α-细辛醚经皮给药贴剂的研究
摘要
α-细辛醚(2，4，5-三甲氧基-1-丙烯基苯，又名α-细辛脑，α-Asaronum)，分子量为208，难溶于水，溶于乙醇、乙醚、冰醋酸、氯仿和石油醚等有机溶剂。无论是胶囊还是片剂，α-细辛醚的生物利用都是很低的，据文献报道，α-细辛醚胶囊和片剂的绝对生物利用度为2.75%～5%，因此，基于透皮给药的优点，根据药物的性质，以及临床应用的需求，我们对α-细辛醚贴剂进行研究。经皮给药系统在研究中遇到的主要困难之一是由于皮肤的屏障作用，药物的经皮渗透速率往往不能满足治疗的需要，选择适宜的透皮促进剂以增加经皮渗透是目前研究最多、应用最广泛的方法。
本课题研究了α-细辛醚透皮吸收促进剂，对α-细辛醚贴剂基质的进行筛选，并制备了α-细辛醚的贴剂，成品通过体外试验、动物体内相对生物利用度的研究，证明了α-细辛醚贴剂透皮吸收的可行性。
研究结果表明，角质层是药物渗透过程中的主要屏障，透皮吸收促进剂Azone和丙二醇可促进α-细辛醚的透皮吸收，促进的效果随丙二醇的浓度而变化，10％的丙二醇对α-细辛醚有良好的促进作用。乙醇能增加α-细辛醚的溶解度，由于溶解度增加，α-细辛醚的透皮速率增加。实验结果表明，Q与t呈线性关系，符合浓度为渗透动力学的Fick’s扩散方程，直线的斜率为稳态透皮速率，与不含Azone的α-细辛醚溶液相比，含5％Azone和5％乙醇的α-细辛醚饱和溶液在39h内的累积透皮量增加了18.2倍，稳态透皮速率由3.3μg/cm~2*h提高到60.1μg/cm~2*h，提高了18.2倍，具有明显的促透作用。氮酮、乙醇和丙二醇合用作为混合促进剂，有利于α-细辛醚在凝胶基质中的透皮吸收。
本实验选用卡巴泊、PVA124、PVA17-88、CMC-Na、西黄蓍胶、HPMC等为凝胶基质原料，以外观和透皮速率为指标，对α-细辛醚基质的组成比例进行考察和筛选。综合考虑基质外观和成型性，
包括保湿、涂展、硬度、粘性等闪素，结合a－细辛醚在基质中的
透皮速率，对a－细辛醚基质的组成比例进行考察筛选，经处方筛
选和厂艺改进，找山粘性适度，凤有良好的涂展性和保湿性，有牧
人的透皮速率的基质。
在本实验中，1比不但外观好，而仕有较好的透皮速率。本制
剂为凝胶骨架控秆，促进剂要冗从基质中缓慢扩散至皮肤表面，然
后与角质层发生作川。分别用。－细辛醚饱和溶液和RS基质，饺用
人鼠、家兔、人皮在Fr。nz扩散池上做体外透皮试验，结果表明，
皮肤米源不同，对。－细辛醚透皮速率不同，人鼠对。－细辛醚的透
皮速率大于家兔和人皮。基质中Q－细辛醚的含量增加，透皮速增
加。但两者之间不呈线性关系。本贴剂是以水溶性高分于化合物或
亲水性物质为主要成分的基质，具有药物容量高。透皮性、贴敷性
、保湿性好、贴着舒适、不污染衣物等忧点。
由于Q一细辛醚是脂溶性很强的药物，水溶性差可能是其口服
制剂生物利用度低的重要原因，而a一细辛醚贴剂能较好地解决这
一问题。实验结果表明a一细辛醚贴剂的生物利用度明显高于胶囊
剂，凝胶贴剂与胶囊剂相对生物利用度为 11 67石％。可见 a一细
辛醚贴剂这一剂型对a一细辛醚的吸收和利用都是较为有的。
贴剂性能考察结果表明，a－细辛醚凝胶贴剂的含量及均匀度符
合中国药典要求并且稳定性良好，皮肤刺激性试验表明a－细辛醚贴
剂除对个别家兔和人有轻微刺檄性外，多数无刺激性。8只家兔和8
位受试者的平均分均小于0石，因此，a－细辛醚凝胶贴剂安全可靠，
无刺激性，可以用于人体。
a -Asaronum (molecular weight 208) is insoluble in water but is soluble in ethanol,ether,glacial acetic acid, chloroform and petroleum ether.As reported,the poor absolute bioavailabi1ity of a-Asaronum was obtained , 2.75% for capsule and 5% for tablet. So,consideringing the character of drug and clinic application , we prepared the a -Asaronum patch.One of the most difficulty in transdermal delivery system is the barrier of the skin which holds back the penetration of drugs to meet with the therapy.The most available method is to select proper promoters. In order to devel op a-Asaronum patch,we have studied proper accelerators and matrix in this thesis.
