CN101612141B - Buprenorphine patch - Google Patents
Buprenorphine patch Download PDFInfo
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- CN101612141B CN101612141B CN200910161838A CN200910161838A CN101612141B CN 101612141 B CN101612141 B CN 101612141B CN 200910161838 A CN200910161838 A CN 200910161838A CN 200910161838 A CN200910161838 A CN 200910161838A CN 101612141 B CN101612141 B CN 101612141B
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- patch
- binding agent
- adhesive
- buprenorphine
- medicine
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Abstract
The invention provides a buprenorphine hydrochloride and/or buprenorphine patch. A binder layer formed on one face of a flexible backing layer of the patch contains a medicament, a penetration enhancer, a tackifier, an antioxidant and a binder. The medicament is the buprenorphine hydrochloride and/or buprenorphine; the penetration enhancer is a mixture of lauric acid diethanolamide, isopropyl myristate and/or isopropyl palmitate; the tackifier is rosin and/or abietate; the antioxidant is vitamin E and the like; and the binder is acrylate adhesive. The patch has the advantages of good transdermal absorption effect of the medicament, no stimulation to the skin, good medicinal stability and higher application value.
Description
Technical field
The present invention relates to pharmaceutical preparation, be specifically related to a kind of percutaneous absorption patch, relate in particular to the percutaneous absorption patch that contains buprenorphin hydrochloride or buprenorphine.
Background technology
Owing to multiple reason, cancer has become the one of the main reasons of human Died Of Disease, and the cancer patient is basically through having miseries such as cancerous pain all through the ages.Therefore, in treatment of cancer, be even more important to the treatment of cancerous pain.In the medicine of alleviating cancerous pain, non-anaesthetic property buprenorphin hydrochloride and/or buprenorphine are more effective, have been used as injection and suppository.But, the effect of paying of the sticky feeling the when medicine of this type dosage form can bring injection pain and suppository to use to the patient in use.In recent years, act as the existing research of purpose skin adhesive preparation to eliminate this pair.But,, have the people to improve the patch (opening flat 4-217926 like the patent documentation spy, 7-10754,7-304672, the flat 10-512551 of special table) of medicine skin permeability with regard to having proposed to use various absorption enhancers because the skin absorption of (hydrochloric acid) buprenorphine is low.Though these patches have improved the skin permeability of medicine, yet effect is undesirable, do not reach the purpose of long term administration, can not satisfy patient's needs.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research design increases buprenorphin hydrochloride and/or buprenorphine skin permeability, realizes long lasting percutaneous patch.
The invention provides a kind of buprenorphine patch.
The present invention utilizes specific absorption enhancer, makes buprenorphin hydrochloride and/or buprenorphine skin permeability suitable and realize the successive administration percutaneous patch in one week.
Patch of the present invention is made up of adhesive phase and flexibility backing layer, contains medicine, transdermal absorption accelerator, viscosifier and binding agent in the adhesive phase that on a face of said flexibility backing layer, forms.Wherein, (1) medicine is buprenorphin hydrochloride and/or buprenorphine; (2) transdermal absorption accelerator is mixture or the mixture of lauric acid diethyl amide and isopropyl palmitate or the mixture of lauric acid diethyl amide, isopropyl myristate and isopropyl palmitate of lauric acid diethyl amide and isopropyl myristate; (3) viscosifier are Colophonium and/or rosin ester; (4) binding agent is an esters of acrylic acid.
Lauric acid diethyl amide promotes the percutaneous of medicine to absorb through the horny layer diffusion coefficient that improves medicine.If but the addition of lauric acid diethyl amide will increase skin irritation greater than 10 weight portions, can not promote drug absorption effectively again less than 1 weight portion.Therefore, binding agent and lauric acid diethyl amide 100: 1 by weight～10 proportionings.
Isopropyl myristate and/or isopropyl palmitate promote the percutaneous of medicine to absorb through the horny layer partition coefficient that increases medicine.If the addition of isopropyl myristate and/or isopropyl palmitate will make the binding agent deliquescing greater than 100 weight portions, the attaching back has residual on skin, can not effectively promote drug absorption again less than 10 weight portions.But, above-mentioned two kinds of different absorption enhancer couplings that promote mechanism, it is then extremely effective to absorb facilitation.
Viscosifier Colophonium and/or rosin ester are very effective for strengthening viscosity, can make patch be attached at skin for a long time.The addition of Colophonium and/or rosin ester is greater than 50 weight portions, and binding agent is really up to the mark, the skin attachment ability; Less than 5 weight portions, then can not play viscosifying action.Therefore, binding agent and viscosifier by weight 100: the 5-50 proportioning.
