CN103893154A - Buprenorphine-containing transdermal delivery system - Google Patents
Buprenorphine-containing transdermal delivery system Download PDFInfo
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- CN103893154A CN103893154A CN201210570734.4A CN201210570734A CN103893154A CN 103893154 A CN103893154 A CN 103893154A CN 201210570734 A CN201210570734 A CN 201210570734A CN 103893154 A CN103893154 A CN 103893154A
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Abstract
The present invention relates to a buprenorphine-containing transdermal delivery system, which contains: (A)an acrylic acid base adhesive composition, wherein the acrylic acid base adhesive composition is a blended substance of (i) an acrylic acid pressure-sensitive adhesive and (ii) a polyacrylic acid resin, (B) a penetration enhancer, wherein the penetration enhancer comprises glycerol triacetate, laurocapram and propylene glycol, and (C) an active drug buprenorphine, wherein the acrylic acid pressure-sensitive adhesive (i) is a (methyl) acrylate copolymer containing (methyl) acrylamide or N,N-substituted monomer thereof, and the polyacrylic acid resin (ii) is a Eudragit polyacrylic acid resin. The transdermal delivery system prepared by mixing the three specific penetration enhancers and the acrylic acid base adhesive composition according to a certain ratio has improved excellent performances in the fields of drug absorption rate, patch mechanical property, processing technology and the like.
Description
Technical field
The present invention relates to a kind of buprenorphine transdermal drug delivery system.In particular, the present invention relates to a kind ofly be mixed by a certain percentage with acrylic based binders compositions and the buprenorphine transdermal drug delivery system at aspects such as transdermal absorption factor, mechanical property and processing technique with premium properties made by specific three kinds of penetrating agents.
Background technology
Buprenorphine (Buprenorphine) is synthetic opiate receptor part excitement-antagonistic sixties in 20th century, has significant analgesic effect, at present mainly with injection and sublingual lozenge formulation application in clinical.But due to injection or sublingual administration, conventionally can blood drug level be raise rapidly at the administration initial stage, and exceed the required dosage level for the treatment of; and cause sense of euphoria; and, because blood level is difficult to maintain a stable state, thereby this medicament can not be continued and effectively reaches analgesic effect.And comparatively speaking, the preparation capable of permeating skin of this medicine have drug bioavailability high, avoid repeat administration, can maintain the advantages such as stable drug plasma treatment concentration.
But, because buprenorphine has relatively high molecular weight (468) and high-melting-point, and be insoluble in organic solvent and water, make the permeability of this medicine on human body skin poor.So in the preparation capable of permeating skin process of this medicine of exploitation, the transdermal amount that how to improve active medicine has become the key technology place of research and development.At present, existing many sections of patents disclose the patented technology that improves buprenorphine skin infiltration capacity with different penetrating agents both at home and abroad.For example: in US Patent No. 6264980, described application levulic acid as percutaneous penetrating agent, and mixed by a certain percentage and make buprenorphine transdermal patch with acrylate copolymer, polyvinylpyrrolidone, this patch has really had and significantly improved in infiltration capacity.But, because levulic acid is solid-state at normal temperatures, so levulic acid must be carried out to supercoolization processing in preparation process, make it be converted into liquid state, then just can be applied in paster substrate, but supercoolization state is labile state in thermodynamic state, can makes levulic acid crystallization through long-time storage or cryogenic conditions, thereby cause the permeability decrease of active medicine.At least one the mixture of having described application polyoxyethylene sorbitan mono fatty acid ester in Chinese patent ZL01800283 and be selected from liquid high-grade aliphatic ester, liquid polyol, lactic acid and glycerol triacetate is as the patch containing buprenorphine of penetrating agent, and the drug osmotic amount of this patch also increases.But, its penetrating agent content higher (accounting for the 6%-50% of tack coat gross weight), the patch making with a high proportion of penetrating agent like this, its mechanical property will certainly reduce greatly, thereby make patch product inevitably occur the phenomenon such as wire drawing, excessive glue, its practicality can obviously decline.In another section of Chinese patent CN97117862, describe and applied the buprenorphine percutaneous absorbent of a kind of glycerine monofatty ester as penetrating agent.But this patch complicated process of preparation, equipment requirements is high, and preparation time long (having 96 hours heat ageing processes), is unfavorable for suitability for industrialized production.In addition the existing buprenorphine patch launch in foreign market at present, (trade name,
napp Phamaceuticals Ltd company produces), this paster is five-layer structure, i.e. (1), the impermeable polyester backing layer of buprenorphine; (2) polyacrylate adhesive layer; (3) polyester layer (terephthalic acids ethylene glycol condensation polymer) separating; (4) containing the hypothallus of solvent, softening agent and the polyacrylic binder of buprenorphine, buprenorphine; (5) protective layer.The paster of this five-layer structure is because complex structure, area are large (as active medicine area 12.5cm
2time, paster area is about 30.6cm
2) make that preparation technology is loaded down with trivial details, restive in production.
