CN1094972A - Release-controlled skin-penetrating therapeutic system and preparation thereof and application - Google Patents
Release-controlled skin-penetrating therapeutic system and preparation thereof and application Download PDFInfo
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- CN1094972A CN1094972A CN 93106174 CN93106174A CN1094972A CN 1094972 A CN1094972 A CN 1094972A CN 93106174 CN93106174 CN 93106174 CN 93106174 A CN93106174 A CN 93106174A CN 1094972 A CN1094972 A CN 1094972A
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Abstract
A kind of release-controlled skin-penetrating therapeutic system and preparation thereof and application, this system is made up of counterdie, drug storage warehouse, speed release-controlled film, adhesion layer, protecting film successively.Skin-penetrating therapeutic is added in the drug storage warehouse with medicine.After the layering processing, through decompressor pressurization excision forming.But be applicable to skin-penetrating therapeutic usefulness medicine such as scopolamine, nicotine, nitroglycerin, 17-, clonidine, fluorobenzene ether-ether, has accurate control dosage, improve the medication health, prolong administration time, release is steady, walk around the first pass effect of liver, the advantage of dwindle between individuality, differences is taken medicine in individual interior each time.
Description
The present invention relates to a kind of release-controlled skin-penetrating therapeutic system and preparation thereof and application.Particularly a kind of percutaneous controlled-release therapy system and preparation and application that utilizes the speed release-controlled film.
Skin is the organ of body surface area's maximum.The simplest transdermal therapeutic system is that ointment is as treating anginal nitrol ointment.It is found that a lot of materials have the function that promotes that drug transdermal absorbs, be referred to as Percutaneous absorption enhancer, (see United States Patent (USP) 3,257 as dimethyl sulfoxine, diformamide or methyl dodecyl sulfoxide, No. 864) or azone (azone, see United States Patent (USP) 4,316, No. 893), all are Percutaneous absorption enhancers, be applied on the conventional formulation ointment, exist the application time short, must be constantly medication and using dosage is not accurate enough, the shortcoming of not enough health again.
In order accurately to control dosage; improve the medication health, prolong administration time, Sinnreich etc. have invented a kind of monolayer substrate diffusion controlled release system; see United States Patent (USP) 5.032; 403 and 5,079, No. 008; system is scattered in the adherent mixture of macromole medicine as drug storage warehouse; impermeable counterdie of drug storage warehouse outer housing and protecting film when the patient uses, are thrown off protecting film and are got final product.But this monolayer substrate diffusion controlled release system in use, because loading dose is big, the drug release rate initial stage is very fast, has very strong shock effect, blood drug level reaches high concentration rapidly, and just trend is steady then, and the medicine higher for therapeutic index is easy to generate toxic and side effects.
At the problems referred to above, one object of the present invention is to provide a kind of accurate control dosage, improves the medication health, prolongs administration time, release release-controlled skin-penetrating therapeutic system stably.
Another object of the present invention is to provide the preparation method of this type of release-controlled skin-penetrating therapeutic system.
A further object of the invention provides the purposes of this type of release-controlled skin-penetrating therapeutic system.
The present invention can realize by the dosage form of making multiple structure, is made up of following part successively:
(a). counterdie: be one deck cover layer, its guarantees containing explosive component and can not seeing through of drug storage warehouse (b), and airborne moisture content is difficult for entering drug storage warehouse (b);
(b). drug storage warehouse: contain active drug substance, constitute skeleton by crosslinked high molecular polymer, medicine disperses to be stored in wherein;
(c). the speed release-controlled film: have two types, a kind of is microporous membrane, and a kind of is non-porous film;
(d). adhesion layer: be pressure-sensitive adhesive agent;
(d). protecting film: adopt foil laminated film.
