CN102293761B - Transdermal Patches Containing Antiemetics - Google Patents
Transdermal Patches Containing Antiemetics Download PDFInfo
- Publication number
- CN102293761B CN102293761B CN201010206421.1A CN201010206421A CN102293761B CN 102293761 B CN102293761 B CN 102293761B CN 201010206421 A CN201010206421 A CN 201010206421A CN 102293761 B CN102293761 B CN 102293761B
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- Prior art keywords
- cyclodextrin
- sensitive adhesive
- antiemetic
- layer
- pressure
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002111 antiemetic agent Substances 0.000 title claims abstract description 53
- 230000003474 anti-emetic effect Effects 0.000 title claims abstract description 50
- 229940125683 antiemetic agent Drugs 0.000 title 1
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- 239000003814 drug Substances 0.000 claims abstract description 83
- 229920000642 polymer Polymers 0.000 claims abstract description 83
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims abstract description 60
- 229940079593 drug Drugs 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 239000003381 stabilizer Substances 0.000 claims abstract description 23
- 238000010521 absorption reaction Methods 0.000 claims abstract description 17
- 239000002356 single layer Substances 0.000 claims abstract description 5
- 239000004615 ingredient Substances 0.000 claims abstract 2
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- 229950001588 ramosetron Drugs 0.000 claims description 84
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- 238000000576 coating method Methods 0.000 claims description 37
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Abstract
本发明公开了一种含止吐剂成份的透皮吸收贴剂，用于预防和治疗抗肿瘤化疗药物引起的恶心、呕吐以及术后的恶心和呕吐，能够在5-7天内有效地经皮肤供给止吐药物，使用方便，安全，有效。该透皮吸收贴剂压敏胶贮库层包含止吐药物、促进剂、粘性聚合物、药物稳定剂和pH调节剂；其中的粘性聚合物为亲脂性的粘性聚合物和亲水性的粘性聚合物组成的混合物；其中的压敏胶贮库层可单层涂布，也可分上、下两层涂布。The invention discloses a transdermal absorption patch containing antiemetic ingredients, which is used for preventing and treating nausea and vomiting caused by anti-tumor chemotherapeutic drugs and postoperative nausea and vomiting, and can be effectively transdermal within 5-7 days. Supply antiemetic drugs, easy to use, safe and effective. The pressure-sensitive adhesive reservoir layer of the transdermal absorption patch contains antiemetic drugs, accelerators, viscous polymers, drug stabilizers and pH regulators; wherein the viscous polymers are lipophilic viscous polymers and hydrophilic viscous polymers A mixture of polymers; the pressure-sensitive adhesive reservoir layer can be coated in a single layer or divided into upper and lower layers.
Description
Technical field
The present invention relates to medical technical field, relate in particular to the percutaneous absorption patch that a kind of energy is supplied with the antiemetic composition in more than enough day effectively, the nausea and vomiting caused for prevention and treatment antitumor drug chemotherapy and postoperative nausea and vomiting.
Background technology
Chemotherapy is one of Main Means of current treating malignant tumor, the gastrointestinal reactions such as yet it causes feels sick, vomiting are one of the most frightened untoward reaction of malignant tumor patient, cause cancer patient's weakness of accepting chemotherapy most and make the symptom that the people is dejected, as can not be effectively controlled, this symptom produces a series of related complication toward the contact meeting, as causing serious dehydration and even malnutrition, some patient has to so ends chemotherapy.
Control at present feel sick, symptoms of emesis the most effective method be to use antiemetic, within 1987, by the appearance of high selectivity 5-hydroxy tryptamine 3 (5-HT3) receptor antagonist of GlaxoSmithKline PLC company exploitation, open emesis and treated brand-new one page, the derivant sequential use of a collection of 5-HT3 receptor antagonist is in clinical, as ondansetron, granisetron, tropisetron, azasetron etc.Its emesis mechanism is: the cytotoxicity chemotherapeutics can cause especially ileal mucous membrane damage of gastrointestinal mucosal, the latter causes the enteric epithelium pheochromocyte to discharge 5-HT, and act on vagal 5-HT3 receptor or transmit mediator by excited chemoreceptor, the reaction thereby the effect vomiting center causes vomiting, the 5-HT3 receptor antagonist is mainly selected to block competitively 5-hydroxy tryptamine and the 5-HT3 receptors bind that gastrointestinal mucosal discharges by height, thereby has the effect that suppresses nausea and vomiting.Because its treatment chemotherapy causes, acute vomiting aspect effective percentage is high, better tolerance, is used as at present nausea and vomiting treatment choice drug.
The route of administration of 5-HT3 receptor antagonist is mainly to be confined to implement in hospital by intravenous administration at present, and makes the patient feel significant discomfort.Oral administration exists that onset is slow, administration is frequent, blood drug level peak valley phenomenon is obvious, suffer from the serious patient who feels sick, vomits and the patient of head and neck cancer and can't pass through oral administration, and the undulatory property of oral administration blood drug level can also cause not reaching good antiemetic effect because departing from the treatment window.In addition, chemotherapy causes nauseating, vomiting can be divided into acute nausea and vomiting, delayed nausea and vomiting.Acute nausea and vomiting betides and gives after chemotherapeutics in 24 hours, and degree is usually serious.Tardy nausea and vomiting occurs in and gives chemotherapeutics after 24 hours, although its order of severity is many, than acute nausea and vomiting, alleviates, and often the persistent period is grown (4-7 days), and Nutritional Status of Patients and quality of life are made a very bad impression.And antiemetic is oral or intravenously administrable all has inconvenience, often do not reach expection treatment and preventive effect.Therefore, still need to study antiemetic preparation more effective, safe, easy to use, good patient compliance.
The drug percutaneous administration has, and duration of efficacy is long, blood drug level steadily, Noninvasive, easy to use, both but long-time continuous is used, also can be as required the advantage such as interruption of the administration at any time, be applicable to very much the 5-HT3 receptor antagonist for feeling sick due to chemotherapy, the treatment of vomiting.
But the difficulty of 5-HT3 receptor antagonist percutaneous dosing is at present: medicine is difficult to see through effective dose and reaches therapeutic effect, reach medicine concentration and usually need use over 100cm
2above patch area, the patient is difficult to accept.Contain in addition basic group in this class pharmaceutical chemistry structure, be easy to mutually combine with the polyacrylic binder of most carboxyl groups, affect the stability of transdermal penetration and the medicine of medicine.Only the granisetron percutaneous absorption patch goes on the market in the U.S. at present, most of patent publication us of other relevant 5-HT3 receptor antagonist percutaneous dosing is all selected the transdermal delivery route of administration possible as the 5-HT3 receptor antagonist simply, does not confirm the treatment ability of described device and solves the problem relevant to these compound transdermal deliveries.
