丹参素纳米柔性脂质体控释型皮肤贴片的研制
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摘要
丹参素是中药唇形科植物丹参(Salvia miltiorriza Bunge)的主要水溶性成分,现代研究证明,丹参素具有保护心肌细胞,扩张冠状动脉,抑制血栓形成,抗动脉粥样硬化等多种药理作用,丹参素对心脏具有良好的生物活性,临床上主要用于治疗冠心病心绞痛。
纳米脂质体技术作为一种药物载体技术,具有适合体内降解、无毒性和无免疫原性、可包裹水、脂溶性两种类型药物、保护被包封药物、减少用药剂量及可修饰产生主动靶向性等诸多优良特性。同时,脂质体脂质双分子层的结构特点决定了其对皮肤角质层类脂屏障的良好渗透性。而新一代脂质体—纳米柔性脂质体,由于其具备变形性,更有利于通过表皮屏障,能进入皮肤更深层,渗透性能更佳。因此将纳米柔性脂质体技术运用于经皮给药系统,研制具有优良透皮特性的载药纳米柔性脂质体,将会极大地拓宽适用于经皮给药的药物范围。
本研究通过不同膜材、处方和工艺的优选,研制具有良好透皮吸收性能的中药经皮给药载体—纳米柔性脂质体。同时,以制备治疗冠心病心绞痛的丹参素纳米柔性脂质体控释型皮肤贴片为研究切入点,制成剂型稳定,包封率、释放度以及经皮吸收性能良好的丹参素控释皮肤贴片,最终形成研制中药有效成分经皮全身给药制剂的新方法,为促进中药有效成分经皮全身给药制剂的研发打下重要的基础。
论文的第一部分采用单因素实验,以包封率为指标,考察制备过程中所使用的磷脂浓度、长循环辅料的用量以及柔性辅料的用量对制备丹参素纳米柔性脂质体的影响。根据其结果,对大豆卵磷脂与胆固醇用量比(A),胆固醇与表面活性剂的用量比(B),卵磷脂与表面活性剂之比(C)三个主要影响因素进行考察,各因素分别取三个水平,通过正交设计实验,对丹参素纳米柔性脂质体的制备工艺和处方进行了筛选。综合考虑各方面因素,最后确定的最佳处方为大豆卵磷脂与胆固醇用量比5:1,胆固醇与表面活性剂的比为1:1,卵磷脂与表面活性剂之比为5:1,以优化工艺制得的丹参素纳米柔性脂质体粒径分布均匀,平均粒径为121.07 nm,平均包封率为(47.26±1.2)%。
论文的第二部分以丙烯酸树脂为主要组分,在丙烯酸树脂加入琥珀酸作为交联剂、柠檬酸三乙酯作为增塑剂,确定丹参素纳米柔性脂质体贴剂的基本组成为:①丙烯酸树脂0.4g;②柠檬酸三乙酯0.11-0.33g;③琥珀酸0.04-0.062g;④氮酮5%;⑤丹参素纳米柔性脂质体混悬液10%。固定处方丙烯酸树脂重量,将柠檬酸三乙酯、琥珀酸的重量范围划分为12个水平,各制成贴剂,同时以贴剂的药物含量、初粘力、持粘力、稳定性为指标对制备的贴剂进行了质量评价,并在此基础上,以初粘力和持粘力为指标,对柠檬酸三乙酯用量和琥珀酸用量两个主要影响因素进行考察,各因素分别取两个水平,通过正交设计实验,对贴剂的处方进行优化,结果表明,丙烯酸树脂0.4g、柠檬酸三乙酯0.23g、琥珀酸0.054g,丹参素纳米柔性脂质体混悬液和氮酮的含量分别为10%和5%的贴剂组方最为理想。
论文的第三部分采用高效液相色谱法对制备的丹参素纳米柔性脂质体透皮贴进行了体外透皮释药试验以及体外释放度测定,以考察其体外透皮率以及体外释药性能,体外透皮释药试验结果显示24小时药物累积透皮量达206±20μg·cm~(-2),而丹参素纳米柔性脂质体贴剂的体外释放试验表明其体外释放度曲线24h内符合Higuchi方程,有显著的缓释效果。
论文第四部分利用垂体后叶素静脉注射造成大鼠急性心肌缺血的动物模型,并采用结扎大鼠冠状动脉左前降支的心肌缺血再灌注损伤造模,观察丹参素纳米柔性脂质体透皮贴对缺血心肌以及心肌缺血后再灌注损伤的保护作用,贴剂对缺血心肌保护作用实验结果表明,电镜下观察药物贴剂组心肌细胞膜完整,线粒体结构基本清晰,肿胀较轻,糖元颗粒明显增加。而贴剂对心肌缺血后再灌注损伤的保护作用实验结果表明,贴剂组对心脏的复灌性心律失常无明显改善,但能显著缩小随后长时间缺血所引起的心肌梗塞范围。
Danshensu is the major water-solubility compound in Salvia miltiorriza Bunge,which is included in Chinese medicinal herbs of labiatae plant.The modern researchs prove that,it has many pharmacological functions such as protecting cardiac muscle cells, expanding aeteria coronaria,restraining thrombogenesis and resisting artherosclerosis.It is beneficial to heart,and can be clinically used to cure coronary heart disease(CHD)and angina pectoris(AP).
