2009-01-05 | 2009-01-05 | Skin paste capable of improving dementia, delusion and myasthenia due to cholinergic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2009100448799A CN101455651A (en) | 2009-01-05 | 2009-01-05 | Skin paste capable of improving dementia, delusion and myasthenia due to cholinergic |
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| Publication Number | Publication Date |
|---|---|
| CN101455651A true CN101455651A (en) | 2009-06-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009100448799A Pending CN101455651A (en) | 2009-01-05 | 2009-01-05 | Skin paste capable of improving dementia, delusion and myasthenia due to cholinergic |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101716163A (en) * | 2009-12-24 | 2010-06-02 | 沈阳药科大学 | Letrozole targeted slow-release transdermal patch and preparation method thereof |
| CN105606744A (en) * | 2015-11-19 | 2016-05-25 | 南京中医药大学 | Method for rapid determination of pharmacokinetics of active ingredients after oral administration of traditional Chinese medicine rhizoma anemarrhenae |
| CN105687087A (en) * | 2016-03-14 | 2016-06-22 | 苏州市贝克生物科技有限公司 | Preparation method of skin-tightening and freckle-removing biological dressing |
-
2009
- 2009-01-05 CN CNA2009100448799A patent/CN101455651A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101716163A (en) * | 2009-12-24 | 2010-06-02 | 沈阳药科大学 | Letrozole targeted slow-release transdermal patch and preparation method thereof |
| CN101716163B (en) * | 2009-12-24 | 2013-07-31 | 沈阳药科大学 | Letrozole targeted slow-release transdermal patch and preparation method thereof |
| CN105606744A (en) * | 2015-11-19 | 2016-05-25 | 南京中医药大学 | Method for rapid determination of pharmacokinetics of active ingredients after oral administration of traditional Chinese medicine rhizoma anemarrhenae |
| CN105687087A (en) * | 2016-03-14 | 2016-06-22 | 苏州市贝克生物科技有限公司 | Preparation method of skin-tightening and freckle-removing biological dressing |
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Open date: 20090617 |