We provide a kind of percutaneous absorption patch containing the antiemetic composition, can in more than enough day, effectively supply with ramosetron or its esters, or bring into play synergistic dexamethasone with ramosetron.At present, have no the report of ramosetron or its esters successful implementation percutaneous dosing both at home and abroad.
Summary of the invention
The objective of the invention is for the deficiencies in the prior art, a kind of percutaneous absorption patch containing the antiemetic composition is provided, the present invention is suitable for ramosetron or its esters or brings into play the transdermal administration of the antiemetic compositions such as synergistic dexamethasone with ramosetron, and reduces to obtain the required patch usable floor area of antiemetic effective blood drug concentration.
The objective of the invention is to be achieved through the following technical solutions:
A kind of percutaneous absorption patch containing the antiemetic composition, its structure comprises backing layer, pressure sensitive adhesive bin-storing layer and adherent layer.Described pressure sensitive adhesive bin-storing layer single coating, described pressure sensitive adhesive bin-storing layer comprises antiemetic, promoter, sticky polymers, medicine stabilizing agent and pH adjusting agent; Described antiemetic, promoter, sticky polymers, medicine stabilizing agent, pH adjusting agent account for pressure sensitive adhesive bin-storing layer total weight percent and are respectively: 0.2-4%, 10-45%, 40-75%, 0.5-15% and 0.2-20%.Described antiemetic composition can be the medically receptible salt that ramosetron or ramosetron become with processed with acid, and content is 0.1-1.0mg/cm
2.Described sticky polymers by lipophilic sticky polymers and hydrophilic sticky polymers by 1-3.5: 1 weight proportion mixes; Described lipophilic sticky polymers can be lipophilic polyacrylate pressure-sensitive, polyisobutylene or silicone rubber; Described hydrophilic sticky polymers can be a kind of in hydrophilic polyacrylate pressure-sensitive, carbomer, cyclodextrin/its derivant or polyvinylpyrrolidone or the mixing of any two.
A kind of percutaneous absorption patch containing the antiemetic composition, its structure comprises backing layer, pressure sensitive adhesive bin-storing layer and adherent layer.Described pressure sensitive adhesive bin-storing layer divides upper and lower layer coating, and the pressure sensitive adhesive bin-storing layer of described upper and lower layer coating all comprises antiemetic, promoter, sticky polymers, medicine stabilizing agent and pH adjusting agent; Described antiemetic composition can be the medically receptible salt that ramosetron or ramosetron become with processed with acid.In the pressure sensitive adhesive bin-storing layer of described upper strata coating, described antiemetic, promoter, sticky polymers, medicine stabilizing agent and pH adjusting agent account for upper strata pressure sensitive adhesive bin-storing layer total weight percent and be respectively: 0.2-3.5%, 10-45%, 45-70%, 1.0-10% and 0.2-15%, described antiemetic content is 0.05-0.5mg/cm
2; In the pressure sensitive adhesive bin-storing layer of described lower floor coating, described antiemetic, promoter, sticky polymers, medicine stabilizing agent, pH adjusting agent account for lower floor's pressure sensitive adhesive bin-storing layer total weight percent and be respectively: 0.3-5.0%, 15-40%, 40-75%, 0.5-15% and 0.5-20%, described antiemetic content is 0.05-0.5mg/cm
2; The weight ratio of the pressure sensitive adhesive bin-storing layer of the pressure sensitive adhesive bin-storing layer of described upper strata coating and lower floor's coating is 0.8-2.5: 1; Described sticky polymers mixes by lipophilic sticky polymers and hydrophilic sticky polymers; Wherein, the weight ratio of upper strata lipotropy sticky polymers and hydrophilic sticky polymers is 3-20: 1, and the weight ratio of lower floor's lipotropy sticky polymers and hydrophilic sticky polymers is 0.2-2.5: 1.Described lipophilic sticky polymers can be lipophilic polyacrylate pressure-sensitive, polyisobutylene or silicone rubber; Described hydrophilic sticky polymers can be a kind of in hydrophilic polyacrylate pressure-sensitive, carbomer, cyclodextrin/its derivant or polyvinylpyrrolidone or the mixing of any two.
Further, the acid of described salify can be organic acid or mineral acid.
Further, described antiemetic composition can also comprise with ramosetron and has synergistic adrenocortical hormone dexamethasone.During single coating, the content of adrenocortical hormone dexamethasone is 0.2-1.5mg/cm
2.During upper and lower layer coating, the content of upper and lower layer adrenocortical hormone dexamethasone is 0.1-0.75mg/cm
2.
Further, described promoter is the mixing penetration enhancer containing laurocapram, mix in penetration enhancer except (1) laurocapram, also comprise: a kind of in (2) saturated or esters of unsaturated fatty acids promoter, it can be ethyl oleate, methyl laurate, glyceryl laurate ester, ethyl palmitate, isopropyl palmitate, olein, glyceryl linolenate, trilaurin, glycerol trioleate, tricaprylin, propylene one laurate, the propylene glycol dilaurate, the caprylic/capric triglyceride, methyl caprate, isopropyl myristate, the oleyl oleate, preferred oil acetoacetic ester and glyceryl laurate ester, (3) a kind of in other class promoter or two kinds, can be that alcohols is as 1,2-propylene glycol, glycerol, hexadecanol, lauryl alcohol, oleyl alcohol, amide-type is as palmitamide, dimethyl formamide, lauramide, diglycollic amide, carbamide and dimethyl acetylamide, nonionic surfactant is as tween 80 and Arlacel-20 etc., preferably alcohols and amide-type in other class promoter.Above-mentioned three class promoter component part by weight are 8-28: 10-35: 45-75.
Further, described lipophilic sticky polymers is polyacrylate pressure-sensitive.
Further, any one in carbomer, cyclodextrin/its derivant and polyvinylpyrrolidone of described hydrophilic sticky polymers mixes and forms with polyacrylate pressure-sensitive.
Further, described cyclodextrin/its derivant can be alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, HP-β-CD, hydroxyethyl-β-cyclodextrin, methyl-beta-schardinger dextrin-, sulfonic acid group-beta-cyclodextrin, by the glucose group-beta-cyclodextrin of other plant extract or synthetic, first-selected HP-β-CD, hydroxyethyl-β-cyclodextrin and sulfonic acid group-beta-cyclodextrin.
Further, described pH adjusting agent can be a kind of or two or more the pH buffer system formed in above-mentioned pH adjusting agent in trometamol, triethanolamine, triethylamine, diglycollic amide, sodium hydroxide, sodium carbonate, sodium bicarbonate, Borax-sodium carbonate buffer.
Further, described medicine stabilizing agent is one or more the mixing in dibutyl phenol, butylated hydroxytoluene, vitamin E, PG, anhydrous sodium sulfite and sodium pyrosulfite.
The invention has the beneficial effects as follows: the present invention utilize the percutaneous drug administration preparation technology provide a kind of can in many days, effectively supply with ramosetron or its salt or with the percutaneous absorption patch of the dexamethasone of the collaborative antiemetic effect of ramosetron performance, and make developed paster area little, steady quality, easy to use, safe, effective.Patch of the present invention is suitable for treating any type of nausea and vomiting relevant to the 5-HT3 receptor activation, comprises nausea and vomiting and postoperative nausea and vomiting that chemotherapy of tumors causes.
The accompanying drawing explanation
Fig. 1 is patch structural representation of the present invention;
Fig. 2 is embodiment 1 prescription paster and contrast paster (not carrying out the pH regulator prescription) through people's Skin permeation rate in vitro-time plot (◆ embodiment 1 paster, ■ contrasts paster);
Fig. 3 is embodiment 2 pasters and contrast paster through dog skin of back accumulation infiltration capacity-time plot (◆ embodiment 1 paster).
The specific embodiment
Ramosetron is high selectivity 5-HT3 receptor antagonist of new generation, but the vagal 5-HT3 receptor of antagonism maincenter and periphery, thus effectively control and treat nauseating, vomiting.Clinically for prevention and the nausea and vomiting that causes for the treatment of chemotherapy, and for reducing the incidence rate of nausea and vomiting in latter 24 hours of operation.Ramosetron, is limited in hospital and implements, and this administering mode is unfavorable for delayed nausea and vomiting mainly with the administration of intravenous injection mode in China.Make percutaneous drug administration preparation, it not only overcomes the inconvenience of drug administration by injection, and single administration can maintain at 5-7 days drug effect, advantageous particularly for the delayed vomiting, withdrawal at any time as required.
Obtain the optimum organization formula by the galenic pharmacy to 5-HT3 receptor antagonist ramosetron or its salt percutaneous administration patch research, can make medicine see through skin in 12-24 hour and reach effective therapeutic dose, and maintain and stablize release 5-7 days.Galenic pharmacy research shows, adopt the mixing cohesive polymer of lipotropy sticky polymers and the combination of hydrophilic sticky polymers, solved and used single lipotropy sticky polymers to be difficult to make percutaneous penetration of drugs to reach the difficult problem of effective infiltration capacity, after the lipotropy sticky polymers adds the hydrophilic sticky polymers of proper ratio, the Skin permeation of ramosetron or its salt increases exponentially.This may embed after lipophilic polymer and make to store the medicine skeleton and become loose with hydrophilic polymer, is beneficial to the release of medicine from skeleton.In addition, hydrophilic polymer improves the patch drug loading, and cyclodextrin and polyvinylpyrrolidone etc. also has stable protective effect to medicine.In addition, the present invention is except the mode that adopts single coating, also can adopt the mode of upper and lower layer coating, particularly the weight ratio when upper strata lipotropy sticky polymers and hydrophilic sticky polymers is 3-20: 1, the weight ratio of lower floor's lipotropy sticky polymers and hydrophilic sticky polymers is 0.2-2.5: 1 o'clock, the Skin permeation of medicine improved than single coating significance ground.
Percutaneous absorption patch of the present invention adopts the mixed accelerators that comprises laurocapram, especially laurocapram, fatty acid ester promoter and 1, the optimum organization of the alcohols such as 2-propylene glycol, when three class promoter component part by weight are 8-28: 10-35: during 45-75, ramosetron is had to particularly preferred collaborative short saturating effect.
In addition, comprise especially pH adjusting agent in combination formula, the environment of a pH 6.0-6.5 is provided, for the short skin osmosis especially fast of weakly basic drugs ramosetron tool, also can makes the sticky polymers of some tool negative groups also be not enough to affect the Skin permeation of medicine.
For some salt medicines, the more difficult enough drug of carrying of fat-soluble sticky polymers, salt medicine itself is the more difficult skin that sees through also.The present invention uses pH adjusting agent, has not only increased the drug loading of fat-soluble sticky polymers to medicine, and has promoted to absorb as the skin of organic base medicine ramosetron and salt thereof.Its reason may be by pH regulator, makes patch system maintain the environment of pH 6.0-6.5, stops containing base medicine and the slow interaction that may exist containing the acidic-group pressure sensitive adhesive, and may a continuous molecularization transfer process be arranged to organic alkali salt.The high drug load of our ramosetron produced according to the present invention and salt thereof is (up to 1.2mg/cm
2) patch, result is placed within 12 months, not observe in patch and crystallization occurred, and between resting period, descending also appears in the Skin permeation of medicament contg and medicine in time.
Antiemetic composition of the present invention, except ramosetron or its salt, can also comprise with ramosetron and have synergistic adrenocortical hormone dexamethasone.Clinical showing, give dexamethasone in I days before chemotherapy, and during Chemotherapy in Patients, digestive tract reaction obviously reduces, and also has no and increase obvious side effect simultaneously.The present invention adopts control-released percutaneous technology, make ramosetron absorbing transmission from skin together with dexamethasone, administration in 12-24 hour before chemotherapy, obtained beyond thought antiemetic effect, voluntarily user is explained them when using patch of the present invention, in the symptom of chemotherapeutic period nausea and vomiting, substantially disappears.
As shown in Figure 1, transdermal patch provided by the present invention is by backing layer, pressure sensitive adhesive bin-storing layer and adherent layer form, but pressure sensitive adhesive bin-storing layer single coating, also can divide upper and lower layer coating, the pressure sensitive adhesive bin-storing layer all comprises antiemetic, promoter, sticky polymers, medicine stabilizing agent and pH adjusting agent.
During single coating, the antiemetic of pressure sensitive adhesive bin-storing layer, promoter, sticky polymers, medicine stabilizing agent, pH adjusting agent account for pressure sensitive adhesive bin-storing layer total weight percent and are respectively: 0.2-4%, 10-45%, 40-75%, 0.5-15% and 0.2-20%.
