CN1148806A - 抗癫痫药物的透皮转运 - Google Patents
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Abstract
本发明公开了一种含有tiagabine或其可药用盐或酯的透皮转运系统,该转运系统可用于治疗癫痫。
Description
本发明涉及透皮药物的转运。更具体地说,本发明涉及抗癫痫药物的转运,特别是(但不局限于)本发明涉及N-(4,4-二(3-甲基噻吩-2-基)-丁-3-烯基)3-哌啶丁酸及其可药用衍生物以治疗有效速率的透皮转运。
癫痫是最常见的严重神经障碍,全世界的发病率类似。
由于癫痫的发作常见于儿童,并且抗癫痫药物通常需要长期服用,这可能会引起不良作用,因此选择适当的给药途径十分重要。
透皮转运药物的途径具有许多优点,例如非侵袭性药物转运,无首过效应,低剂量,以及对常规剂型(即片剂或胶囊)存在给药问题的患者具有良好的依从性。
因此透皮途径是长期治疗癫痫患者特别是治疗癫痫儿童的良好选择。转运各种药物或其它药剂的透皮系统在美国专利7,978,532和PCT申请WO91/09592中有描述。
USP5,010,090公开了N-(丁烯基取代的)氮杂环羧酸,其中的化合物可增强GABA的神经传导,因此所述化合物可用于治疗癫痫。
USP5,010,090中具体公开了N-(4,4-二(3-甲基噻吩-2-基)-丁-3-烯基)3-哌啶丁酸的盐酸盐。
C.Braestrup等在Int.Congr.Ser.-Exerpta Med.,1987,750(Pharmacology),125-8中公开了N-(4,4-二(3-甲基噻吩-2-基)-丁-3-烯基)3-哌啶丁酸盐酸盐的各种异构体。N-(4,4-二(3-甲基噻吩-2-基)-丁-3-烯基)3-哌啶丁酸的R-异构体在本发明中以其的普通名tiagabine使用。
已发现tiagabine可用于治疗癫痫。本发明涉及一种将tiagabine透皮给予癫痫患者特别是儿童癫痫患者的药物转运剂型,该剂型包括tiagabine及一种有效的渗透促进剂。
Silvestri & Cannon的一项研究(未发表)表明,由于缺乏渗透性使得转运tiagabine的透皮贴剂不可行。用Franz扩散池体系(Franz diffusion cellsystem)进行体外扩散实验来评价盐酸tiagabine在人尸体皮肤上的渗透性。选择pH值为6.4和10.4的缓冲液作为适当供体和受体液,在这些条件下所得到的结论为透皮贴剂每日转运大于10mg的tigabine是不可能的。
现在意外发现,将tiagabine混合到适用于透皮转运的基质中即可透皮施用治疗有效量的tiagabine,所述基质含有一种有效的渗透促进剂。
由于两性药物相当大的偶极矩及其低的脂溶解度使得它们很难通过完整皮肤吸收。两性药物不能制成非离子药物。在所有的pH值,至少存在一种离子基。人们不设想两性离子会达到适当的皮肤通量而使透皮给药为实际应用。
意外地,通过选择使用促进剂可以使tiagabine以可接受的量通过人体皮肤给药,尽管已知tiagabine是两性离子。
本领域的专业人员可选择已知的渗透促进剂,优选促进剂选自:a)饱和的或不饱和脂肪酸,优选C14-C22酸,更优选C18酸,特别是油酸或其酯的丙二醇溶液,B)具体的化合物如红没药醇(6-甲基-2-(4-甲基-3-环己-1-基)-5-庚烯-2-醇)的乙醇溶液,桉油醇(1,3,3-三甲基-2-氧二环[2.2.2]辛烷)的乙醇溶液,羟丙基-β-环糊精(HPCD)或癸基甲基亚砜(DMS)。
另外,通过选择tiagabine的可药用烷基酯或者tiagabiue和有机酸之间的离子对也可增强促进作用。
也可通过在tiagabine的氮原子和适当有机酸如油酸或水杨酸之间形成离子对而达到本发明的渗透促进作用。
另外,tiagabine的C1-6烷基酯具有良好的渗透性。更具体地说,tiagabine的乙基酯可促进渗透。
本发明的透皮转运系统包括有效量的tiagabine,它的盐,离子对或酯。
特别地,本发明包括以下盐及其水合物:乙酸盐、苯甲酸盐、富马酸盐、磷酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、乳酸盐、水杨酸盐、硫酸盐、酒石酸盐、琥珀酸盐和盐酸盐。
由于避开了首过肝脏代谢, 药物可以较低的每日剂量经人体皮肤膜转运到体循环中(Todd P.A.& Goa K.L.,Drugs 40(4):第583-607页(1990))。这是适宜的,因为低剂量形式可避免一些高剂量口服治疗的副作用。
tiagabine的日剂量为每公斤体重0.1-10mg,优选每公斤体重0.3-2mg。