Counterdie (a) is formed for macromolecular material, is the holder of transdermal therapeutic system device, and drug storage warehouse (b) adheres on it.It must stop active chemistry the passing through of liquid component particularly in the drug storage warehouse, can stop that again the airborne moisture content of external environment (moisture) enters drug storage warehouse (b) simultaneously; It is again the outer protection layer of transdermal therapeutic system device, and material can be low-density or high density macromolecule polyalcohol, available aluminium foil composite polyethylene film, polychloroethylene film, nylon resin film, cellulose acetate membrane etc.The present invention adopts poly tetrafluoroethylene especially, and its physics, chemical property are more good, can tolerate the corrosion of nearly all chemical substance, and nontoxic, quality is level and smooth, and shape body surface with oneself changes in the variation of shape.The present invention goes back the precoating layer organic solvent-resistant on this base film material silicone rubber adhesive agent F-4G(China morning twilight institute one branch of the Ministry of Chemical Industry produces) or the production of FS-203(SHANGHAI RESEARCH INSTITUTE OF SYNTHETIC RESINS), to guarantee that drug storage warehouse (b) closely adheres on it, increases the drug storage warehouse volume to a greater extent.
Drug storage warehouse (b) is positioned between counterdie (a) and the speed release-controlled film (c), form by crosslinked high molecular polymer, the high molecular polymer that is suitable for has asynthetic rubber such as Butadiene block copolymer, ethylene/butadiene to inlay homopolymer, hot melt-ethylene-vinyl acetate copolymer (EVA), and other synthetic and natural macromolecular material, as gel, agarose etc.The preferential 103 block room temperature vulcanized silicone rubbers that adopt of the present invention are as substrate, coat on the non-woven fabrics, this silicone rubber is the cross-linked structure that the polydimethylsiloxane of carboxy blocking, poly-methyl ethoxy siloxanes sulfuration back form, it is widely used in medical material, have resistance to water, oil resistivity and permeability preferably, to the human body nonhazardous.
Speed release-controlled film (c) is positioned between drug storage warehouse (b) and the adhesion layer (d), and material is high density or low-density polyethylene film, can the tool micropore, can be non-porous film, and the present invention selects 0.03～0.05 millimeter thickness high density or low-density polyethylene film for use.
Adhesion layer (d) is positioned between speed release-controlled film (c) and the protecting film (e); can adopt pressure-sensitive adhesive agent polyisobutylene, silicone rubber, polyacrylate; optimization polypropylene acid esters of the present invention (is monomer with the 2-ethyl hexyl acrylate), this material is nontoxic to human body, and skin is not had sensitization; waterproof, viscosity stabilized; not aging, high cohesion does not contain additive; small-molecule substance content is few, and glue-spread is little.
Protecting film (e) adopts foil laminated film, easily opens from the transdermal therapeutic system device during use, does not involve adhesive agent, and drug storage warehouse active medicine and solvent are had impermeability.
Can add Percutaneous absorption enhancer in the drug storage warehouse of the present invention (b), as dimethyl sulfoxine, diformamide, methyl dodecyl sulfoxide, azone, propylene glycol etc.
The normal temperature crosslinked silicone rubber substrate of drug storage warehouse of the present invention (b) is to be mixed by 103 block room temperature vulcanized silicone rubbers, ethyl orthosilicate, dibutyl tin dilaurate.
The optimum formula of the normal temperature crosslinked silicone rubber substrate of drug storage warehouse (b) is: the ratio of 103 block room temperature vulcanized silicone rubbers, ethyl orthosilicate, dibutyl tin dilaurate is 100: 6: 2.
The coating layer thickness of adhesion layer of the present invention (d) is with 15～30 grams/square metre be good, the pressure-sensitive adhesive agent of employing polyacrylate.
The preparation technology of release-controlled skin-penetrating therapeutic system of the present invention is as follows:
1. prepare drug storage warehouse substrate:
With ultrasonic stirring 103 block room temperature vulcanized silicone rubbers 1 minute, slowly drip ethyl orthosilicate, ultrasonic agitation 3～6 minutes slowly drips dibutyl tin dilaurate, ultrasonic agitation 3～6 minutes.
2. speed release-controlled film (d), adhesion layer (d) and protecting film (d) complex making method:
The pressure-sensitive adhesive agent of polyacrylate is coated on the polyethylene film, presses foil laminated film.
3. counterdie is handled:
Polytetrafluoroethylene film is handled coating one deck F-4G or FS-203 silicone rubber adhesive agent through modification.