Firstly,we study the comparetive bioavailability in vivo to prove the feasibility of a -Asaronum patch. The results revealed that the main barrier in penetration of a-Asaronum is tratacorneum.
Azone and propanediol can accelerate the permeation of a -Asaronum. And the effect of promotion depended on the concentration of propanediol.Ten percent of propanediol exhibited the good effect of penetration promotion. Furthermore,alcohol can increase the solubility of a -Asaronum in skin which is helpful to increase the permeation rate.It is abserved that the permeation was accordent to Pick1 s diffuse equation for the linear relation between Q and t.The slope of the line is the permeation rate in stable state.
As a good accelerator,Azone can increase the permeation rate of a-Asaronum.Compared with the controlled group,the accumulativea-Asaronum permeation from the a -Asaronum solution with Azone is 18.2 times 1arger,stable
permeation rate of 60.1ug/ml is 18.2 times higher . The permeation is accelarated obviously.
Gel matrix is made of water-soluble high polyme or hydro-philic compounds.It can hold more drugs and has good permeation rate,In this study,we select carbapol,PVA124,PVA17-88,CMC-Na,gum tragacanth,HPMC as the raw material of the gel matrix and mix some of them in the proper proportion of material according to its outward appearance,fi gurat i on and permeation rate.
Consequently R5 is chosen as the proper patch which belongs to controled-release gel matrix dosage. The accelerator diffuses from the matrix to the skin surface,then takes action with the strara corneum. The compound penetration accelerator .composed of Azone,alcohol and propanediol,is good for permeation of a-Asaronum from gel matrix.
ffe conducted transdermal experiments on Franz diffuse cell .using rat,rabbit and human skin in vitro,a-Asaronum saturated solution and R5 matrix are used in the experiments.As a result,The transdermal penetration rate of a -Asaronum is different as the skin of different species changes. The transdermal penentra-tion rate of rat is higher than that of the rabbit and human.The transdermal penetration rate of a-Asaronum increases with the increase of the amount of a -Asaronum in the matrix,but their relationship is not linearly corre1ated.
Due to the strong 1 ipophi 1 ity,the bioavailability of a -Asaronum oral preparation is very low. But the a-Asaronum gel patch can solve this problem .The result
of the experiment proves that the bioavailability of a -Asaronum patch is absolutely higher than that of capsule or tablet. The comparative bioavailability ofa-Asaronum patch to capsule is 1167. 6%. So, a-Asa-ronum patch is a good preparation for the absorption and utilization of a -Asaronum.
The resule of the patch performance indicates that the drug content and distribution correspond to the criteria.The irritant test of skin proves that the a -Asaronum patch has no irritation to the most of rabbits and men,apart from some slight irritation to individual rabbits and men. The average score of 8 rabbits and 8 man is less-than 0.6, there fore ,the a -Asaronum patch is safe and without irri tation.The patch can be applied on man.