Nanometer lipid body(LB)technique is a kind of medicinal trager technique,has so many fine characteristics,such as fitting degradation in vivo,degradation,no immunogenicity,and it could wrap up the two kinds of medicines that conclude water solubility and liposolubility,it also could protect the enveloped medicines and reduce the dosage of medicine, modify to produce the initiative targets.Meanwhile,the construction features of lipid bimolecular leaflet in lipid body determine the fine osmolarity anti the lipid barrier in osmolarity.The new generation lipid body-ultratlexible nanoliposomes,because of its deformability,it profits to pass epidermis barricade,so it could enter the further deep layer of skin, the osmolarity is better.So that we apply the ultratlexible nanoliposomes to the percutem dministration system,then we manufacture the carrying drugs ultratlexible nanoliposomes that possesses fine characteristics of penetrating skin,it would be able to enlarge the medicine scope which is percutem administration overwhelmingly.
This research manufactures the carrying drugs ultratlexible nanoliposomes that possesses fine characteristics of penetrating skin through optimization of different membrane materials,prescriptions and tecniques.And also,we put the preparation of the skin tabellae adhaesivus Danshinol of carrying drugs ultratlexible nanoliposomes that possesses fine characteristics of penetrating skin of the type of controlled release that is treated coronary heart disease and angina pectoris as the research cut-in point.We make the skin tabellae adhaesivus Danshino of controlled release of the stable dosage form,the rate of envelop,the degree of release and the fine function of percutaneous absorption.At last,we hope to form the new methods of manufacturing praeparatum that the active component in traditional Chinese medicine administering percutem,and it make the important foundation of promoting the manufacturing praeparatum that the active component in traditional Chinese medicine administering per cutem.
The primary part of essay applys the single factor experiments,puts the rate of envelop as index,we investigate in the process of preparation, the effect of the density of phospholipid,the dosis of accessories in long circulation,the dosis of flexibility accessories on preparation of Ultraflexible Nanoliposomes of Danshensu.According to the results,we investigating three main influential factors,including the volume ratio of soybean lecithin and cholesterin(A),the volume ratio of cholesterin and surface acting agents(B),the dosage ratio of lecithin and surface acting agents(C).Each factor is taken three levels,through the orthogonal design experiments,we make the screening of the crafts and prescriptions of preparation on Ultraflexible Nanoliposomes of Danshensu.Combination of considering all round of factors,we eventually defined the best prescription is the dosis ratio of the lecithin of soya bean and cholesterin is 5:1,the dosage ratio of cholesterin and surface acting agents is 1:1,the dosage ratio of lecithin and surface acting agents is 1:1.In the prepared with optimized crafts of Ultraflexible Nanoliposomes of Danshensu,the particle diameter is distributed uniformity,the mean diameter is 121.07nm,the average envelop ratio is(45.35±3.49)%.