Therefore medicine buprenorphine among the present invention and/or buprenorphin hydrochloride less stable, in order to improve stability of drug, have added antioxidant in the composition of patch.Antioxidant is one or more of vitamin E, Vitamin E acetate, hydroxy-methylbenzene dibutyl ester and butylhydroxy anisole, serves as preferred with vitamin E and Vitamin E acetate especially.Binding agent and antioxidant are by 100: the weight proportion of 0.1-10.
The binding agent that uses among the present invention is the copolymer of monomer A and monomers B; Said monomer A is the alkyl acrylate that contains 4-8 carbon number; Said monomers B is the vinyl polar monomer.
With the alkyl acrylate that contains 4-8 carbon atom and polar monomer 51-95 by weight: the copolymer that the 5-49 copolymerization forms serves as preferred.Alkyl acrylate can be butylacrylate, 1-Octyl acrylate and 2-EHA etc.Polar monomer can be acrylic acid, methacrylic acid, vinyl acetate, vinyl pyrrolidone, 2-hydroxyethyl acrylate or methacrylic acid-2-hydroxyethyl ester etc.
Above-mentioned binding agent also can be selected commercially available article for use, like DURO-TAC 87-2051 and DURO-TAC87-2677 (production of national of the United States's starch company), MAS683 and MASCOS10 (Japanese CosMED Pharmaceutical Co., Ltd produce).
In order to strengthen the cohesiveness of adhesive phase, can use the method for being known usually that adhesive phase is built bridge.Bridging method comprises ultraviolet method, gamma-rays method etc., perhaps can add bridging agents such as PIC, organic metal salt, metal-chelator.Above-mentioned binding agent also can form through building bridge, and chemical bridging agents such as PIC, ethyl acetoacetate base aluminum plasma type bridging agent is added in the binding agent make its bridge formation.DURO-TAC 87-2677 can build bridge voluntarily, need not to add bridging agent.
Medicine among the present invention is buprenorphin hydrochloride or buprenorphine, also can be both mixtures.The addition of buprenorphin hydrochloride and/or buprenorphine is that binding agent 100 weight portions are added the 5-35 weight portion.Patch Chinese medicine content is less than 5wt%, and the skin transit dose of medicine is not enough; And content surpasses 35wt%, then uses back patch Chinese medicine residual quantity to increase, and causes waste.
The adding of medicine can be adopted and drug solution joined mixed back forms the method that contains the medicine adhesive layer in the binding agent of solution shape; Also can adopt methods such as impregnation, transfer, spraying that medicine is joined in the adhesive phase, can select appropriate method according to the rerum natura of medicine.
Flexibility backing layer according to the invention uses does not have particular determination to medicine impermeability backing layer material, generally with patch class and the employed back lining materials of cataplasma class preparation.For example cellulose acetate, ethyl cellulose, polyvinyl resin, acrylic resin, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, chlorovinyl resinoid, protochloride vinyl, vinyl acetate-chloride copolymer, polyamide, mylar, ABS resin, SIS resin, SEBS resin, carbamic acid resin, silicones and aluminium foil etc.In addition, the back lining materials of being addressed can be weaving cotton cloth or adhesive-bonded fabric of being made into of fiber by above-mentioned material, also can be by the film material of above-mentioned material, weave cotton cloth or adhesive-bonded fabric is composited.The thickness of said backing layer does not have particular provisions, is used for the backing layer thickness that skin sticks and is generally 10-1000mm, and be preferred with 20-100mm.
The thickness of adhesive phase does not have particular determination yet in the patch of the present invention, general thickness in the 5-200 mu m range, 10～100 μ m preferably.
As stated, patch buprenorphin hydrochloride of the present invention and/or buprenorphine skin permeability are good, safe, practical.Patch medicine percutaneous good absorbing effect of the present invention, non-stimulated to skin, medicine stability is good, and big using value is arranged, and patch can be attached at skin for a long time and not come off, and can be made into the transdermal formulation that attaches a week.
The specific embodiment
Further specify the present invention through following non-limiting examples.
Synthesizing of adhesive A
Get ethyl acetate 2000g, 2-EHA 700g, vinyl acetate 200g, acrylic acid 100g and azo diethyl butyronitrile 0.05g; Join in the 5000ml container that has agitator; Polymerization is 15 hours under nitrogen atmosphere and 75 ℃ of conditions, makes adhesive A 1000g.
Binding agent B's is synthetic
In above-mentioned 100g adhesive A solution, add ethyl acetoacetate base aluminum 0.03g, mix homogeneously, binding agent B 100.03g obtains after the drying building bridge.