Consider the practical problem existing in above-mentioned prior art, the present inventor is through intensive research, finds to mix by a certain percentage and can make all good buprenorphine transdermal patches of a kind of drug permeability, mechanical property and preparation technology with specific three kinds of penetrating agents and acrylate pressure sensitive adhesive.Complete thus the present invention.
Summary of the invention
A kind of buprenorphine transdermal drug delivery system, described system comprises:
(A) acrylic based binders compositions, its blend by following material forms: (i) acrylic compounds pressure sensitive adhesive and (ii) polyacrylic resin;
(B) penetrating agent, it is combined by glycerol triacetate, laurocapram and propylene glycol;
(C) active medicine, buprenorphine.
Wherein said acrylate pressure sensitive adhesive (i) is for containing (methyl) acrylamide or its N, (methyl) acrylate copolymer of N substituted monomer; Described polyacrylic resin (ii) is Eudragit class polyacrylic resin.
Acrylate pressure sensitive adhesive described in the present invention refers to the polymer substance that a class known in the art adopts acrylic acid and derivant copolymerization thereof to generate, there is saturated hydrocarbon main chain and lateral chain of ester group, can obtain the sticking acrylic compounds pressure sensitive adhesive of tool by changing comonomer and side-chain radical.Conventional monomer has the compounds such as acrylic acid, butyl acrylate, acrylic acid 2-diethyl acetamidomalonate, vinylacetate, 2-ethoxy acrylic acid.Acrylate pressure sensitive adhesive used in the present invention is acrylic based binders compositions mentioned in Chinese patent CN200410000394, this acrylic based binders compositions at least comprises a kind of component (A) containing (methyl) acrylamide or its N, (methyl) acrylate copolymer of N substituted monomer and a kind of component (B) are containing (methyl) acrylic copolymer of tertiary amine groups or quaternary ammonium group, this contact adhesive can load more active medicine, improve release amount of medicine and stabilized release rate, and the side effect such as stimulation and sensitization to skin is little.
The penetrating agent using in the present invention refers to that a class well known in the art can overcome the material of skin barrier effect, increase drug transdermal speed or increase drug transdermal amount.Wherein laurocapram can significantly strengthen skin permeation rate to hydrophilic or hydrophobic drug, and best working concentration is 0.5%-5%, better with propylene glycol synergistic action effect.
In the present invention, importantly glycerol triacetate, laurocapram and propylene glycol are merged and used, osmotic effect is obviously increased.If penetrating agent is only selected the one in three, osmosis will be obviously not enough, and only select wherein two kinds, and osmosis can not produce a desired effect.In addition, the use amount (% by weight) of three kinds of penetrating agents is respectively glycerol triacetate 0.5%-4%, laurocapram 0.1%-3% and propylene glycol 1%-5%, if exceed this scope, be difficult to reach the aggregative indicator that improves drug permeability and keep patch excellent mechanical performances.Above-mentioned glycerol triacetate, laurocapram and propylene glycol preferred content (% by weight) are respectively 1%-4%, 0.5%-1% and 1%-4%.
Active medicine buprenorphine preferred content (% by weight) in the present invention is 4%-18%.If its use amount is lower than 4%, transdermal amount can not meet the treatment effective dose of this medicament; Contrary, if use amount higher than 18%, the transdermal amount of active medicine has no longer included obvious increase, so consider it is inappropriate from the angle of economy.More preferably 6%-13% of active medicine buprenorphine use amount of the present invention.