The second part of essay is put the acrylic resins as the principal agent, add amber as cross linking agent in acrylic resins,add citric acid tri-ethyl ester as elasticizer,we make sure the fundamental compositions of Ultraflexible Nanoliposomes of Danshensu are①0.4g acrylic resins,②0.11-0.33g citric acid tri-ethyl ester;③0.04-0.062g succinic acid;④5%Laurocapram;⑤10%Suspension of Ultraflexible Nanoliposomes of Danshensu.We fix the weight of acrylic resins in prescription,and divide the weight scope of tri-ethyl ester and succinum to 12 levels,then prepare the patch each.At the same time,we make the quality evaluation through putting the medicine content,initial viscous force,keeping viscous force and constancy of patch as index.And in this foundation,we investigate the dosage of tri-ethyl ester and succinic acid the two main influencing factors through putting the viscous force and the keeping viscous force as index,and each factor is get two levels,we optimize the prescription of patch with the experiment of orthogonal design.At last, the results indicate that,the best prescription of patch is 0.4g acrylic resins,0.23g citric acid tri-ethyl ester,0.054g succinic acid,the contents of suspension of Ultraflexible Nanoliposomes of Danshensu and Laurocapram are 10%and 5%respectively.
The third part of essay is through the high efficiency liquid chromatography,we make the experiments of extraorgan penetrating skin and releasing drugs and determine the degree of releasing in extraorgan.It is to investigate the skin permeation rate and the performance of releasing drugs in extraorgan.The results of experiments in extraorgan penetrating skin and releasing drugs show the quantity of accumulated penetrating skin of drugs in 24 hours is 206±20μg·cm~2,and the experiments of vitro releasing with the patch of Ultraflexible Nanoliposomes of Danshensu indicates that the curve of vitro releasing meets Higuchi equation within 24 hours with a significant slow-release effect.
In the fourth part of essay,we utilize intravenous injection of hypophysin to cause the animal model that rats have the acute myocardial ischemia(AMI),and make model in applying to ligate the left anterior descending coronary artery of rats to cause heart muscle ischemical reperfusion injury.We observe the patch of penetrating skin in Ultraflexible Nanoliposomes of Danshensu protecting cardiac muscles of ischemia and postischemic reperfusion damage.The experimental results of the ischemia myocardial preservation with this patch indicate that.we observe the cardiac muscle cell membrane complete in the group of drugs patch with the electron microscope,the structure of mitochondria is essential clear and slightly swelling,glyc-element particles increase obviously.The experimental results of the postischemic reperfusion damage in cardiac muscles of preservation with this patch indicate that, the group of patch has no obvious improvement arrhythmia of irrigatation again,but coold significantly contract the scope of myocardial infarct caused of ischemia long time afterward.
