中药挥发油对盐酸巴马汀纳米柔性脂质体药剂学性能的影响
|
摘要
柔性脂质体(flexible nano-liposomes,FL)是一种优良的给药载体,但液体状态下的药物泄漏已严重阻碍了其进一步广泛应用,因此,抑制药物泄漏已成为亟待解决的行业共性技术问题。本文将5种常见挥发油如艾叶油(Folium Artemisiae Argyi oil,FA)、桉叶油(Folium Eucalypti oil,FE)、茉莉油(Arabian Jasmine oil,AJ)、丁香油(Syzygium Aromaticum oil,SA)和连翘油(Fructus Forsythiae oil,FF)分别包埋于盐酸巴马汀纳米柔性脂质体(palmatine chloride loaded flexible nano-liposomes,PFL)的脂质双分子层内,通过体外泄漏曲线评价筛选能够降低PFL药物泄漏的最佳挥发油及其用量水平;考察包埋挥发油后对PFL包封率、粒径、电位、变形性与结构的影响,并通过白兔阴道给药考察其对黏膜的刺激性;最后,采用水平双室扩散池评价挥发油对PFL体外透皮透黏膜给药行为的影响。结果显示,5种挥发油均能不同程度地抑制PFL内水相中药物的泄漏,但艾叶油抑制泄漏的程度显著优于其他4种挥发油(P<0.05),且艾叶油与脂质质量比为1∶6时具有最佳的抑制泄漏作用;包埋艾叶油的PFL与PFL在包封率、粒径、电位与变形性等方面无显著性差异(P>0.05),且二者层状囊泡结构相似;包埋艾叶油后也进一步增强了PFL促进内水相中药物透皮透黏膜的吸收能力,而对白兔阴道黏膜无刺激性。综上,在柔性脂质体的磷脂膜中包埋合适的挥发油(如艾叶油)不仅可在一定程度上抑制内水相中药物的泄漏,且能够增强柔性脂质体促进药物透皮透黏膜的吸收。因此,本文为克服液体状态下纳米柔性脂质体药物泄漏提供了一种新方法和新思路。
Flexible liposomes are an excellent drug delivery nanocarrier,however,the leakage of drugs from liposomes has become common technical obstacle in the industry and also hindered its further application seriously.It is very urgent and necessary to avoid or reduce the leakage of drugs from liposomes.In this work,five kinds of essential oils such as Folium Artemisiae Argyi oil(FA),Folium Eucalypti oil(FE),Arabian Jasmine oil(AJ),Syzygium Aromaticum oil(SA) and Fructus Forsythiae oil(FF) were encapsulated in the lipid bilayer of palmatine chloride(PC) loaded flexible nano-liposomes(PFL),then the optimal essential oil and its dosage level were determined by the external leakage curve of PC.The female Japanese white rabbits were used to evaluate the vaginal irritancy potential of liposomes samples.The pharmaceutical properties such as encapsulation efficiency,particle size,zeta potential,deformability and structure of liposomes samples were evaluated.In order to investigate the permeability of liposomes samples to deliver PC across skin and mucous membrane in vitro,the side-by-side diffusion cells were used.The results showed that the leakage of hydrosoluble PC from PFL was reduced at different degrees by the essential oils in the lipid bilayer of PFL,however,the reduction in leakage degree was obviously higher for FA than thoses of FE,AJ,SA and FF(P < 0.05),and the highest reduction in leakage degree was obtained when the FA and lipid mass ratio was 1∶6.The encapsulation efficiency,particle size,zeta potential and deformability of PFL were not significantly changed after FA was encapsulated in the lipid bilayer of the PFL(P > 0.05),so did the lamellar structure of PFL.In addition,the transdermal and transmucosal permeability of PC were also enhanced obviously by encapsulating FA in the lipid bilayer of PFL,and there was no vaginal/vulvar irritation observed in the rabbits.In summary,the drug leakage was reduced by encapsulating suitable essential oil(such as FA) in the lipid bilayer of flexible liposomes,and the vaginal mucosa permeability were improved for the drug.These results provide a novel technique in the improvement of flexible nano-liposomes for drug delivery.
Flexible liposomes are an excellent drug delivery nanocarrier,however,the leakage of drugs from liposomes has become common technical obstacle in the industry and also hindered its further application seriously.It is very urgent and necessary to avoid or reduce the leakage of drugs from liposomes.In this work,five kinds of essential oils such as Folium Artemisiae Argyi oil(FA),Folium Eucalypti oil(FE),Arabian Jasmine oil(AJ),Syzygium Aromaticum oil(SA) and Fructus Forsythiae oil(FF) were encapsulated in the lipid bilayer of palmatine chloride(PC) loaded flexible nano-liposomes(PFL),then the optimal essential oil and its dosage level were determined by the external leakage curve of PC.The female Japanese white rabbits were used to evaluate the vaginal irritancy potential of liposomes samples.The pharmaceutical properties such as encapsulation efficiency,particle size,zeta potential,deformability and structure of liposomes samples were evaluated.In order to investigate the permeability of liposomes samples to deliver PC across skin and mucous membrane in vitro,the side-by-side diffusion cells were used.The results showed that the leakage of hydrosoluble PC from PFL was reduced at different degrees by the essential oils in the lipid bilayer of PFL,however,the reduction in leakage degree was obviously higher for FA than thoses of FE,AJ,SA and FF(P < 0.05),and the highest reduction in leakage degree was obtained when the FA and lipid mass ratio was 1∶6.The encapsulation efficiency,particle size,zeta potential and deformability of PFL were not significantly changed after FA was encapsulated in the lipid bilayer of the PFL(P > 0.05),so did the lamellar structure of PFL.In addition,the transdermal and transmucosal permeability of PC were also enhanced obviously by encapsulating FA in the lipid bilayer of PFL,and there was no vaginal/vulvar irritation observed in the rabbits.In summary,the drug leakage was reduced by encapsulating suitable essential oil(such as FA) in the lipid bilayer of flexible liposomes,and the vaginal mucosa permeability were improved for the drug.These results provide a novel technique in the improvement of flexible nano-liposomes for drug delivery.