本课题研究了α-细辛醚透皮吸收促进剂，对α-细辛醚贴剂基质的进行筛选，并制备了α-细辛醚的贴剂，成品通过体外试验、动物体内相对生物利用度的研究，证明了α-细辛醚贴剂透皮吸收的可行性。
研究结果表明，角质层是药物渗透过程中的主要屏障，透皮吸收促进剂Azone和丙二醇可促进α-细辛醚的透皮吸收，促进的效果随丙二醇的浓度而变化，10％的丙二醇对α-细辛醚有良好的促进作用。乙醇能增加α-细辛醚的溶解度，由于溶解度增加，α-细辛醚的透皮速率增加。实验结果表明，Q与t呈线性关系，符合浓度为渗透动力学的Fick’s扩散方程，直线的斜率为稳态透皮速率，与不含Azone的α-细辛醚溶液相比，含5％Azone和5％乙醇的α-细辛醚饱和溶液在39h内的累积透皮量增加了18.2倍，稳态透皮速率由3.3μg/cm~2*h提高到60.1μg/cm~2*h，提高了18.2倍，具有明显的促透作用。氮酮、乙醇和丙二醇合用作为混合促进剂，有利于α-细辛醚在凝胶基质中的透皮吸收。
本实验选用卡巴泊、PVA124、PVA17-88、CMC-Na、西黄蓍胶、HPMC等为凝胶基质原料，以外观和透皮速率为指标，对α-细辛醚基质的组成比例进行考察和筛选。综合考虑基质外观和成型性，
包括保湿、涂展、硬度、粘性等闪素，结合a－细辛醚在基质中的
透皮速率，对a－细辛醚基质的组成比例进行考察筛选，经处方筛
选和厂艺改进，找山粘性适度，凤有良好的涂展性和保湿性，有牧
人的透皮速率的基质。
在本实验中，1比不但外观好，而仕有较好的透皮速率。本制
剂为凝胶骨架控秆，促进剂要冗从基质中缓慢扩散至皮肤表面，然
后与角质层发生作川。分别用。－细辛醚饱和溶液和RS基质，饺用
人鼠、家兔、人皮在Fr。nz扩散池上做体外透皮试验，结果表明，
皮肤米源不同，对。－细辛醚透皮速率不同，人鼠对。－细辛醚的透
皮速率大于家兔和人皮。基质中Q－细辛醚的含量增加，透皮速增
加。但两者之间不呈线性关系。本贴剂是以水溶性高分于化合物或
亲水性物质为主要成分的基质，具有药物容量高。透皮性、贴敷性
、保湿性好、贴着舒适、不污染衣物等忧点。
由于Q一细辛醚是脂溶性很强的药物，水溶性差可能是其口服
制剂生物利用度低的重要原因，而a一细辛醚贴剂能较好地解决这
一问题。实验结果表明a一细辛醚贴剂的生物利用度明显高于胶囊
剂，凝胶贴剂与胶囊剂相对生物利用度为 11 67石％。可见 a一细
辛醚贴剂这一剂型对a一细辛醚的吸收和利用都是较为有的。
贴剂性能考察结果表明，a－细辛醚凝胶贴剂的含量及均匀度符
合中国药典要求并且稳定性良好，皮肤刺激性试验表明a－细辛醚贴
剂除对个别家兔和人有轻微刺檄性外，多数无刺激性。8只家兔和8
位受试者的平均分均小于0石，因此，a－细辛醚凝胶贴剂安全可靠，
无刺激性，可以用于人体。
a -Asaronum (molecular weight 208) is insoluble in water but is soluble in ethanol,ether,glacial acetic acid, chloroform and petroleum ether.As reported,the poor absolute bioavailabi1ity of a-Asaronum was obtained , 2.75% for capsule and 5% for tablet. So,consideringing the character of drug and clinic application , we prepared the a -Asaronum patch.One of the most difficulty in transdermal delivery system is the barrier of the skin which holds back the penetration of drugs to meet with the therapy.The most available method is to select proper promoters. In order to devel op a-Asaronum patch,we have studied proper accelerators and matrix in this thesis.