The polytetrafluoroethylene film modification is handled and can be adopted the hydrochloric acid modification to handle, and also can adopt sodium-ammonia solution etch, sodium-naphthalene-tetrahydrofuran solution etch, sodium-naphthalene-ethylene glycol diethyl ether solution corrosion method, irradiation grafting method, plasma method, surface applied method, alkali liquor circumfluence method, potassium acetate to dissolve method etc.
4. making release-controlled skin-penetrating therapeutic system:
The corrosion resistant plate that will have 1.0 millimeters thick of 5 centimetres of circular opens of diameter is pressed on the counterdie; the circular non-woven of 3.57 centimetres of diameters is arranged in opening central authorities; drip 0.25ml drug storage warehouse substrate on non-woven fabrics; its surface cure of waiting; speed release-controlled film, adhesion layer and protecting film complex are pressed on the solidified drug storage warehouse substrate, use the decompressor pressurization cutting forming of the band mould that coincide with opening.
Because the effect of the low permeability, particularly keratodermatitis of skin, the medicine with release-controlled skin-penetrating therapeutic function must possess:
1. require medicine to have fat-soluble preferably and water solublity, can overcome the effect of keratodermatitis, have the medicine of q.s to enter blood circulation, reach effective blood drug concentration;
2. the better tolerance of skin;
3. but prolonged application is in prevention, treatment or replacement therapy.
Because these harsh requirements, the medicine that satisfies condition is few, and applicable have scopolamine, nicotine, nitroglycerin, 17-, clonidine, a fluorobenzene ether-ether (etofenamate) etc.
The present invention is further illustrated below in conjunction with embodiment.
Embodiment one: the nicotine release-controlled skin-penetrating therapeutic system
The nicotine release-controlled skin-penetrating therapeutic system is that transdermal active substance nicotine is joined in the drug storage warehouse substrate, the pharmaceutical dosage form through further processing, the treatment that is used to give up smoking.
1. prepare drug storage warehouse substrate:
1) prescription: 100 parts of 103 block room temperature vulcanized silicone rubbers
6 parts of ethyl orthosilicates
2 parts of dibutyl tin dilaurates
108 parts of 40% nicotine alcoholic solution
2) compound method:
With ultrasonic stirring 103 block room temperature vulcanized silicone rubbers 1 minute, slowly drip ethyl orthosilicate, ultrasonic agitation 5 minutes adds 40% nicotine solution, and ultrasonic agitation 5 minutes slowly drips dibutyl tin dilaurate, ultrasonic agitation 5 minutes.
2. speed release-controlled film, adhesion layer and protecting film complex making method:
The pressure-sensitive adhesive agent of polyacrylate is coated on the polyethylene film (15～30 grams/square metre), press foil laminated film.
3. counterdie is handled:
0.05～0.2 millimeters thick polytetrafluoroethylene film is handled coating one deck 0.02～0.05 millimeters thick F-4G or FS-203 silicone rubber adhesive agent through modification.
4. making release-controlled skin-penetrating therapeutic system:
The corrosion resistant plate that will have 1.0 millimeters thick of 5 centimetres of circular opens of diameter is pressed on the counterdie; be arranged in opening central authorities with the circular non-woven of 3.57 centimetres of diameters; drip 0.25ml and contain the drug storage warehouse substrate of medicine on non-woven fabrics; its surface cure of waiting; speed release-controlled film, adhesion layer and protecting film complex are pressed on the solidified drug storage warehouse substrate, use the decompressor pressurization cutting forming of the band mould that coincide with opening.
Embodiment two: the nitroglycerin release-controlled skin-penetrating therapeutic system
The nitroglycerin release-controlled skin-penetrating therapeutic system is the anti-anginal drug nitroglycerin to be joined in the drug storage warehouse substrate pharmaceutical dosage form through further processing.
1. prepare drug storage warehouse substrate:
1) prescription: 100 parts of 103 block room temperature vulcanized silicone rubbers
6 parts of ethyl orthosilicates
2 parts of dibutyl tin dilaurates
108 parts of 10% nitroglycerin lactose solutions
2) compound method:
With ultrasonic stirring 103 block room temperature vulcanized silicone rubbers 1 minute, slowly drip ethyl orthosilicate, ultrasonic agitation 5 minutes adds 10% nitroglycerin lactose solution, and ultrasonic agitation 5 minutes slowly drips dibutyl tin dilaurate, ultrasonic agitation 5 minutes.