During upper and lower layer coating, upper and lower layer pressure sensitive adhesive bin-storing layer all comprises antiemetic, promoter, sticky polymers, medicine stabilizing agent and pH adjusting agent; In the pressure sensitive adhesive bin-storing layer of upper strata coating, antiemetic, promoter, sticky polymers, medicine stabilizing agent and pH adjusting agent account for upper strata pressure sensitive adhesive bin-storing layer total weight percent and are respectively: 0.2-3.5%, 10-45%, 45-70%, 1.0-10% and 0.2-15%; In the pressure sensitive adhesive bin-storing layer of lower floor's coating, antiemetic, promoter, sticky polymers, medicine stabilizing agent, pH adjusting agent account for lower floor's pressure sensitive adhesive bin-storing layer total weight percent and are respectively: 0.3-5.0%, 15-40%, 40-75%, 0.5-15% and 0.5-20%; The weight ratio of the pressure sensitive adhesive bin-storing layer of the pressure sensitive adhesive bin-storing layer of upper strata coating and lower floor's coating is 0.8-2.5: 1.
The antiemetic composition can be the medically receptible salt that ramosetron or ramosetron become with processed with acid.The acid of salify can be organic acid or mineral acid, such as hydrochloric acid, sulphuric acid, maleic acid etc.During single coating, antiemetic content is 0.1-1.0mg/cm
2, during upper and lower layer coating, upper and lower layer antiemetic content is 0.05-0.5mg/cm
2.Antiemetic can also comprise with ramosetron and has synergistic adrenocortical hormone dexamethasone, and during single coating, the content of adrenocortical hormone dexamethasone is 0.2-1.5mg/cm
2.During upper and lower layer coating, the content of upper and lower layer adrenocortical hormone dexamethasone is 0.1-0.75mg/cm
2.
Promoter in the pressure sensitive adhesive bin-storing layer, its effect is the percutaneous permeability of raising and regulating drug.What the present invention adopted is the mixed accelerators containing laurocapram, mix in penetration enhancer except (1) laurocapram, also comprise: a kind of in (2) saturated or esters of unsaturated fatty acids promoter, in the present invention, laurocapram and fatty acid ester promoter are share for ramosetron collaborative transdermal enhancing effect are arranged, compare alone laurocapram, the Skin permeation that share the fatty acid ester medicine has improved 30-80% not to be waited, fatty acid ester promoter can be ethyl oleate, methyl laurate, ethyl palmitate, isopropyl palmitate, glyceryl laurate ester, olein, glyceryl linolenate, trilaurin, glycerol trioleate, tricaprylin, propylene one laurate, the propylene glycol dilaurate, the caprylic/capric triglyceride, methyl caprate, isopropyl myristate, the oleyl oleate, preferred oil acetoacetic ester and glyceryl laurate ester, (3) a kind of in other class promoter or two kinds, can be that alcohols is as 1,2-propylene glycol, glycerol, hexadecanol, lauryl alcohol, oleyl alcohol, amide-type is as palmitamide, dimethyl formamide, lauramide, diglycollic amide, carbamide and dimethyl acetylamide, nonionic surfactant is as tween 80 and Arlacel-20 etc., the preferred alcohols of other class promoter and amide-type.Above-mentioned three class promoter component part by weight are 8-28: 10-35: 45-75, no matter single coating or upper and lower layer coating, mixed accelerators content is even, all accounts for the 10-45% (W/W) of pressure sensitive adhesive bin-storing layer gross weight, and preferential amount is 20-40% (w/w).
Sticky polymers is selected the mixture of lipotropy and hydrophilic sticky polymers, requires sticky polymers have drug depot and adhere to two functions the pharmaceutical chemistry inertia.According to it, to drug penetration through skin with to the meeting of patch molding, during single coating, the weight ratio of lipophilic sticky polymers and hydrophilic sticky polymers is 1-3.5: 1.During upper and lower layer coating, the weight ratio of upper strata lipotropy sticky polymers and hydrophilic sticky polymers is 3-20: 1, and the weight ratio of lower floor's lipotropy sticky polymers and hydrophilic sticky polymers is 0.2-2.5: 1.During single coating, sticky polymers content accounts for the 40-75% (W/W) of pressure sensitive adhesive bin-storing layer gross weight, during upper and lower layer coating, upper strata sticky polymers content accounts for the 45-70% (W/W) of upper strata pressure sensitive adhesive bin-storing layer gross weight, and lower floor's sticky polymers content accounts for the 40-75% (W/W) of lower floor's pressure sensitive adhesive bin-storing layer gross weight.Medicine dissolution is dispersed in polymer with liquid microcoulomb form form in penetration enhancer, by changing polymer Chinese medicine content, liquid microcoulomb density, the content of penetration enhancer and ratio, the drug release rate of scalable paster and percutaneous rate.
Lipophilic sticky polymers, can select lipophilic polyacrylate pressure-sensitive, polyisobutylene or silicone rubber, optimization polypropylene acid esters pressure sensitive adhesive.Hydrophilic sticky polymers, can select a kind of in hydrophilic polyacrylate pressure-sensitive, carbomer, cyclodextrin/its derivant or polyvinylpyrrolidone or two kinds, optimization polypropylene acid esters pressure sensitive adhesive and other sticky polymers a kind of.Cyclodextrin and derivant thereof can be alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, HP-β-CD, hydroxyethyl-β-cyclodextrin, methyl-beta-schardinger dextrin-, sulfonic acid group-beta-cyclodextrin, by the glucose group-beta-cyclodextrin of other plant extract or synthetic, first-selected HP-β-CD, hydroxyethyl-β-cyclodextrin and sulfonic acid group-beta-cyclodextrin.
Medicine stabilizing agent in the pressure sensitive adhesive bin-storing layer shields to ramosetron or its salt, makes drug quality stable.It can be one or more the mixing of dibutyl phenol, butylated hydroxytoluene, vitamin E, PG, anhydrous sodium sulfite and sodium pyrosulfite.During single coating, the medicine stabiliser content accounts for the 0.5-15% (W/W) of pressure sensitive adhesive bin-storing layer gross weight, and preferred amounts is 1.0-10% (w/w).During upper and lower layer coating, upper strata medicine stabiliser content accounts for the 1.0-10% (W/W) of upper strata pressure sensitive adhesive bin-storing layer gross weight, and preferred amounts is 1.5-8% (w/w).Lower floor's medicine stabiliser content accounts for the 0.5-15% (w/w) of lower floor's pressure sensitive adhesive bin-storing layer gross weight, and preferred amounts is 1.0-12% (w/w).