术语“有效量”应理解为其可足以达到所需效果,也就是说,可治疗癫痫。就此而言,透皮转运系统每日可转运约0.01mg至约10mg(每公斤体重)的tiagabine或其盐或酯。优选贴剂实例的详述
本发明优选的实例为微密封的透皮tiagabine贴剂,其具有一个不影响tiagabine吸收和转运的衬背和粘贴于此的硅氧烷聚合物基质,该硅氧烷聚合物基质是具有约10至200微米微密封室的交联硅橡胶,微密封室是在硅橡胶与含有tiagabine的亲水性溶剂系统和可促进tiagabine转运和扩散的疏水性溶剂系统混合后交联形成的,当微密封的tiagabine贴粘贴到皮肤上时,tiagabine即以治疗有效的恒定速率通过生物可接受的硅氧烷聚合物基质扩散,所述亲水性溶剂不能通过生物可接受的聚合物基质扩散。
本发明最优选的实例是含有生物可接受的硅氧烷聚合物基质的微密封透皮tiagabine转运体系,其中生物上可接受的硅氧烷聚合物基质具有遍布体系的微密封室,所述微密封室含有10%重量百分比的tiagabine的6-22%(重量百分比),其与乳糖混合在含有促进剂混合物的亲水性溶剂系统中,另外含有5至15重量百分比的疏水性溶剂,该溶剂选自矿物油以及从椰子油中获得的油或者它们的混合物。代表性的椰子油衍生物包括棕榈酸异丙酯和miglyol油。微密封室是通过硅氧烷聚合物与含有tiagobine及促进剂混合物的亲水性溶剂系统乳化后交联形成的。
一般而言,欲制备本发明的透皮tiagabine贴剂,应在适当亲水性促进剂混合物中制备含有10%tiagabine-乳糖混合物的饱和溶液。在该制剂中应保持tiagabine-乳糖混合物过量以使人工或机械混合约5至10分钟后得到均匀糊剂。将此均匀糊剂与所需量的疏水性溶剂或类似的溶剂混合物如矿物油、棕榈酸异丙酯或其混合物加到硅氧烷弹性体-MDX 4-4210弹性体(Dow Corning,Midland,Mich.)中。在真空下低剪切防爆混合罐中将所有组分混合5至15分钟。加入聚合催化剂,继续在深刻性混合15至30分钟。最后的混合物为粘性,借助混合装置将其倒入洁净干燥的不锈钢板中。对于2×4cm贴剂而言,应将适当量的最后混合物倒入12”×12”的不锈钢板中,该板装有5.0mm至1.2mm所需厚度的边框。将适当材料如铝箔放在倾倒物上,随聚合物的形成而将没有边框且与下板当直径的上板挤压填充到模型中。在四个角上用螺丝钉将模型固定,将其置于60℃空气循环的烘箱中。2小时后,取出模型,冷却,将粘附在铝箔上的熟化后药贴材料剥离,切成适当大小的药贴,例如2×4cm(带铝箔衬背)。然后将药贴贮存在密闭容器中。
以下详细描述本发明。实施例1
不同类型有效渗透促进剂对tiagabine的作用如下所述:渗透步骤
使用Franz玻璃扩散池(Franz,T.J.:Curr.Probl.Dermatol.,1978:7;58-68)。
在白种人腹部或胸部皮肤上进行实验,该皮肤从外科手术后获得并在-20℃保存不超过3个月。解冻后,用剃刀剥去皮肤样品上的脂肪组织,得到表皮和真皮厚度约2mm的皮肤膜。
将人皮肤膜放入磨砂面的玻璃室中(扩散面积1.77平方厘米)。用夹子连接玻璃室。为确保角质层膜完整,将pH值为7.4的每毫升0.05M的磷酸盐缓冲液置于皮肤的表皮面,同时使皮肤的下部分与相同介质接触。
当在32℃使皮肤平衡1小时后,用Lutron DM 6023电容仪测量电容。低于0.150μF的值表明角质层是完整的。当进行电容实验后,去除供体室和受体室的磷酸盐缓冲液。将皮肤的表皮面暴露在实验室环境条件下,而使皮肤的下部分与受体介质(含有0.05M磷酸盐缓冲液,pH 7.4,0.05mg/ml硫酸庆大霉素,32℃)接触。在使用供体相前,将受体介质与皮肤平衡1小时。
供体相由tiagabine的介质(含有不同渗透促进剂,参见表1)悬浮液组成。欲制备供体相,将tiagabine加到含有促进剂的溶液中,于室温搅拌72小时后,溶液被tiagabine饱和。将500μl供体相置于皮肤表皮面,闭合下进行实验。通过0.22μm的Milipore滤器过滤后,用HPLC测定供体相中tiagabine的浓度。
为了研究,如果通过使用HPLC方法使皮肤的某些物质出现在色谱上。则将不含tiagabine的溶液置于渗透池的皮肤表皮面。
为了评价不同妇女皮肤之间tiagabine渗透性的差异,将含有tiagabine饱和水溶液的标准溶液用作每个妇女皮肤的供体相。
在适当间隔,从受体相取出样品并用新鲜的受体溶液代替以保持下沉状态。用HPLC测定受体溶液中的tiagabine含量。结果