2. speed release-controlled film, adhesion layer and protecting film complex are made with embodiment one.
3. counterdie is handled with embodiment one.
4. make release-controlled skin-penetrating therapeutic system with embodiment one.
5. nitroglycerin release-controlled skin-penetrating therapeutic system transdermal test in vitro speed experiment:
Because the skin absorbs performance and the people of little Corii Sus domestica are approaching, select for use the piglets skin that exsomatizes to do the percutaneous rate experiment.With a piglets leather jacket in a diffuser casing [referring to T.J.Franz, Invest.Dermatol 64,190-195(1975)], Deponit is attached on the Corii Sus domestica outer surface, timing sampling utilizes high-pressure liquid phase method to measure percutaneous rate and cumulative release amount.
Time point (hour) percutaneous rate (microgram/square centimeter/hour) cumulative release amount (milligram)
0.5 82 0.41
1.0 47 0.64
2.0 37 1.02
4.0 29 1.60
8.0 23 2.52
16.0 20 4.12
24.0 15 5.35
Experiment shows that the drug release rate of nitroglycerin is steady, and shock effect is little, is similar to zero-order release.
Release-controlled skin-penetrating therapeutic system of the present invention has accurate control dosage, improve the medication health, prolong administration time, release is advantage stably, compare with traditional peroral dosage form, also have the first pass effect of walking around liver, avoided adopting the fluctuation of the blood concentration that other administering mode multiple dosing interval treatment causes, dwindle between individuality, individual in the advantage of the difference of each time between taking medicine.
Claims (13)
1, a kind of release-controlled skin-penetrating therapeutic system is made up of counterdie, drug storage warehouse, speed release-controlled film, adhesion layer, protecting film successively, it is characterized in that:
(1) the awkward permeable macromolecular material of counterdie is formed, available aluminium foil composite polyethylene film, polychloroethylene film, nylon resin film, cellulose acetate membrane, poly tetrafluoroethylene one of them;
(2) drug storage warehouse is that crosslinked high molecular polymer is formed, available Butadiene block copolymer, ethylene/butadiene inlay homopolymer, hot melt ethylene-ethyl acetate copolymer (EVA), gel, agarose, 103 block room temperature vulcanized silicone rubbers one of them;
(3) fast release-controlled film can be with high density or low-density polyethylene film, the tool or the micropore of not having;
(4) adhesion layer adopts pressure-sensitive adhesive agent, available polyisobutylene, silicone rubber, polyacrylate one of them;
(5) protecting film adopts foil laminated film.
2, release-controlled skin-penetrating therapeutic system according to claim 1 is characterized in that:
(1), counterdie adopts poly tetrafluoroethylene;
(2), drug storage warehouse adopts normal temperature crosslinked silicone rubber;
(3), adhesion layer adopts the pressure-sensitive adhesive agent of polyacrylate (is monomer with the 2-EHA).
3, release-controlled skin-penetrating therapeutic system according to claim 1 and 2 is characterized in that precoating layer silicone rubber adhesive agent F-4G or FS-203 on the base film material.
4, according to claim 1,2, one of 3 described release-controlled skin-penetrating therapeutic systems, the thickness that it is characterized in that the counterdie poly tetrafluoroethylene is 0.05～0.2 millimeter, and the silicone rubber thickness of precoating is 0.03～0.05 millimeter.
5, release-controlled skin-penetrating therapeutic system according to claim 1 and 2 is characterized in that the speed release-controlled film selects 0.03～0.05 millimeter thickness high density or low-density polyethylene film for use.
6, release-controlled skin-penetrating therapeutic system according to claim 1 and 2 is characterized in that drug storage warehouse adopts normal temperature crosslinked silicone rubber substrate to coat on the non-woven fabrics.
7, according to claim 1,2, one of 6 described release-controlled skin-penetrating therapeutic systems, its feature is that 103 block room temperature vulcanized silicone rubbers, ethyl orthosilicate, dibutyl tin dilaurate mix in drug storage warehouse substrate, and this substrate is coated on the non-woven fabrics.