PH adjusting agent is for regulating pressure sensitive adhesive storage storehouse pH to 6.0-6.5, can trometamol, triethanolamine, triethylamine, diglycollic amide, be a kind of or two or more the pH buffer system formed in above-mentioned pH adjusting agent in sodium hydroxide, sodium carbonate, sodium bicarbonate, Borax-sodium carbonate buffer.During single coating, pH adjusting agent content accounts for the 0.2-20% (W/W) of pressure sensitive adhesive bin-storing layer gross weight.During upper and lower layer coating, upper strata pH adjusting agent content accounts for the 0.2-15% (W/W) of upper strata pressure sensitive adhesive bin-storing layer gross weight, and lower floor's pH adjusting agent content accounts for the 0.5-20% (w/w) of lower floor's pressure sensitive adhesive bin-storing layer gross weight.
Backing layer requires pliable and tough; be attached on skin soft comfortable; play a part to cover and the protection drug depot; back lining materials is impermeable membrane; available high density polyethylene (HDPE); Low Density Polyethylene, polypropylene, polyvinyl chloride; ethylene-ester acid ethylene copolymer; polyester, ketopyrrolidine, polyvinyl alcohol; poly-amino methyl; the composite membrane of metal aluminum foil etc. or aforementioned high polymer and metal aluminum foil, optimal material be by Low Density Polyethylene through the vacuum aluminum-coated PAP polyethylene-aluminum-polyethylene composite membrane of making, Low Density Polyethylene and poly-amino methyl.
Adherent layer is polyester film or the paper of surface through the silicone oil release treatment.
The present invention uses patch to the Cisplatin-induced Vomiting antiemetic effect by isolated skin permeability test, pharmacodynamics, irritation test and volunteer, and the effectiveness and reliability of the antiemetic transdermal patch provided is provided.
Following is concrete evaluation methodology:
Isolated skin permeability test: carry out the isolated skin permeability test with Valia-Chien two-chamber osmotic pond and estimate the percutaneous penetration of drugs situation, in vitro application on human skin or dog skin are fixed on osmotic cell, epidermal area is outside, paster is affixed on epidermal area, adds the normal saline 4ml of people's 20% PEG400 in receiving chamber.The about 0.65cm of pond mouth effective area
2, the speed with starlike magnetic grain with 500rpm stirs, and osmotic cell, by 32 ℃ of constant temperature of water-bath chuck, respectively at the stipulated time sampling, adds the acceptable solution of equivalent after sampling.Measure the drug level in penetrating fluid by the HPLC method.Accumulation infiltration capacity Q with different time maps to time t, calculates the Skin permeation of medicine.
Dog pharmacodynamics test (cisplatin being caused to the protective effect of Beagle dog vomiting): 30 of Beagle dogs, the male and female dual-purpose, body weight 9-11.3kg, be divided into 5 groups by body weight, 6 every group.Test first 1 day lower back side skin and shave hair, fasting 12h.Negative control group gives blank paster (not containing medicine, only containing sticky polymers), positive controls injection ramosetron 30 μ g/kg, another 3 administration groups give respectively the ramosetron patch basic, normal, high three dosage, 24 hours intravenous injection cisplatin 10mg/kg after the patch administration, positive controls injection ramosetron gives the cisplatin of same dose after 0.5 hour.Observe each group vomiting number of times of dog and persistent period (from the 1st vomiting of animal to last 1 vomiting persistent period) in 4h, record vomiting incubation period (finishing to the time of the 1st vomiting of animal from the injection cisplatin).Viewing duration is freely drunk water, and after the injection nauseant, 12h recovers feed.
Rabbit irritation test: 6 of New Zealand white rabbit, female 3 heros 3, body weight 1.9-2.3kg.Test first 24 hours in mono-of spinal column both sides, white rabbit back each unhairing 6 * 8cm, paste the embodiment paster 4 * 4cm that writes out a prescription in unhairing district, right side, onesize blank paster pastes (except not containing ramosetron in unhairing district, left side, all the other are identical with embodiment), cover two layers of gauze, with the nonirritant immobilization with adhesive tape.Remove paster after 6h, with acetone, wash away residue.After removing residue, 1,24,48 and 72 hour viewing test position dermoreaction, record without situations such as erythema and edema, goes forward side by side to assassinate and swash reaction and stimulus intensity evaluation.In except 1,24,48,72 hour inspection rabbit after medicine, testing local skin.
Below describe according to drawings and embodiments the present invention in detail, it is more obvious that purpose of the present invention and effect will become.
Prescription (monolayer, 43cm
2patch feeds intake):
Ramosetron 0.0258g laurocapram (Az) 0.12g
1,2-PD (1,2-PG) 0.30g ethyl palmitate 0.06g
Polyvinylpyrrolidone (PVP-K30) 0.15g trometamol is appropriate
Hydroxyethyl-β-cyclodextrin (0.1g) PG 0.03g
Polyacrylate (87-4098, american chemical starch company) 1.0g
Preparation method: get ramosetron and the hydroxyethyl-β-cyclodextrin of recipe quantity, add appropriate anhydrous alcohol solution; Separately get the polyacrylate of recipe quantity, add Az, PG, PVP, ethyl palmitate, PG and ethyl acetate, stir, with appropriate triethanolamine, regulate pH to 6.0-6.5; Drug solution is slowly added wherein, the limit edged stirs, vacuum outgas again.Above-mentioned rubber cement is coated with into to certain thickness even thin layer on aluminum-plastic composite membrane, and 80 ℃ are dried 30 minutes, backing layer in covering.Cut into prescribed level and get final product with segment cutter, every 10cm
2paster includes ramosetron 6.0mg.
This embodiment patch carries out people's isolated skin permeability test, and medicine kept comparatively constant infiltration rate after between 12-24 hour, reaching maximum infiltration rate in 168 hours as a result, and the per day infiltration capacity of 7 days is 684 μ g/20cm
2.Notes of Key Data patch is suitable for using the time limit in 5-7 days, and patch can be used in 12-24 hour before chemotherapy.In addition, compare not containing the contrast patch of polyvinylpyrrolidone and hydroxyethyl-β-cyclodextrin, the Skin permeation of embodiment patch exceeds 45%.
Embodiment 2
Prescription (upper and lower layer, 43cm
2patch feeds intake):
Upper strata:
Ramosetron 0.0043g laurocapram (Az) 0.05g
1,2-PD (1,2-PG) 0.20g glyceryl laurate ester 0.04g
Polyvinylpyrrolidone (PVP-K30) 0.10g triethanolamine is appropriate
PG 0.01g polyacrylate (87-2852, american chemical starch company) 0.5g
Lower floor:
Ramosetron 0.0043g laurocapram (Az) 0.03g
1,2-PD (1,2-PG) 0.20g glyceryl laurate ester 0.02g
Polyvinylpyrrolidone (PVP-K30) 0.15g triethanolamine is appropriate
PG 0.005g rom Eudragit RL30D (German Romo Co.,Ltd) 0.3g
Polyacrylate (87-2852, american chemical starch company) 0.2g
Preparation method: upper strata: the ramosetron of getting recipe quantity, add Az, PG, PVP, glyceryl laurate ester, PG, polyacrylate and appropriate ethyl acetate, stir, regulate pH to 6.0-6.5 with appropriate triethanolamine, vacuum outgas, the upper strata rubber cement is coated with into to certain thickness even thin layer on adherent layer, and 80 ℃ are dried 30 minutes.Lower floor: the Eudragit RL30D that gets recipe quantity, after adding appropriate dehydrated alcohol, add ramosetron, Az, PG, PVP, glyceryl laurate ester, PG, polyacrylate and appropriate ethyl acetate, stir, regulate pH to 6.0-6.5 with appropriate triethanolamine, vacuum outgas is coated with into certain thickness even thin layer by lower floor's rubber cement on aluminum-plastic composite membrane, and 60 ℃ are dried 30 minutes.Upper strata and lower floor is laminating, cut into prescribed level and get final product with segment cutter.Every 10cm
2paster is containing ramosetron 2.0mg.
This embodiment patch contrasts patch 1 and (does not only add triethanolamine and regulate pH with ramosetron, the same embodiment of other composition and the preparation technology of writing out a prescription) carry out people's isolated skin permeability test, the permeation rate of drugs-time graph is shown in Fig. 2, result shows that medicine still kept comparatively constant infiltration rate after between 12-24 hour, reaching maximum infiltration rate in 120-168 hour, and the per day infiltration capacity of 7 days is 401 μ g/20cm
2.Notes of Key Data patch is suitable for using the time limit in 5-7 days, and patch can be used in 12-24 hour before chemotherapy.For the drug percutaneous drug-delivery preparation, the infiltration capacity of medicine is directly proportional to the paster area, can design the patch of different area specification, meets the clinical demand of different amounts.Compare the contrast patch without pH adjusting agent, the Skin permeation of embodiment patch exceeds 27%.In addition, the patch that we have prepared containing single lipotropy polyacrylate 87-2852 (does not only contain PVP and Eudragit RL30D, other composition and the same embodiment of preparation), and compare with embodiment, carried out people's isolated skin permeability test, result shows, uses single lipotropy polyacrylate, and the Skin permeation of medicine is markedly inferior to embodiment (P<0.05).
Embodiment 3
Prescription (upper and lower layer, 43cm
2patch feeds intake):
Upper strata:
Ramosetron HCl 0.01g 1,2-PD (PG) 0.15g
Dibutyl phenol 0.01g ethyl oleate 0.04g
Dimethyl formamide 0.05g laurocapram (Az) 0.04g
Polyvinylpyrrolidone (PVP-K30) 0.10g
Polyacrylate (87-2825, american chemical starch company) 0.5g trometamol is appropriate
Lower floor:
Ramosetron HCl 0.0072g 1,2-PD (PG) 0.2g
Dibutyl phenol 0.01g ethyl oleate 0.02g
Dimethyl formamide 0.03g laurocapram (Az) 0.02g
Rom Eudragit RL100 (German Romo Co.,Ltd) 0.2g
Polyacrylate (87-2825, american chemical starch company) 0.3g trometamol is appropriate
Preparation method: upper strata: the Ramosetron HCl of getting recipe quantity, add appropriate ethanol ultrasonic dissolution, add PG, PVP, Az, ethyl oleate, dimethyl formamide, dibutyl phenol, polyacrylate and appropriate ethyl acetate, stir, regulate pH to 6.0-6.5 with the appropriate amounts of ammonia butantriol, vacuum outgas is coated with into certain thickness even thin layer by the upper strata rubber cement on adherent layer, and 80 ℃ are dried 30 minutes.Lower floor: the Eudragit RL100 that gets recipe quantity, after adding appropriate anhydrous alcohol solution, add Ramosetron HCl, PG, Az, ethyl oleate, dimethyl formamide, dibutyl phenol and polyacrylate, stir, regulate pH to 6.0-6.5 with appropriate triethanolamine, vacuum outgas is coated with into certain thickness even thin layer by lower floor's rubber cement on aluminum-plastic composite membrane, and 80 ℃ are dried 30 minutes.Upper strata and lower floor is laminating, cut into prescribed level and get final product with segment cutter.Every 10cm
2the hydrochloric ramosetron 4.0mg of paster.
This embodiment patch with contrast the ramosetron patch and carry out dog isolated skin permeability test, result shows (Fig. 3), kept comparatively constant Skin permeation after medicine reached maximum infiltration rate in 12-24 hour in 168 hours, per day infiltration capacity reaches 511 μ g/20cm
2.Under pH adjusting agent, the drug loading of medicine increases, and has improved the drug osmotic amount of unit are simultaneously, reduces the medication area.
Dog pharmacodynamics test: embodiment 2 patches carry out bit dog pharmacodynamics test, (do not contain medicine with blank paster, only containing sticky polymers) negative contrast, with the positive contrast of ramosetron injection, 3 embodiment patch administration groups give respectively patch 1,2 and 3cm
2/ kg (is equivalent to give ramosetron 0.4,0.8,1.2mg/kg).Pharmacodynamic result shows (table 1), the drug effect of embodiment 2 ramosetron patches is consistent with its injection, three dosage group acute vomitings that all energy effectively preventing chemotherapeutics causes, obviously reduce the vomiting number of times, extend vomiting incubation period and shorten the vomiting persistent period, comparing high dose group in patch, the low dose group vomiting is slightly short incubation period, the vomiting persistent period is slightly long, but there was no significant difference.
Rabbit irritation test: embodiment 3 patches carry out the rabbit irritation test, and medicated patches and blank patch are showed no the symptoms such as erythema and edema as a result.