代表tiagabine渗透率的通量(J)如下所示:(见:Scheuplein,R.J.&Blank,I.H.:Physiol.Rev.1971:51;702-747) 其中dq/dt是渗透的稳态速率或者受体溶液中出现的溶质(μg/小时),A是暴露皮肤的面积(1.77平方厘米)。从等式1及dq/dt图线性部分的斜率计算通量。
平行测定通量J计算平均值和标准偏差。
体外数据表明,通过透皮贴转运的预计剂量优选为5-100平方厘米大小,更优选大小为30平方厘米。
每日转运剂量=J.A
J=通量(μg.cm-22.4小时-1)
A=贴剂面积(30cm2)下表为所得结果:
表1
扩散池测量结果
x:平均值s.d.:标准偏差n.p.:无渗透作用*:含有tiagabine饱和水溶液的标准溶液**:从30cm2贴剂转运的药量。实施例2含有油酸(E)的tiagabine贴剂
皮肤样品 | 制剂,tiagabine和促进剂 | 供体相中的tiagabine浓度mg/ml | tigabine的通量(J)μg.cm-2.24小时-1x±s.d. | **每日转运的毫克量 |
A | 磷酸盐缓冲液pH=7.5标准* | 325 | 7.4±3.215.5±8.5 | 0.220.47 |
B | 甘油标准* | 5125 | n.p.73.2±17.4 | 02.20 |
C | 丙二醇标准* | 14725 | n.p.39.5±13.2 | 00.19 |
D | 聚乙二醇400标准* | 12025 | n.p.5.6±0.44 | 00.17 |
E | 10%油酸的丙二醇溶液10%油酸乙酯的丙二醇溶液标准* | 15317927 | 224±6758.0±22.440.2±22.1 | 6.721.741.21 |
皮肤样品 | 制剂,tiagabine和促进剂 | 供体相中的tiagabine浓度mg/ml | tigabine的通量(J)μg.cm-2.24小时-1x±s.d. | **每日转运的毫克量 |
F | 10%红没药醇的乙醇/水(66/33v/v)溶液10%桉油醇的乙醇/水(66/33v/v)溶液乙醇/水(66/33v/v) | 330306296 | 227±32.840.1±11.38.2±2.2 | 6.811.200.25 |
G | 10%癸基甲基亚砜的乙醇/水 | 364 | 71.5±21.8 | 2.15 |
(33/66v/v)溶液10%HPCD的乙醇/水(33/66v/v)溶液乙醇/水(33/66v/v) | 243300 | 5.4±1.17.2±1.5 | 0.160.22 |
将10%tiagabine-乳糖混合物(55克)与25.0克10%(体积/体积)油酸的丙二醇溶液混合5分钟。将上述混合物的均匀糊剂加到157.5克MDX 4-4210弹性体(Dow Corning,Midland,Mich.)中。在最初脱气下混合约10分钟后,与低剪切混合器中得到均匀分散体。在该分散体中加入12.5克MDX4-4210弹性体熟化剂,继续搅拌15分钟。将最后的混合物倒入5cm边框的12”×12”不锈钢板上以支持熟化剂。将铝箔(12”×12”)放到每个板上并将其与12”×12”的不锈钢板压到模型中。用螺丝钉将模型固定在四个角上,置于约60℃的空气循环烘箱中约2小时。冷却后,将附着在铝箔衬背上的聚合物基质从模型中除去,切成1.6×3.2cm的药贴,使用前贮存在密闭容器中。实施例3含有红没药醇的tiagabine贴剂
将10%tiagabine-乳糖混合物(55克)与25.0克10%红没药醇的乙醇/水(66/33%,体积/体积)溶液混合约5分钟。将上述混合物的均匀糊剂加到157.5克MDX 4-4210弹性体(Dow Corning,Midland,Mich.)中。在最初脱气下混合约10分钟后,与低剪切混合器中得到均匀分散体。在该分散体中加入12.5克MDX 4-4210弹性体熟化剂,继续搅拌15分钟。将最后的混合物倒入5cm边框的12”×12”不锈钢板上以支持熟化剂。将铝箔(12”×12”)放到每个板上并将其与12”×12”的不锈钢板压到模型中。用螺丝钉将模型固定在四个角上,置于约60℃的空气循环烘箱中约2小时。冷却后,将附着在铝箔衬背上的聚合物基质从模型中除去,切成1.6×3.2cm的药贴,使用前贮存在密闭容器中。实施例4含有癸基甲基亚砜的tiagabine贴剂
将10%tiagabine-乳糖混合物(55克)与25.0克10%癸基甲基亚砜的乙醇/水(33/66%,体积/体积)溶液混合约5分钟。将上述混合物的均匀糊剂加到157.5克MDX 4-4210弹性体(Dow Corning,Midland,Mich.)中。在最初脱气下混合约10分钟后,与低剪切混合器中得到均匀分散体。在该分散体中加入12.5克MDX 4-4210弹性体熟化剂,继续搅拌15分钟。将最后的混合物倒入5cm边框的12”×12”不锈钢板上以支持熟化剂。将铝箔(12”×12”)放到每个板上并将其与12”×12”的不锈钢板压到模型中。用螺丝钉将模型固定在四个角上,置于约60℃的空气循环烘箱中约2小时。冷却后,将附着在铝箔衬背上的聚合物基质从模型中除去,切成1.6×3.2cm的药贴,使用前贮存在密闭容器中。
Claims (11)
1.一种透皮转运系统,含有一种或多种渗透促进剂和一种化合物,该化合物选自tiagabine、其可药用盐、可药用C1-6烷基酯或tiagabine和水杨酸或油酸的离子对。
2.权利要求1的转运系统,其中的可药用盐是乙酸盐、苯甲酸盐、富马酸盐、磷酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、乳酸盐、水杨酸盐、硫酸盐、酒石酸盐、琥珀酸盐和盐酸盐以及其水合物。
3.权利要求1-2的转运系统,其中的渗透促进剂选自含有饱和及不饱和脂肪酸及其酯的丙二醇溶液,红没药醇的乙醇/水溶液,桉油醇的乙醇/水溶液,羟丙基-β-环糊精的乙醇/水溶液或癸基甲基亚砜的乙醇/水溶液。
4.权利要求1-3的转运系统,其中所述化合物以每日每公斤体重约0.01毫克至约10毫克的量转运。
5.权利要求1的转运系统,其中的渗透促进剂和化合物分散在基质中。
6.权利要求3的转运系统,其中的渗透促进剂是油酸的丙二醇溶液。
7.权利要求3的转运系统,其中的渗透促进剂是红没药醇的乙醇/水溶液。
8.权利要求3的转运系统,其中的渗透促进剂是癸基甲基亚砜的乙醇/水溶液。
9.一种促进选自tiagabine及其可药用盐和酯的化合物透过人或非人类皮肤及膜的方法,包括使用选自含有饱和及不饱和脂肪酸及其酯的丙二醇溶液,红没药醇的乙醇/水溶液,桉油醇的乙醇/水溶液,羟丙基-β-环糊精的乙醇/水溶液或癸基甲基亚砜的乙醇/水溶液的渗透促进剂。
10.一种治疗癫痫的方法,包括透皮给予有效量的选自tiagabine及其可药用盐和酯的化合物。
11.权利要求9的方法,其中所述化合物以每日每公斤体重约0.01毫克至约10毫克的量转运。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DK0577/94 | 1994-05-20 | ||
DK57794 | 1994-05-20 |
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CN1148806A true CN1148806A (zh) | 1997-04-30 |
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CN95193165A Pending CN1148806A (zh) | 1994-05-20 | 1995-05-17 | 抗癫痫药物的透皮转运 |
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US (1) | US5750140A (zh) |
EP (1) | EP0760656A1 (zh) |
JP (1) | JPH10500415A (zh) |
KR (1) | KR970703146A (zh) |
CN (1) | CN1148806A (zh) |
AU (1) | AU698131B2 (zh) |
BR (1) | BR9507736A (zh) |
CA (1) | CA2190837C (zh) |
CZ (1) | CZ338196A3 (zh) |
FI (1) | FI964619A (zh) |
HU (1) | HUT75864A (zh) |
IL (1) | IL113793A (zh) |
NO (1) | NO964915D0 (zh) |
NZ (1) | NZ287012A (zh) |
PE (1) | PE2596A1 (zh) |
RU (1) | RU2152784C1 (zh) |
SK (1) | SK281076B6 (zh) |
TW (1) | TW372875B (zh) |
WO (1) | WO1995031976A1 (zh) |
ZA (1) | ZA954118B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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US5914333A (en) * | 1996-07-31 | 1999-06-22 | Novo Nordisk A/S | Treatment of psychotic disorders |
US6316010B2 (en) | 1997-06-12 | 2001-11-13 | The Procter & Gamble Company | Cosmetic compositions |
GB9712271D0 (en) * | 1997-06-12 | 1997-08-13 | Procter & Gamble | Cosmetic composition |
GB9712269D0 (en) * | 1997-06-12 | 1997-08-13 | Procter & Gamble | Cosmetic composition |
US6537537B2 (en) | 1997-06-12 | 2003-03-25 | The Procter & Gamble Company | Water-in-silicone emulsion cosmetic compositions |
GB9712272D0 (en) * | 1997-06-12 | 1997-08-13 | Procter & Gamble | Cosmetic composition |
IE970588A1 (en) | 1997-08-01 | 2000-08-23 | Elan Corp Plc | Controlled release pharmaceutical compositions containing tiagabine |
WO1999006045A1 (en) * | 1997-08-01 | 1999-02-11 | Elan Corporation, Plc | Controlled release pharmaceutical compositions containing tiagabine |
FR2771292B1 (fr) * | 1997-11-21 | 2000-02-18 | Ethypharm Lab Prod Ethiques | Spheroides contenant de la tiagabine, procede de preparation et compositions pharmaceutiques |
WO2003080072A1 (en) * | 2002-03-18 | 2003-10-02 | Cady Roger K | Preemptive prophylaxis of migraine |
KR102665710B1 (ko) | 2017-08-24 | 2024-05-14 | 노보 노르디스크 에이/에스 | Glp-1 조성물 및 그 용도 |
US20230082544A1 (en) | 2020-02-18 | 2023-03-16 | Novo Nordisk A/S | Pharmaceutical formulations |
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GB2105990B (en) * | 1981-08-27 | 1985-06-19 | Nitto Electric Ind Co | Adhesive skin patches |
SE8904296D0 (sv) * | 1989-12-21 | 1989-12-21 | Pharmacia Ab | Transdermal system |
DK58291D0 (da) * | 1991-04-02 | 1991-04-02 | Novo Nordisk As | Krystalinsk stof og dets fremstilling |
-
1995
- 1995-05-12 US US08/440,155 patent/US5750140A/en not_active Expired - Lifetime
- 1995-05-17 EP EP95919972A patent/EP0760656A1/en active Pending
- 1995-05-17 RU RU96124084/14A patent/RU2152784C1/ru active
- 1995-05-17 CA CA002190837A patent/CA2190837C/en not_active Expired - Fee Related