Embodiment 1-3, comparative example 1～5
Press the proportioning shown in the table 1, in binding agent, add buprenorphine, buprenorphin hydrochloride, lauric acid diethyl amide, isopropyl myristate, isopropyl palmitate and rosin ester (waste river KCC, rosin ester GA-90AF); Form transdermal formulation solution behind the uniform mixing; On polyethylene terephthalate (PET) film, film, the thickness that control is filmed, the thickness that makes dry caudacoria is 100 μ m; Drying is 8 hours under 60 ℃ of temperature, makes percutaneous absorption patch after the solvent evaporates.
Table 1
A is an adhesive A in the last table; B is binding agent B; C is binding agent DUR-TAC 87-2677; D is binding agent: MASCOS10
To resulting percutaneous absorption patch, skin adherence and skin residual, skin irritation, stability are measured, the result lists in the table 2.
Adhering skin property and residual test
In the skin irritation test, when peeled off at the white rabbit back, observing paster had noresidue on skin with the percutaneous absorption adhesive patch.The result shows embodiment 1-5, comparative example 1-4 noresidue on skin, but comparative example 5 noresidue on skin.
The skin irritation test
It is 3.14cm that the percutaneous absorption patch that makes is cut into area
2(circular patch of diameter 2cm) size, (male, body weight 2.2～2.5kg) 24 hours was peeled off paster after 30 minutes, and perusal is pasted the erythema of paying the position and generated situation to be attached at Japan kind white rabbit back.Evaluation methodology is pressed the Draiz method and is implemented (nineteen fifty-nine FDA, Federal Register in 1973), and according to the determinating reference of note down, the meansigma methods that gained is counted is as skin irritation sex index.
No erythema 0 point
Very slight erythema 1 point (just can identify)
Erythema 2 points very clearly
Moderate erythema 3 points
The erythema of height also has slight crust to form 4 points
The result shows embodiment 1-5, and comparative example 1,3 skin irritations are low, but comparative example 2 shows stronger skin irritation.
Cross cruel stability test
It is 3.14cm that the percutaneous absorption patch that makes is cut into area
2(circular patch of diameter 2cm) size is packaged in the aluminium foil bag as the obedient sheet of test, under 60 ℃ of conditions, preserves for 4 weeks, measures the stability of patch.To test obedient sheet after 4 weeks and place erlenmeyer flask, add ethanol extraction, with HPLC pharmaceutical concentration.Test result is with respect to the medicament contg (with percentage calculation) before the stability test.
The result shows embodiment 1-5, and comparative example 1-3 all demonstrates more than 85% stable, embodiment 2-5 especially, and comparative example 1,3 shows better stability.
Long-term patch test
It is 3.14cm that the percutaneous absorption patch that makes is cut into area
2(circular patch of diameter 2cm) size is attached at 3 volunteers' chest as the obedient sheet of test, observes the attaching situation in the week.
The result shows embodiment 1-5, and comparative example 1-3 all demonstrates the long-term adhesiveness more than 3 days, and embodiment 3-5 especially, comparative example 1-3 demonstrate better long-term adhesiveness more than 7 days.
Select the less embodiment 1,2,3,4,5 of problem in skin adherence and skin residual, skin irritation, stability and the long-term patch test and the percutaneous absorption patch of comparative example 1,3 to carry out medicine percutaneous absorption test (n=3) as follows, the result lists in table 3.Skin adherence and skin residual, skin irritation, stability and long-term patch test result are listed in the table 2.
Table 2
| Skin tackness and skin residual | Skin irritation | Stability | Long-term patch test | |
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 comparative examples 1 comparative example 2 comparative examples 3 comparative examples 4 comparative examples 5 | Well, noresidue is good, and noresidue is good, and noresidue is good, and noresidue is good, and noresidue is good, and noresidue is good, and noresidue is good, a little less than the noresidue non-adhesiveness cohesive force, has residual | 0.25 0.5 0.5 0.25 0 0.5 2.0 0.25 - - | 88 90 98 94 90 93 87 97 - - | Came off after coming off after 4 days 5 days that not having in 7 days comes off and do not have in 7 days and come off that not having in 7 days comes off and do not have in 7 days and come off that not having in 7 days comes off and do not have in 7 days come off-- |
The test of medicine Percutaneously absorbable
People's isolated skin (thickness is 700 microns) is sandwiched on the Franz diffusion cell that has recirculated water; Water temperature is controlled at 37 ℃; The acceptable solution of skin corium side is water: PEG400=70: 30 mixed liquor; Percutaneous absorption patch is affixed on the horny layer side of skin, and the medicine that under condition of stirring, carried out 168 hours sees through test.Take acceptable solution after 50 hours, 100 hours and 168 hours, use the high-performance liquid chromatogram determination drug concentrations, try to achieve the accumulation transit dose of medicine.