After table 1: embodiment 3 patch administration 24h, anti-cisplatin causes the effect of telling (n=6, X ± SD)
Embodiment 4
Prescription (upper and lower layer, 43cm
2patch feeds intake):
Upper strata:
Ramosetron 0.0115g lauramide 0.04g
Glyceryl laurate ester 0.08g laurocapram (Az) 0.06g
1,2-PD (PG) 0.10g butylated hydroxytoluene 0.03g
Polyvinylpyrrolidone (PVP-K30) 0.05g
Polyacrylate (87-4098, american chemical starch company) 0.7g triethanolamine is appropriate
Lower floor:
Ramosetron 0.01g HP-β-CD (HP-β-CD) 0.20g
Polyvinylpyrrolidone (PVP-K30) 0.10g lauramide 0.04g
Glyceryl laurate ester 0.04g laurocapram (Az) 0.04g
1,2-PD (PG) 0.20g butylated hydroxytoluene 0.02g
Polyacrylate (87-4098, american chemical starch company) 0.3g triethanolamine is appropriate
Preparation method: upper strata: ramosetron, PVP, PG, Az, glyceryl laurate ester, lauramide, butylated hydroxytoluene and the polyacrylate of getting recipe quantity, add appropriate ethyl acetate, stir, add triethanolamine and regulate in right amount pH to 6.0-6.5, vacuum outgas, the upper strata rubber cement is coated with into to certain thickness even thin layer on adherent layer, and 80 ℃ are dried 30 minutes.Lower floor: the ramosetron, PVP and the HP-β-CD that get recipe quantity, after adding appropriate ethanol ultrasonic dissolution, add PG, Az, glyceryl laurate ester, lauramide, butylated hydroxytoluene and polyacrylate, add appropriate ethyl acetate-ethanol (1: 1) mixed solvent, stir, add triethanolamine and regulate in right amount pH to 6.0-6.5, vacuum outgas, lower floor's rubber cement is coated with into to certain thickness even thin layer on aluminum-plastic composite membrane, and 80 ℃ are dried 30 minutes.Upper strata and lower floor is laminating, cut into prescribed level and get final product with segment cutter.Every 10cm
2paster is containing ramosetron 5.0mg.
In vitro application on human skin permeability test: embodiment 4 patches carry out people's isolated skin permeability test, result shows that medicine is approximately reaching maximum infiltration rate in 12 hours, and keeping constant infiltration rate in 168 hours (7 days), the per day infiltration capacity of 7 days is 745 μ g/20cm
2.Notes of Key Data patch can be used in 12-24 hour before chemotherapy, keeps comparatively constant Skin permeation in 5-7 days due to patch, and the Delayed onset of pointing out it to cause for chemotherapy vomiting has effect preferably.
Volunteer is used patch to estimate the Cisplatin-induced Vomiting antiemetic effect: embodiment 4 prescription patches are used voluntarily through the routine cancer patient of hospital 25, and compare with commercially available ramosetron injection (300 μ g/2ml), carry out at random the evaluation of intersection clinical treatment.Case 25 examples, the male 14, and the women 11, age 20-65 year, pulmonary carcinoma 10 examples wherein, breast carcinoma 8 examples, colon cancer 7 examples, they all accept High-dose Cisplatin Chemotherapy 50-100mg/m
2.The volunteer is divided into two groups of A and B at random, and the A group period 1 is being used cisplatin to use ramosetron patch 15cm in abdominal part in first 12 hours
2, second round 300 μ g ramosetron injection for the 30min vein before chemotherapy; The B group period 1 300 μ g ramosetron injection 30min vein for before chemotherapy, used first 12 hours of cisplatin in abdominal part use ramosetron patch 15cm second round
2.Ramosetron patch and injection are respectively approximately 60% and 69% the 1st day complete control rate for nausea and vomiting as a result, effective percentage is respectively 85% and 88%, two medication effects are similar, there was no significant difference, but 2nd, 3 days ramosetron patches significantly are better than ramosetron injection (P<0.05) to complete control rate and the effective percentage of nausea and vomiting, illustrate that patch has good control action for Delayed onset vomiting due to chemotherapy.Injection and patch untoward reaction are all slight, and main manifestations is dizziness, headache, constipation, diarrhoea, anxiety, and patient's reaction is better for the toleration of patch.
Embodiment 5
Prescription (upper and lower layer, 43cm
2patch feeds intake):
Upper strata:
Ramosetron 0.007g dexamethasone 0.0158g
HP-β-CD (HP-β-CD) 0.15g ethyl palmitate 0.06g
Laurocapram (Az) 0.06g 1,2-PD (PG) 0.10g
Butylated hydroxytoluene 0.03g
Polyacrylate (87-4098, american chemical starch company) 0.5g triethanolamine is appropriate
Lower floor:
Ramosetron 0.006g dexamethasone 0.01g
Ethyl palmitate 0.04g laurocapram (Az) 0.04g
1,2-PD (PG) 0.15g butylated hydroxytoluene 0.02g
Rom Eudragit RS 100 (German Romo Co.,Ltd) 0.3g
Polyacrylate (87-4098, american chemical starch company) 0.3g triethanolamine is appropriate
Preparation method: upper strata: the ramosetron, dexamethasone and the HP-β-CD that get recipe quantity, after adding appropriate ethanol ultrasonic dissolution, add Az, PG, ethyl palmitate, butylated hydroxytoluene and polyacrylate 87-4098, add appropriate dehydrated alcohol, stir, triethanolamine is regulated pH to 6.0-6.5, vacuum outgas in right amount, the upper strata rubber cement is coated with into to certain thickness even thin layer on adherent layer, and 80 ℃ are dried 30 minutes.Lower floor: after getting recipe quantity Eudragit RS 100 and adding appropriate dissolve with ethanol, add ramosetron, dexamethasone, Az, PG, ethyl palmitate, butylated hydroxytoluene and polyacrylate 87-4098, add appropriate dehydrated alcohol, stir, triethanolamine is regulated pH to 6.0-6.5 in right amount, vacuum outgas is coated with into certain thickness even thin layer by lower floor's rubber cement on aluminum-plastic composite membrane, and 60 ℃ are dried 30 minutes.Upper strata and lower floor is laminating, cut into prescribed level and get final product with segment cutter.Every 10cm
2paster includes ramosetron 3mg, containing dexamethasone 6mg.
In vitro application on human skin permeability test: embodiment 5 patches carry out people's isolated skin permeability test, result shows that medicine is approximately reaching maximum infiltration rate in 12 hours, and ramosetron and dexamethasone keep constant infiltration rate in 168 hours (7 days), the ramosetron per day infiltration capacity of 7 days is 750 μ g/20cm
2, the dexamethasone per day infiltration capacity of 7 days is 2050 μ g/20cm
2.Notes of Key Data patch can be used in 12-24 hour before chemotherapy, keeps constant Skin permeation in 7 days due to patch, and the Delayed onset of pointing out it to cause for chemotherapy vomiting has effect preferably.