- 1995-05-17 CN CN95193165A patent/CN1148806A/zh active Pending
- 1995-05-17 WO PCT/DK1995/000194 patent/WO1995031976A1/en not_active Application Discontinuation
- 1995-05-17 HU HU9603206A patent/HUT75864A/hu unknown
- 1995-05-17 CZ CZ963381A patent/CZ338196A3/cs unknown
- 1995-05-17 BR BR9507736A patent/BR9507736A/pt not_active IP Right Cessation
- 1995-05-17 SK SK1482-96A patent/SK281076B6/sk unknown
- 1995-05-17 JP JP7529988A patent/JPH10500415A/ja active Pending
- 1995-05-17 NZ NZ287012A patent/NZ287012A/en unknown
- 1995-05-17 AU AU25599/95A patent/AU698131B2/en not_active Ceased
- 1995-05-19 ZA ZA954118A patent/ZA954118B/xx unknown
- 1995-05-19 IL IL11379395A patent/IL113793A/xx not_active IP Right Cessation
- 1995-05-19 PE PE1995269113A patent/PE2596A1/es not_active Application Discontinuation
- 1995-05-26 TW TW084105009A patent/TW372875B/zh active
-
1996
- 1996-11-19 FI FI964619A patent/FI964619A/fi unknown
- 1996-11-19 NO NO964915A patent/NO964915D0/no not_active Application Discontinuation
- 1996-11-20 KR KR1019960706589A patent/KR970703146A/ko not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
WO1995031976A1 (en) | 1995-11-30 |
JPH10500415A (ja) | 1998-01-13 |
NZ287012A (en) | 1998-09-24 |
NO964915L (no) | 1996-11-19 |
CA2190837A1 (en) | 1995-11-30 |
IL113793A0 (en) | 1995-08-31 |
ZA954118B (en) | 1996-11-19 |
SK148296A3 (en) | 1997-06-04 |
PE2596A1 (es) | 1996-02-12 |
HU9603206D0 (en) | 1997-01-28 |
TW372875B (en) | 1999-11-01 |
KR970703146A (ko) | 1997-07-03 |
HUT75864A (en) | 1997-05-28 |
IL113793A (en) | 1999-12-31 |
NO964915D0 (no) | 1996-11-19 |
SK281076B6 (sk) | 2000-11-07 |
BR9507736A (pt) | 1997-08-19 |
CZ338196A3 (en) | 1997-06-11 |
EP0760656A1 (en) | 1997-03-12 |
US5750140A (en) | 1998-05-12 |
FI964619A0 (fi) | 1996-11-19 |
CA2190837C (en) | 2005-08-02 |
RU2152784C1 (ru) | 2000-07-20 |
FI964619A (fi) | 1996-11-19 |
AU698131B2 (en) | 1998-10-22 |
AU2559995A (en) | 1995-12-18 |
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