8,, it is characterized in that the ratio of 103 block room temperature vulcanized silicone rubbers, ethyl orthosilicate, dibutyl tin dilaurate in the drug storage warehouse substrate is preferable with 100: 6: 2 according to claim 1,2,6,7 described release-controlled skin-penetrating therapeutic systems.
9, according to claim 1,2 described release-controlled skin-penetrating therapeutic systems, it is characterized in that to add Percutaneous absorption enhancer in the drug storage warehouse.
10, release-controlled skin-penetrating therapeutic system according to claim 1 and 2 is characterized in that the thickness of adhesion layer is preferably 15～30 gram/square metre polyacrylic acid acid fracturing sensitive adhesives.
11, a kind of method for preparing release-controlled skin-penetrating therapeutic system comprises:
(1) preparation drug storage warehouse substrate:
With ultrasonic stirring 103 block room temperature vulcanized silicone rubbers 1 minute, slowly drip ethyl orthosilicate, ultrasonic agitation 3～6 minutes slowly drips medicine or its solution, and ultrasonic agitation 3～6 minutes slowly drips dibutyl tin dilaurate, ultrasonic agitation 3～6 minutes;
(2) speed release-controlled film (d), adhesion layer (d) and protecting film (d) complex making method:
The pressure-sensitive adhesive agent of polyacrylate is coated on the polyethylene film, presses foil laminated film;
(3) counterdie is handled:
Polytetrafluoroethylene film is handled coating one deck F-4G or FS-203 silicone rubber adhesive agent through modification;
(4) make release-controlled skin-penetrating therapeutic system:
The corrosion resistant plate that will have 1.0 millimeters thick of 5 centimetres of circular opens of diameter is pressed on the counterdie; the circular non-woven of 3.57 centimetres of diameters is arranged in opening central authorities; drip 0.25ml drug storage warehouse substrate on non-woven fabrics; its surface cure of waiting; speed release-controlled film, adhesion layer and protecting film complex are pressed on the solidified drug storage warehouse substrate, use the decompressor pressurization cutting forming of the band mould that coincide with opening.
12, a kind of application of release-controlled skin-penetrating therapeutic system is characterized in that the medicine that is suitable for satisfies following condition:
(1) has fat-soluble preferably and water solublity, can overcome the effect of keratodermatitis, have the medicine of q.s to enter blood circulation, reach effective blood drug level;
(2) better tolerance of skin;
(3) but prolonged application in prevention, treatment or replacement therapy.
13, the application of release-controlled skin-penetrating therapeutic system according to claim 12 is characterized in that the medicine that is suitable for has: scopolamine, nicotine, nitroglycerin, 17-, clonidine, fluorobenzene ether-ether (etofenamate).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93106174 CN1094972A (en) | 1993-05-21 | 1993-05-21 | Release-controlled skin-penetrating therapeutic system and preparation thereof and application |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 93106174 CN1094972A (en) | 1993-05-21 | 1993-05-21 | Release-controlled skin-penetrating therapeutic system and preparation thereof and application |
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| CN1094972A true CN1094972A (en) | 1994-11-16 |
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| CN 93106174 Pending CN1094972A (en) | 1993-05-21 | 1993-05-21 | Release-controlled skin-penetrating therapeutic system and preparation thereof and application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100438859C (en) * | 2001-08-24 | 2008-12-03 | Lts勒曼治疗系统股份公司 | Transdermal therapeutic system (TTS) with fentanyl as active ingredient |
| CN103893155A (en) * | 2012-12-26 | 2014-07-02 | 江苏康倍得药业有限公司 | Drug transdermal patch |
-
1993
- 1993-05-21 CN CN 93106174 patent/CN1094972A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100438859C (en) * | 2001-08-24 | 2008-12-03 | Lts勒曼治疗系统股份公司 | Transdermal therapeutic system (TTS) with fentanyl as active ingredient |
| CN103893155A (en) * | 2012-12-26 | 2014-07-02 | 江苏康倍得药业有限公司 | Drug transdermal patch |
| CN103893155B (en) * | 2012-12-26 | 2018-11-06 | 江苏康倍得药业股份有限公司 | A kind of drug transdermal patch |
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| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |