CN103384533A - 双氯芬酸二乙铵的改进透皮渗透的药用贴剂 - Google Patents
双氯芬酸二乙铵的改进透皮渗透的药用贴剂 Download PDFInfo
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- CN103384533A CN103384533A CN201080071026.5A CN201080071026A CN103384533A CN 103384533 A CN103384533 A CN 103384533A CN 201080071026 A CN201080071026 A CN 201080071026A CN 103384533 A CN103384533 A CN 103384533A
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- Prior art keywords
- diclofenac
- preparation
- diethyl ammonium
- medical patch
- citrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
Abstract
一种组合物中的双氯芬酸二乙铵的改进透皮渗透的药用贴剂,所述组合物包含丙烯酸类共聚物和柠檬酸酯。
Description
本发明涉及一种双氯芬酸二乙铵的改进透皮渗透的药用贴剂。
已知有很多双氯芬酸盐,其中双氯芬酸二乙铵已经显示出特定的药理学利益,然而,其具有低的皮肤渗透。
本发明的目的在于提供一种药用贴剂,其促进双氯芬酸二乙铵的透皮渗透。
此目的通过将所述双氯芬酸二乙铵盐分散于在可应用于人体皮肤的柔性支持物上涂布的聚合物基质中而实现。
特别地,所述聚合物基质由包含39%至55%的丙烯酸类聚合物、4%至12%的双氯芬酸二乙铵以及42%至55%的柠檬酸酯的组合物组成,所述百分比由重量相对于所述组合物的总重量计算。
优选地,所述柠檬酸酯是柠檬酸三丁酯,所述聚合物基质是由在水性分散体中的具有平均分子量为800000的丙烯酸乙酯和甲基丙烯酸甲酯共聚物组成。
已证实上述组合物能非常有效地促进双氯芬酸二乙铵的透皮渗透。
通过下面给出的非限制性实施例将更好地理解本发明的药用贴剂。
实施例1
用于分散在含有柠檬酸三丁酯的组合物中的双氯芬酸二乙铵透皮渗透的药用贴剂(制剂1)
将27.5g柠檬酸三丁酯、3.5g双氯芬酸二乙铵和69g平均分子量为800000的丙烯酸乙酯/甲基丙烯酸甲酯共聚物的水性分散体在室温下依次逐渐倒入混合器中(搅动2小时)。
这种类型的水性分散体是已知的,其名称为EudragitRNE40。该EudragitRNE40是浓度为40wt%的水性聚合物分散体。
使产生的水性聚合物系统静置,以使得空气被完全除去。
用刮刀(通过基质涂布机器模型LTE-S)将用这种方式得到的组合物涂布在硅胶覆盖的保护片上,在60℃的温度下干燥15分钟的时间,然后结合到由无纺布或纬丝和经编织物(warp fabric)形成的柔性支持物上。
刮刀与保护片之间的距离使得获得包含1mg/cm2的双氯芬酸的药用贴剂。
在操作的最后,将获得的药用贴剂剪切,并保藏在密封容器中。
体外渗透法
用于透皮渗透研究的皮肤获自经历美容外科手术患者的腹部。在切除后24小时内,将收集的全部皮肤密封在塑料真空袋中,并冷却至-20℃。在制备之前,使皮肤恢复至室温,并小心地去除多余的脂肪。
将皮肤部分切成正方形,接着将皮肤在60℃水中浸泡1分钟后,用镊子从剩余的组织中小心地将人表皮部分分离出来。在实验使用之前,对样品进行仔细检查,以验明是否存在损伤;所述操作是在将样品置于Franz扩散细胞上之前进行,其中角膜层朝上与贴剂样品相接触。Franz细胞的顶部和底部用ParafilmR密封,并借助于夹子固定。
这些垂直面细胞具有大约5ml/0.636cm2的扩散度。对每个细胞的接收体积单个进行大小、测定。用含有100μg/mlNaN3作为防腐剂的新鲜脱气的0.9%NaCl溶液充填接收室。
需要特别留意防止接收室内的0.9%NaCl溶液和表皮之间出现气泡。整个实验期间,用循环水浴将包含缓冲液的Franz细胞维持在37℃,这样表皮表面的温度是32±1℃。只有接收室与37℃下循环的水相接触,每个Franz细胞都配有磁力搅拌器。在预设的时间点(1、2、6、8、24小时)时,从接收室取出0.2ml样品。通过HPLC对取出的样品直接进行分析,以确定已经渗透通过表皮的组分的浓度。用渗透通过皮肤的药物总量相对于时间的函数来计算渗透数据。所有数值确定为三次重复实验的平均值。
通过HPLC分析(HP1100,Chemstation,Hewlett Packard)来确定双氯芬酸的浓度。在室温下将20ml样品注射进反相柱C18中(C18Nova-Pak,4.6-150mm;Waters Spa,米兰,意大利)。洗脱组合物是乙腈/水/醋酸(50/46/4v/v)。流量为1.5ml/分钟。波长设定为254nm。通过双氯芬钠标准曲线(0.3-20μg/ml)来确定药物浓度。
结果
24小时后,已经渗透的双氯芬酸量为14.1±1.8μg/cm2,稳流为每小时0.8±0.0μg/cm2。
实施例2
用于分散在含有癸二酸二丁酯的组合物中的双氯芬酸二乙铵透皮渗透的药用贴剂(制剂2)
与实施例1中所描述的不同,将27.5g癸二酸二丁酯、3.5g双氯芬酸二乙铵、69g平均分子量为800000的丙烯酸乙酯/甲基丙烯酸甲酯共聚物的水性分散体在室温下依次逐渐倒入混合器中(搅动2小时)。
制备中所涉及到的操作以及后续的分析与实施例1中所描述的那些相同。
结果
24小时后,已经渗透的双氯芬酸的量为1.0±0.6μg/cm2,稳流为每小时0.1±0.1μg/cm2。
实施例3
用于分散在含有三醋汀的组合物中的双氯芬酸二乙铵的透皮渗透的药用贴剂(制剂3)
与实施例1中所描述的不同,将27.5g三醋汀、3.5g双氯芬酸二乙铵、69g平均分子量为800000的丙烯酸乙酯/甲基丙烯酸甲酯共聚物的水性分散体在室温下依次逐渐倒入混合器中(搅动2小时)。
制备中所涉及到的操作以及后续的分析与实施例1中所描述的那些相同。
结果
24小时后,已经渗透的双氯芬酸的量为1.9±0.3μg/cm2,稳流为每小时0.1±0.0μg/cm2。
实施例4
用于分散在含有柠檬酸三丁酯的组合物中的双氯芬酸二乙铵的透皮渗透的药用贴剂(制剂4、5和6)
与实施例1中所描述的不同,将34g柠檬酸三丁酯、3.7g双氯芬酸二乙铵和62.3g丙烯酸乙酯/甲基丙烯酸甲酯共聚物的水性分散体(制剂4),24g柠檬酸三丁酯、3.5g双氯芬酸二乙铵和72.5g丙烯酸乙酯/甲基丙烯酸甲酯共聚物的水性分散体(制剂5),27.1g柠檬酸三丁酯、4.9g双氯芬酸二乙铵和68g丙烯酸乙酯/甲基丙烯酸甲酯共聚物的水性分散体(制剂6)在室温下依次逐渐倒入混合器中(搅动2小时)。
所述水性分散体的平均分子量为800000。
制备中所涉及到的操作以及后续的分析与实施例1中所描述的那些相同。
双氯芬酸盐溶解于柠檬酸三丁酯中。
结果
24小时后,制剂4中已经渗透的双氯芬酸的量为15.8±2.3μg/cm2,制剂5中为13.1±3.3μg/cm2,制剂6中为17.1±1.7μg/cm2。稳流由图表线性部分的斜率来确定,制剂4中为每小时0.9±0.1μg/cm2,制剂5中为每小时0.7±0.2μg/cm2,制剂6中为每小时1.1±0.3μg/cm2.