Paster structure in the present invention is lamination layer structure, comprises backing layer, drug-reservoir layer and protective layer, and wherein drug-reservoir layer comprises active pharmaceutical ingredient and adhesive composition and penetrating agent.Its processing technique, is first by medical solid organic solvent dissolution, then mixes with penetrating agent solution, fully stirs and makes mix homogeneously, and gained mixture is added in adhesive composition, whether evenly then measures upper, middle and lower layer medicament contg with homogenizer.Obtain after uniform colloid,, to back lining materials, dry with the coating machine such as roller type or scraper type or hardened coating, then with protective layer pressing, die-cut, pack and obtain the paster of tool three-decker.Such paster has the advantages such as processing technique is easy, equipment requirements is not high, easy to use.
The invention provides all good buprenorphine transdermal patches of a kind of drug permeability, mechanical property and preparation technology.
Detailed description of the invention
Further explain the present invention below by embodiment, but embodiment is to the present invention and do not constitute any limitation." % " using in embodiment is " % by weight " of each component in drug-reservoir layer.
Embodiment 1
Get 76.5g acrylate pressure sensitive adhesive (dry gum base), 8g Eudragit RS100,1.0g glycerol triacetate, 0.5g laurocapram, 4.0g propylene glycol, 10g buprenorphine and 100g ethyl acetate, mix and blend 2 hours, solid matter is all dissolved, and the part of evaporation loss again adds ethyl acetate and supplies.Above-mentioned solution is layered on ethylene-vinyl acetate copolymer microporous membrane, and thickness is 50um, at 60 DEG C, is dried 2 hours.Compound with monolayer silication PET polyester film.
It is 25cm that the paster obtaining is cut into area
2specification, be applied in depilation mouse back, time remaining 24 hours.The percent of the amount calculating drug permeability of paster Chinese medicine before this paster is used at nude mouse back and after 24 hours by high-efficient liquid phase color spectrometry.
Embodiment 2 to 4, comparative example 1 to 4
Make paster by the method for embodiment 1, the penetrating agent that wherein used and the content of acrylate pressure sensitive adhesive change to some extent, as shown in table 1.
Table 1 result shows, embodiment 1 to 4 all shows good drug permeability and good viscous force, initial bonding strength, wherein embodiment 1 best results of holding.On the other hand, in the time that three kinds of penetrating agents only have one or both to merge use, its mechanism can obviously reduce, as comparative example 1 to 3; And in the time not using penetrating agent, drug osmotic amount is more inadequate, as comparative example 4.
Claims (7)
1. a buprenorphine transdermal drug delivery system, described system comprises:
(A) acrylic based binders compositions, its blend by following material forms: (i) acrylic compounds pressure sensitive adhesive and (ii) polyacrylic resin;
(B) penetrating agent, it is combined by glycerol triacetate, laurocapram and propylene glycol;
(C) active medicine, buprenorphine.
Wherein said acrylate pressure sensitive adhesive (i) is for containing (methyl) acrylamide or its N, (methyl) acrylate copolymer of N substituted monomer; Described polyacrylic resin (ii) is Eudragit class polyacrylic resin.
2. the transdermal drug delivery system of claim 1, wherein the shared weight ratio of each component is: component A accounts for 70%-95%, and i: ii=10-1; B component accounts for 1%-12%; Component C accounts for 4%-18%.
2. the transdermal drug delivery system of claim 1, wherein the shared weight ratio of each component is: component A accounts for 80%-90%, and i: ii=10-7; B component accounts for 4%-7%; Component C accounts for 6%-13%.
3. the transdermal drug delivery system of claim 1, by the weighing scale of all components, wherein comprises glycerol triacetate, the laurocapram of 0.1%-3% and the propylene glycol of 1%-5% of 0.5%-4%.
4. the transdermal drug delivery system of any one of claims 1 to 3, wherein said containing (methyl) acrylamide or its N, (methyl) acrylate copolymer of N substituted monomer forms by being selected from following monomer copolymerization: (methyl) acrylic acid, (methyl) acrylic acid C
1-10arrcostab, 2-EHA, vinyl acetate, α-methacrylic acid, acrylonitrile, Methacrylamide, acrylamide, isobutoxy Methacrylamide, methoxy acrylamide, diamino ethyl methacrylate, N-butoxymethyl acrylamide, dimethylaminoethyl methacrylic acid, diethyllaminoethyl methacrylate, diisopropyl acrylamide; And/or
Described Eudragit class polyacrylic resin is selected from
l100,
s100,
rL100,
rS100,
e100,
l100-55,
e PO,
rL PO,
rS PO and composition thereof.