Firstly,we study the comparetive bioavailability in vivo to prove the feasibility of a -Asaronum patch. The results revealed that the main barrier in penetration of a-Asaronum is tratacorneum.
Azone and propanediol can accelerate the permeation of a -Asaronum. And the effect of promotion depended on the concentration of propanediol.Ten percent of propanediol exhibited the good effect of penetration promotion. Furthermore,alcohol can increase the solubility of a -Asaronum in skin which is helpful to increase the permeation rate.It is abserved that the permeation was accordent to Pick1 s diffuse equation for the linear relation between Q and t.The slope of the line is the permeation rate in stable state.
As a good accelerator,Azone can increase the permeation rate of a-Asaronum.Compared with the controlled group,the accumulativea-Asaronum permeation from the a -Asaronum solution with Azone is 18.2 times 1arger,stable
permeation rate of 60.1ug/ml is 18.2 times higher . The permeation is accelarated obviously.
Gel matrix is made of water-soluble high polyme or hydro-philic compounds.It can hold more drugs and has good permeation rate,In this study,we select carbapol,PVA124,PVA17-88,CMC-Na,gum tragacanth,HPMC as the raw material of the gel matrix and mix some of them in the proper proportion of material according to its outward appearance,fi gurat i on and permeation rate.
Consequently R5 is chosen as the proper patch which belongs to controled-release gel matrix dosage. The accelerator diffuses from the matrix to the skin surface,then takes action with the strara corneum. The compound penetration accelerator .composed of Azone,alcohol and propanediol,is good for permeation of a-Asaronum from gel matrix.
ffe conducted transdermal experiments on Franz diffuse cell .using rat,rabbit and human skin in vitro,a-Asaronum saturated solution and R5 matrix are used in the experiments.As a result,The transdermal penetration rate of a -Asaronum is different as the skin of different species changes. The transdermal penentra-tion rate of rat is higher than that of the rabbit and human.The transdermal penetration rate of a-Asaronum increases with the increase of the amount of a -Asaronum in the matrix,but their relationship is not linearly corre1ated.
Due to the strong 1 ipophi 1 ity,the bioavailability of a -Asaronum oral preparation is very low. But the a-Asaronum gel patch can solve this problem .The result
of the experiment proves that the bioavailability of a -Asaronum patch is absolutely higher than that of capsule or tablet. The comparative bioavailability ofa-Asaronum patch to capsule is 1167. 6%. So, a-Asa-ronum patch is a good preparation for the absorption and utilization of a -Asaronum.
The resule of the patch performance indicates that the drug content and distribution correspond to the criteria.The irritant test of skin proves that the a -Asaronum patch has no irritation to the most of rabbits and men,apart from some slight irritation to individual rabbits and men. The average score of 8 rabbits and 8 man is less-than 0.6, there fore ,the a -Asaronum patch is safe and without irri tation.The patch can be applied on man.
引文
[1] 杨正鸿，吴闯，α—细辛醚在人体的生物利用度研究．中国医院药学杂志，1997，17(4)：165-167
[2] 杨玉．α-细辛脑治疗 148 例慢性阻塞性肺部疾病．新药与临床，1986，5(4)：210
[2] 刘立东，凌树森，α—细辛醚透皮吸收研究．中国药房，1994，5(3)：12—14
[2] 杨玉．α-细辛脑治疗 148 例慢性阻塞性肺部疾病．新药与临床，1986，5(4)：210
[2] 刘立东，凌树森，α—细辛醚透皮吸收研究．中国药房，1994，5(3)：12—14