最后结论
由使用源自一个和相同供体的表皮的实施例1、2和3所得到的结果显示,与三醋汀(制剂3)和癸二酸二丁酯(制剂2)相比,柠檬酸三丁酯(制剂1)能够改进双氯芬酸盐渗透通过皮肤。
从统计学上看,在实施例4中,不同的柠檬酸三丁酯的量并没有显著降低(制剂5)或增加(制剂4)已渗透双氯芬酸的量;通过增加聚合物系统中的药物浓度(制剂6)能够达到相同的结果。
Claims (3)
1.一种双氯芬酸二乙铵的改进透皮渗透的药用贴剂,其由表面涂布有组合物的柔性支持物组成,所述组合物包含聚合物层,该聚合物层有至少一种双氯芬酸盐分散在其内部,其特征在于所述组合物包含39%至55%的丙烯酸类聚合物、4%至12%的双氯芬酸二乙铵以及42%至55%的柠檬酸酯,所述百分比通过重量相对于所述组合物的总重量计算。
2.如权利要求1所述的药用贴剂,其特征在于所述柠檬酸酯是柠檬酸三丁酯。
3.如权利要求1和2所述的药用贴剂,其特征在于所述丙烯酸类聚合物是在水性分散体中的具有平均分子量为800000的丙烯酸乙酯和甲基丙烯酸甲酯共聚物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/EP2010/070882 WO2012089256A1 (en) | 2010-12-29 | 2010-12-29 | Medicated patch for improved transdermal permeation of diclofenac diethylammonium |
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CN103384533A true CN103384533A (zh) | 2013-11-06 |
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CN201080071026.5A Pending CN103384533A (zh) | 2010-12-29 | 2010-12-29 | 双氯芬酸二乙铵的改进透皮渗透的药用贴剂 |
Country Status (5)
Country | Link |
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EP (1) | EP2658576A1 (zh) |
CN (1) | CN103384533A (zh) |
BR (1) | BR112013016998A2 (zh) |
EA (1) | EA201390980A1 (zh) |
WO (1) | WO2012089256A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3474831A1 (en) | 2016-06-23 | 2019-05-01 | Corium International, Inc. | Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent |
KR20230109782A (ko) | 2016-07-27 | 2023-07-20 | 코리움, 엘엘씨 | 아민 약물의 나트륨 바이카보네이트 제자리 전환 구동된경피성 전달 |
US11173132B2 (en) | 2017-12-20 | 2021-11-16 | Corium, Inc. | Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point |
IT202000011686A1 (it) * | 2020-05-20 | 2021-11-20 | Fidia Farm Spa | Cerotto medicato a lento rilascio |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS61280426A (ja) * | 1985-06-04 | 1986-12-11 | Ikeda Mohandou:Kk | 消炎鎮痛用貼付剤 |
KR19990026792A (ko) * | 1997-09-26 | 1999-04-15 | 김윤 | 디클로페낙 디에틸암모늄염을 함유한 매트릭스형 패취제제 |
DE19812413C1 (de) * | 1998-03-20 | 1999-06-10 | Sanol Arznei Schwarz Gmbh | Transdermales Therapeutisches System (TTS) Oxybutynin enthaltend |
-
2010
- 2010-12-29 EP EP10798143.3A patent/EP2658576A1/en not_active Withdrawn
- 2010-12-29 EA EA201390980A patent/EA201390980A1/ru unknown
- 2010-12-29 CN CN201080071026.5A patent/CN103384533A/zh active Pending
- 2010-12-29 BR BR112013016998A patent/BR112013016998A2/pt not_active IP Right Cessation
- 2010-12-29 WO PCT/EP2010/070882 patent/WO2012089256A1/en active Application Filing
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Publication number | Publication date |
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WO2012089256A1 (en) | 2012-07-05 |
EP2658576A1 (en) | 2013-11-06 |
BR112013016998A2 (pt) | 2016-10-25 |
EA201390980A1 (ru) | 2013-11-29 |
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