5. the transdermal drug delivery system of claim 4, wherein said containing (methyl) acrylamide or its N, (methyl) acrylate copolymer of N substituted monomer, is formed by 1%-5% acrylamide, 30%-40% butyl acrylate, 35%-50% 2-EHA, 15%-25% vinyl acetate and the copolymerization of 0.5%-2% α-methacrylic acid.
6. the transdermal drug delivery system of claim 1-5, wherein said system comprises, and based on the weighing scale of all components, accounts for the acrylic compounds pressure sensitive adhesive of 70%-80%, accounts for 7%-9%'s
rS100 or
e100, accounts for the glycerol triacetate of 1%-4%, account for 0.5%-1% laurocapram, account for the propylene glycol of 1%-4% and account for the buprenorphine of 8%-12%.
7. the transdermal drug delivery system of claim 1, its structure is made up of backing layer, drug-reservoir layer and protective layer, does not comprise speed release-controlled film, it is characterized in that described drug-reservoir layer comprises the component described in claim 1 to 6 any one transdermal drug delivery system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210570734.4A CN103893154A (en) | 2012-12-26 | 2012-12-26 | Buprenorphine-containing transdermal delivery system |
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| CN201210570734.4A CN103893154A (en) | 2012-12-26 | 2012-12-26 | Buprenorphine-containing transdermal delivery system |
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| CN103893154A true CN103893154A (en) | 2014-07-02 |
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| CN201210570734.4A Pending CN103893154A (en) | 2012-12-26 | 2012-12-26 | Buprenorphine-containing transdermal delivery system |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113952319A (en) * | 2021-11-30 | 2022-01-21 | 烟台大学 | Skeleton type transdermal patch containing buprenorphine and preparation method thereof |
| CN114681457A (en) * | 2022-06-01 | 2022-07-01 | 济南广盛源生物科技有限公司 | Buprenorphine transdermal solution and preparation method and application thereof |
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| US5026556A (en) * | 1988-11-10 | 1991-06-25 | Norwich Eaton Pharmaceuticals, Inc. | Compositions for the transdermal delivery of pharmaceutical actives |
| CN1362879A (en) * | 2000-02-25 | 2002-08-07 | 帝人株式会社 | Patches containing buprenorphine hydrochloride |
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| CN101612141A (en) * | 2009-07-29 | 2009-12-30 | 考司美德制药株式会社 | Buprenorphine patch |
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2012
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| US5026556A (en) * | 1988-11-10 | 1991-06-25 | Norwich Eaton Pharmaceuticals, Inc. | Compositions for the transdermal delivery of pharmaceutical actives |
| CN1362879A (en) * | 2000-02-25 | 2002-08-07 | 帝人株式会社 | Patches containing buprenorphine hydrochloride |
| CN1640500A (en) * | 2004-01-13 | 2005-07-20 | 王树明 | Acrylic acid base adhesive composition, and its medicinal composition and transdermal treating system |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113952319A (en) * | 2021-11-30 | 2022-01-21 | 烟台大学 | Skeleton type transdermal patch containing buprenorphine and preparation method thereof |
| CN114681457A (en) * | 2022-06-01 | 2022-07-01 | 济南广盛源生物科技有限公司 | Buprenorphine transdermal solution and preparation method and application thereof |
| CN114681457B (en) * | 2022-06-01 | 2022-08-26 | 济南广盛源生物科技有限公司 | Buprenorphine transdermal solution and preparation method and application thereof |
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Address after: Zhongshan science and Technology Park, Zhongxin road along the Yangtze River Industrial Development Zone in Nanjing City, Jiangsu Province, No. 709 211500 Applicant after: Jiangsu Kang times pharmaceutical Limited by Share Ltd Address before: Zhongshan science and Technology Park, Zhongxin road along the Yangtze River Industrial Development Zone in Nanjing City, Jiangsu Province, No. 709 211500 Applicant before: JIANGSU KBD PHARMACEUTICAL CO., LTD. |
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Application publication date: 20140702 |