纳米脂质体技术作为一种药物载体技术,具有适合体内降解、无毒性和无免疫原性、可包裹水、脂溶性两种类型药物、保护被包封药物、减少用药剂量及可修饰产生主动靶向性等诸多优良特性。同时,脂质体脂质双分子层的结构特点决定了其对皮肤角质层类脂屏障的良好渗透性。而新一代脂质体—纳米柔性脂质体,由于其具备变形性,更有利于通过表皮屏障,能进入皮肤更深层,渗透性能更佳。因此将纳米柔性脂质体技术运用于经皮给药系统,研制具有优良透皮特性的载药纳米柔性脂质体,将会极大地拓宽适用于经皮给药的药物范围。
本研究通过不同膜材、处方和工艺的优选,研制具有良好透皮吸收性能的中药经皮给药载体—纳米柔性脂质体。同时,以制备治疗冠心病心绞痛的丹参素纳米柔性脂质体控释型皮肤贴片为研究切入点,制成剂型稳定,包封率、释放度以及经皮吸收性能良好的丹参素控释皮肤贴片,最终形成研制中药有效成分经皮全身给药制剂的新方法,为促进中药有效成分经皮全身给药制剂的研发打下重要的基础。
论文的第一部分采用单因素实验,以包封率为指标,考察制备过程中所使用的磷脂浓度、长循环辅料的用量以及柔性辅料的用量对制备丹参素纳米柔性脂质体的影响。根据其结果,对大豆卵磷脂与胆固醇用量比(A),胆固醇与表面活性剂的用量比(B),卵磷脂与表面活性剂之比(C)三个主要影响因素进行考察,各因素分别取三个水平,通过正交设计实验,对丹参素纳米柔性脂质体的制备工艺和处方进行了筛选。综合考虑各方面因素,最后确定的最佳处方为大豆卵磷脂与胆固醇用量比5:1,胆固醇与表面活性剂的比为1:1,卵磷脂与表面活性剂之比为5:1,以优化工艺制得的丹参素纳米柔性脂质体粒径分布均匀,平均粒径为121.07 nm,平均包封率为(47.26±1.2)%。
论文的第二部分以丙烯酸树脂为主要组分,在丙烯酸树脂加入琥珀酸作为交联剂、柠檬酸三乙酯作为增塑剂,确定丹参素纳米柔性脂质体贴剂的基本组成为:①丙烯酸树脂0.4g;②柠檬酸三乙酯0.11-0.33g;③琥珀酸0.04-0.062g;④氮酮5%;⑤丹参素纳米柔性脂质体混悬液10%。固定处方丙烯酸树脂重量,将柠檬酸三乙酯、琥珀酸的重量范围划分为12个水平,各制成贴剂,同时以贴剂的药物含量、初粘力、持粘力、稳定性为指标对制备的贴剂进行了质量评价,并在此基础上,以初粘力和持粘力为指标,对柠檬酸三乙酯用量和琥珀酸用量两个主要影响因素进行考察,各因素分别取两个水平,通过正交设计实验,对贴剂的处方进行优化,结果表明,丙烯酸树脂0.4g、柠檬酸三乙酯0.23g、琥珀酸0.054g,丹参素纳米柔性脂质体混悬液和氮酮的含量分别为10%和5%的贴剂组方最为理想。
论文的第三部分采用高效液相色谱法对制备的丹参素纳米柔性脂质体透皮贴进行了体外透皮释药试验以及体外释放度测定,以考察其体外透皮率以及体外释药性能,体外透皮释药试验结果显示24小时药物累积透皮量达206±20μg·cm~(-2),而丹参素纳米柔性脂质体贴剂的体外释放试验表明其体外释放度曲线24h内符合Higuchi方程,有显著的缓释效果。
论文第四部分利用垂体后叶素静脉注射造成大鼠急性心肌缺血的动物模型,并采用结扎大鼠冠状动脉左前降支的心肌缺血再灌注损伤造模,观察丹参素纳米柔性脂质体透皮贴对缺血心肌以及心肌缺血后再灌注损伤的保护作用,贴剂对缺血心肌保护作用实验结果表明,电镜下观察药物贴剂组心肌细胞膜完整,线粒体结构基本清晰,肿胀较轻,糖元颗粒明显增加。而贴剂对心肌缺血后再灌注损伤的保护作用实验结果表明,贴剂组对心脏的复灌性心律失常无明显改善,但能显著缩小随后长时间缺血所引起的心肌梗塞范围。
Danshensu is the major water-solubility compound in Salvia miltiorriza Bunge,which is included in Chinese medicinal herbs of labiatae plant.The modern researchs prove that,it has many pharmacological functions such as protecting cardiac muscle cells, expanding aeteria coronaria,restraining thrombogenesis and resisting artherosclerosis.It is beneficial to heart,and can be clinically used to cure coronary heart disease(CHD)and angina pectoris(AP).
Nanometer lipid body(LB)technique is a kind of medicinal trager technique,has so many fine characteristics,such as fitting degradation in vivo,degradation,no immunogenicity,and it could wrap up the two kinds of medicines that conclude water solubility and liposolubility,it also could protect the enveloped medicines and reduce the dosage of medicine, modify to produce the initiative targets.Meanwhile,the construction features of lipid bimolecular leaflet in lipid body determine the fine osmolarity anti the lipid barrier in osmolarity.The new generation lipid body-ultratlexible nanoliposomes,because of its deformability,it profits to pass epidermis barricade,so it could enter the further deep layer of skin, the osmolarity is better.So that we apply the ultratlexible nanoliposomes to the percutem dministration system,then we manufacture the carrying drugs ultratlexible nanoliposomes that possesses fine characteristics of penetrating skin,it would be able to enlarge the medicine scope which is percutem administration overwhelmingly.