Volunteer is used patch to estimate the Cisplatin-induced Vomiting antiemetic effect: embodiment 5 prescription patches are used (first 24 hours use ramosetron patch 15cm of chemotherapy voluntarily through the routine cancer patient of hospital 15
2), and compare with commercially available ramosetron injection (300 μ g/2ml), carry out at random the evaluation of intersection clinical treatment.The using method of chemotherapeutic and Bendectin and evaluation methodology are identical with embodiment 4.Ramosetron patch and injection are respectively approximately 75% and 68% the 1st day complete control rate for nausea and vomiting as a result, effective percentage is respectively 92% and 86%, the effective percentage of patch is higher than injection 5-6%, though without statistical significant difference, it is better that the patient reacts.Particularly the 2nd, 3,4 days ramosetron patches significantly are better than ramosetron injection (P<0.05) to complete control rate and the effective percentage of nausea and vomiting, illustrate that patch has good control action for Delayed onset vomiting due to chemotherapy.Injection and patch untoward reaction are all slight, and patient's reaction is better for the toleration of patch.
Embodiment 6
Prescription (monolayer, 43cm
2feed intake)
Ramosetron 0.0172g isopropyl palmitate 0.10g
1,2-PD (PG) 0.2g laurocapram (Az) 0.10g
Polyvinylpyrrolidone (PVP-K30) 0.10g triethanolamine is appropriate
Rom Eudragit L100 (German Romo Co.,Ltd) 0.4g
PG 0.02g polyacrylate (87-2852, american chemical starch company) 0.6g
Preparation method: the Eudragit L100 that gets recipe quantity, after adding appropriate anhydrous alcohol solution, add ramosetron, isopropyl palmitate, Az, PG, PVP, polyacrylate and appropriate ethyl acetate, stir, triethanolamine is regulated pH to 6.0 in right amount, and vacuum outgas is coated with into rubber cement certain thickness even thin layer on aluminum-plastic composite membrane, 80 ℃ are dried 30 minutes, with segment cutter, cut into prescribed level and get final product.Every 10cm
2paster is containing ramosetron 4mg.
In vitro application on human skin permeability test: embodiment 6 patches are through people's isolated skin permeability test, and result shows that medicine is approximately reaching maximum infiltration rate in 15 hours, and keep constant infiltration rate in 168 hours, and the per day infiltration capacity of 7 days is 647 μ g/20cm
2,
Embodiment 7-10
Embodiment 7-10 formula and average daily people's isolated skin infiltration capacity are in Table 2, and result shows that the average daily transdermal penetration amount of embodiment 7-10 medicine is at 300-800 μ g/20cm
2between, meet the clinical requirement of the dosage for this medicine.
Table 2: embodiment 7-10 percutaneous absorption patch formula
| Example | 7 (monolayers) | 8 (upper and lower layers) | 9 (upper and lower layers) | 10 (upper and lower layers) |
| LMSQ (mg) | 4.3 | Upper: 20, under: 10 | Upper: 8, under: 7 | Hydrochloric acid LMSQ is upper: 20, under: 23 |
| Dexamethasone | / | / | Upper: 20, under: 15.2 | / |
| Az(g) | 0.07 | Upper: 0.05, under: 0.03 | Upper: 0.06, under: 0.04 | Upper: 0.07, under: 0.05 |
| Fatty acid ester promoter | Ethyl oleate 0.07 | Methyl laurate (upper: 0.04, under: 0.02) | Glyceryl laurate ester (upper: 0.05, under: 0.03) | Ethyl oleate (upper: 0.02, under: 0.02) |
| Other promoter (g) | 1，2-PG 0.3 | 1,2-PG (upper: 0.1, under: 0.1), | Glycerol 0 (upper: 0.15, under: 0.1) and | 1,2-PG (upper: 0.15, under: 0.1), |
| Tween 80 (upper: 0.02, under: 0.01) | Dimethyl formamide (upper: 0.1, under: 0.1) | Palmitamide (upper: 0.06, under: 0.04) | ||
| PH adjusting agent | Triethanolamine | Triethylamine | Triethanolamine | Trometamol |
| Stabilizing agent (g) | Butylated hydroxytoluene (0.04) | Dibutyl phenol (upper: 0.03, under: 0.02) | Anhydrous sodium sulfite (upper: 0.04, under: 0.06) | PG 0 (upper: 0.03, under: 0.02) |
| Hydrophilic sticky polymers (g) | Eudragit RL100 (0.2) | Eudragit L100 (upper: 0.1, under: 0.2) | PVP (upper: 0.1, under: 0.05), and ethoxy-β-cyclodextrin (under: 0.12) | PVP (upper: 0.1, under: 0.05) carbomer (upper: 0.1, under: 0.3) |
| Parent's ester sticky polymers (g) | 87-2353(0.7) | 87-2825 (upper: 0.6, under: 0.3) | 87-2054 (upper: 0.9, under: 0.3) | 87-2825 (upper: 0.7, under: 0.3) |
| People's isolated skin day infiltration capacity (μ g/20cm 2) | 305 | 812 | 560 | 720 |
Annotate: 1. above is 43cm
2the patch inventory.
2. abbreviation: LMSQ: ramosetron; HP-β-CD: HP-β-CD; 1,2-PG:1, the 2-propylene glycol; PVP: polyvinylpyrrolidone; Az: laurocapram.
The present invention is illustrated by above description and embodiment, more than is described as nonrestrictively, does not limit claim scope of the present invention.
Claims (7)
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| CN104706725A (en) * | 2013-12-10 | 2015-06-17 | 天津市山佳医药科技有限公司 | Compound red sage root transdermal absorption patch and preparation method thereof |
| CN104288455B (en) * | 2014-11-10 | 2018-06-19 | 青岛市中心医院 | A kind of transdermal slow-release patch for treating tumour skin diabrosis |
| CN110013602B (en) * | 2019-04-17 | 2021-10-26 | 杨高云 | Glove for treating acral vitiligo and preparation method thereof |
| CN110585174B (en) * | 2019-08-30 | 2023-05-26 | 浙江省医学科学院 | Transdermal sustained-release patch for resisting schizophrenia |
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| US6440453B1 (en) * | 1999-06-25 | 2002-08-27 | Novosis Pharma Ag | Transdermal systems for release of 5-HT3 receptor antagonists and their use in anti-emetic treatment |
| CN1747724A (en) * | 2003-02-05 | 2006-03-15 | 思特肯有限公司 | Transpigranisetron |
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| US6440453B1 (en) * | 1999-06-25 | 2002-08-27 | Novosis Pharma Ag | Transdermal systems for release of 5-HT3 receptor antagonists and their use in anti-emetic treatment |
| CN1747724A (en) * | 2003-02-05 | 2006-03-15 | 思特肯有限公司 | Transpigranisetron |
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