The result shows that embodiment 1-5 demonstrates the excellent drug transdermal characteristic, and the transdermal characteristic of comparative example 1,3 is relatively poor.
Table 3
Claims (3)
1. buprenorphine patch is made up of adhesive phase and flexibility backing layer, it is characterized in that, contains medicine, transdermal absorption accelerator, viscosifier, binding agent and antioxidant in the adhesive phase that forms on the face of said flexibility backing layer; Said medicine is buprenorphine or buprenorphin hydrochloride; Transdermal absorption accelerator is the mixture of lauric acid diethanolamine and isopropyl palmitate and nutmeg acid esters; Viscosifier are rosin ester; Binding agent is adhesive A or binding agent B; Antioxidant is the hydroxy-methylbenzene dibutyl ester; Said adhesive A and binding agent B make through following method:
Get ethyl acetate 2000g, 2-EHA 700g, vinyl acetate 200g, acrylic acid 100g and azo diethyl butyronitrile 0.05g; Join in the 5000ml container that has agitator; Polymerization is 15 hours under nitrogen atmosphere and 75 ℃ of conditions, makes adhesive A 1000g;
In above-mentioned 100g adhesive A solution, add ethyl acetoacetate base aluminum 0.03g, mix homogeneously, binding agent B 100.03g obtains after the drying building bridge.
2. patch according to claim 1; It is characterized in that said patch contains buprenorphin hydrochloride 15g, lauric acid diethanolamine 4g, nutmeg acid esters 20g, isopropyl palmitate 15g, rosin ester 15g, hydroxy-methylbenzene dibutyl ester 0.3g, adhesive A 100g.
3. patch according to claim 1; It is characterized in that said patch contains buprenorphin hydrochloride 15g, lauric acid diethanolamine 3g, nutmeg acid esters 15g, isopropyl palmitate 20g, rosin ester 25g, hydroxy-methylbenzene dibutyl ester 0.5g, binding agent B 100g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910161838A CN101612141B (en) | 2009-07-29 | 2009-07-29 | Buprenorphine patch |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910161838A CN101612141B (en) | 2009-07-29 | 2009-07-29 | Buprenorphine patch |
Publications (2)
| Publication Number | Publication Date |
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| CN101612141A CN101612141A (en) | 2009-12-30 |
| CN101612141B true CN101612141B (en) | 2012-10-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910161838A Active CN101612141B (en) | 2009-07-29 | 2009-07-29 | Buprenorphine patch |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2013205080B2 (en) * | 2012-12-12 | 2016-07-07 | Lts Lohmann Therapie-Systeme Ag | Transdermal Delivery System |
| CN103893154A (en) * | 2012-12-26 | 2014-07-02 | 江苏康倍得药业有限公司 | Buprenorphine-containing transdermal delivery system |
| CN103211800A (en) * | 2013-03-26 | 2013-07-24 | 河南羚锐制药股份有限公司 | Patch used for treating nausea and vomiting, and preparation method thereof |
| US20200297985A1 (en) * | 2017-12-14 | 2020-09-24 | Lts Lohmann Therapie-Systeme Ag | Microneedle array having an active ingredient in the form of salts |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1185317A (en) * | 1996-07-19 | 1998-06-24 | 日东电工株式会社 | Buprenorphine percutaneous absorbent |
| CN1362879A (en) * | 2000-02-25 | 2002-08-07 | 帝人株式会社 | Patches containing buprenorphine hydrochloride |
| CN101397479A (en) * | 2007-09-28 | 2009-04-01 | 荒川化学工业株式会社 | Adhesion-imparting agent, adhesive or adhesive composite, bonding or adhesive belt and medical paster |
| CN101455650A (en) * | 2007-12-06 | 2009-06-17 | 考司美德制药株式会社 | Percutaneous absorption patch and its production method |
-
2009
- 2009-07-29 CN CN200910161838A patent/CN101612141B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1185317A (en) * | 1996-07-19 | 1998-06-24 | 日东电工株式会社 | Buprenorphine percutaneous absorbent |
| CN1362879A (en) * | 2000-02-25 | 2002-08-07 | 帝人株式会社 | Patches containing buprenorphine hydrochloride |
| CN101397479A (en) * | 2007-09-28 | 2009-04-01 | 荒川化学工业株式会社 | Adhesion-imparting agent, adhesive or adhesive composite, bonding or adhesive belt and medical paster |
| CN101455650A (en) * | 2007-12-06 | 2009-06-17 | 考司美德制药株式会社 | Percutaneous absorption patch and its production method |
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| Publication number | Publication date |
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| CN101612141A (en) | 2009-12-30 |
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