This research manufactures the carrying drugs ultratlexible nanoliposomes that possesses fine characteristics of penetrating skin through optimization of different membrane materials,prescriptions and tecniques.And also,we put the preparation of the skin tabellae adhaesivus Danshinol of carrying drugs ultratlexible nanoliposomes that possesses fine characteristics of penetrating skin of the type of controlled release that is treated coronary heart disease and angina pectoris as the research cut-in point.We make the skin tabellae adhaesivus Danshino of controlled release of the stable dosage form,the rate of envelop,the degree of release and the fine function of percutaneous absorption.At last,we hope to form the new methods of manufacturing praeparatum that the active component in traditional Chinese medicine administering percutem,and it make the important foundation of promoting the manufacturing praeparatum that the active component in traditional Chinese medicine administering per cutem.
The primary part of essay applys the single factor experiments,puts the rate of envelop as index,we investigate in the process of preparation, the effect of the density of phospholipid,the dosis of accessories in long circulation,the dosis of flexibility accessories on preparation of Ultraflexible Nanoliposomes of Danshensu.According to the results,we investigating three main influential factors,including the volume ratio of soybean lecithin and cholesterin(A),the volume ratio of cholesterin and surface acting agents(B),the dosage ratio of lecithin and surface acting agents(C).Each factor is taken three levels,through the orthogonal design experiments,we make the screening of the crafts and prescriptions of preparation on Ultraflexible Nanoliposomes of Danshensu.Combination of considering all round of factors,we eventually defined the best prescription is the dosis ratio of the lecithin of soya bean and cholesterin is 5:1,the dosage ratio of cholesterin and surface acting agents is 1:1,the dosage ratio of lecithin and surface acting agents is 1:1.In the prepared with optimized crafts of Ultraflexible Nanoliposomes of Danshensu,the particle diameter is distributed uniformity,the mean diameter is 121.07nm,the average envelop ratio is(45.35±3.49)%.
The second part of essay is put the acrylic resins as the principal agent, add amber as cross linking agent in acrylic resins,add citric acid tri-ethyl ester as elasticizer,we make sure the fundamental compositions of Ultraflexible Nanoliposomes of Danshensu are①0.4g acrylic resins,②0.11-0.33g citric acid tri-ethyl ester;③0.04-0.062g succinic acid;④5%Laurocapram;⑤10%Suspension of Ultraflexible Nanoliposomes of Danshensu.We fix the weight of acrylic resins in prescription,and divide the weight scope of tri-ethyl ester and succinum to 12 levels,then prepare the patch each.At the same time,we make the quality evaluation through putting the medicine content,initial viscous force,keeping viscous force and constancy of patch as index.And in this foundation,we investigate the dosage of tri-ethyl ester and succinic acid the two main influencing factors through putting the viscous force and the keeping viscous force as index,and each factor is get two levels,we optimize the prescription of patch with the experiment of orthogonal design.At last, the results indicate that,the best prescription of patch is 0.4g acrylic resins,0.23g citric acid tri-ethyl ester,0.054g succinic acid,the contents of suspension of Ultraflexible Nanoliposomes of Danshensu and Laurocapram are 10%and 5%respectively.
The third part of essay is through the high efficiency liquid chromatography,we make the experiments of extraorgan penetrating skin and releasing drugs and determine the degree of releasing in extraorgan.It is to investigate the skin permeation rate and the performance of releasing drugs in extraorgan.The results of experiments in extraorgan penetrating skin and releasing drugs show the quantity of accumulated penetrating skin of drugs in 24 hours is 206±20μg·cm~2,and the experiments of vitro releasing with the patch of Ultraflexible Nanoliposomes of Danshensu indicates that the curve of vitro releasing meets Higuchi equation within 24 hours with a significant slow-release effect.
In the fourth part of essay,we utilize intravenous injection of hypophysin to cause the animal model that rats have the acute myocardial ischemia(AMI),and make model in applying to ligate the left anterior descending coronary artery of rats to cause heart muscle ischemical reperfusion injury.We observe the patch of penetrating skin in Ultraflexible Nanoliposomes of Danshensu protecting cardiac muscles of ischemia and postischemic reperfusion damage.The experimental results of the ischemia myocardial preservation with this patch indicate that.we observe the cardiac muscle cell membrane complete in the group of drugs patch with the electron microscope,the structure of mitochondria is essential clear and slightly swelling,glyc-element particles increase obviously.The experimental results of the postischemic reperfusion damage in cardiac muscles of preservation with this patch indicate that, the group of patch has no obvious improvement arrhythmia of irrigatation again,but coold significantly contract the scope of myocardial infarct caused of ischemia long time afterward.
引文
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