引文
[1]Manconi M,Mura S,Sinico C,et al.Development and characterization of liposomes containing glycols as carriers for diclofenac[J].Colloids Surf A Physicochem Eng Asp,2009,342:53-58.
[2]Subongkot T,Wonglertnirant N,Songprakhon P,et al.Visualization of ultradeformable liposomes penetration pathways and their skin interaction by confocal laser scanning microscopy[J].Int J Pharm,2013,441:151-161.
[3]Li C,Deng L,Zhang Y,et al.Silica-coated ethosome as a novel oral delivery system for enhanced oral bioavailability of curcumin[J].Acta Pharm Sin(药学学报),2012,47:1541-1547.
[4]Elsayed MMA,Abdallah OY,Naggar VF,et al.Lipid vesicles for skin delivery of drugs:reviewing three decades of research[J].Int J Pharm,2007,332:1-16.
[5]Li WZ,Zhao N,Zhou YQ,et al.Post-expansile hydrogel foam aerosol of PG-liposomes:a novel delivery system for vaginal drug delivery applications[J].Eur J Pharm Sci,2012,47:162-169.
[6]Paveli??,?kalko-basnet N,Filipovi?-gr?i?J,et al.Development and in vitro evaluation of a liposomal vaginal delivery system for acyclovir[J].J Control Release,2005,106:34-43.
[7]Hu YZ,Li M,Zhang TT,et al.Preparation of liposomal artesunate dry powder inhalers and the effect on the acute lung injury of rats[J].Acta Pharm Sin(药学学报),2016,51:1906-1912.
[8]Zhang WJ,Yang DX,Feng LL,et al.Modification by wheat germ agglutinin delays the ocular elimination of liposome[J].Acta Pharm Sin(药学学报),2014,49:543-549.
[9]Xu Y,Shi L,Deng YH.Effect of polyethylene glycol-lipid derivatives on the stability of grafted liposomes[J].Acta Pharm Sin(药学学报),2011,46:1178-1186.
[10]Zhang D,Xu H,Hu MN,et al.“PEG dilemma”for liposomes and its solving approaches[J].Acta Pharm Sin(药学学报),2015,50:252-260.
[11]Li WZ,Hao XL,Zhao N,et al.Propylene glycol-embodying deformable liposomes as a novel drug delivery carrier for vaginal fibrauretine delivery applications[J].J Control Release,2016,226:107-114.
[12]Li WZ,Han WX,Zhao N,et al.Studies on the preparation and transdermal drug delivery of hydrogel patches of palmatine loaded flexible nano-liposomes[J].Chin J Vet Drug(中国兽药杂志),2016,50:46-50.
[13]Mahor S,Rawat A,Dubey PK,et al.Cationic transfersomes based topical genetic vaccine against hepatitis B[J].Int J Pharm,2007,340:13-19.
[14]Fichorova RN,Mendonca K,Yamamoto HS,et al.A quantitative multiplex nuclease protection assay reveals immunotoxicity gene expression profiles in the rabbit model for vaginal drug safety evaluation[J].Toxicol Appl Pharm,2015,285:198-206.
[15]Wang HJ,Liu MF,Du S.Optimization of madecassoside liposomes using response surface methodology and evaluation of its stability[J].Int J Pharm,2014,473:280-285.
[16]Zhao Q,Li WZ,Cheng YC,et al.Studies on the transdermal delivery of palmatine by several volatile oils as penetration enhancers[J].Appl Chem Ind(应用化工),2016,45:186-189.
[2]Subongkot T,Wonglertnirant N,Songprakhon P,et al.Visualization of ultradeformable liposomes penetration pathways and their skin interaction by confocal laser scanning microscopy[J].Int J Pharm,2013,441:151-161.
[3]Li C,Deng L,Zhang Y,et al.Silica-coated ethosome as a novel oral delivery system for enhanced oral bioavailability of curcumin[J].Acta Pharm Sin(药学学报),2012,47:1541-1547.
[4]Elsayed MMA,Abdallah OY,Naggar VF,et al.Lipid vesicles for skin delivery of drugs:reviewing three decades of research[J].Int J Pharm,2007,332:1-16.
[5]Li WZ,Zhao N,Zhou YQ,et al.Post-expansile hydrogel foam aerosol of PG-liposomes:a novel delivery system for vaginal drug delivery applications[J].Eur J Pharm Sci,2012,47:162-169.
[6]Paveli??,?kalko-basnet N,Filipovi?-gr?i?J,et al.Development and in vitro evaluation of a liposomal vaginal delivery system for acyclovir[J].J Control Release,2005,106:34-43.
[7]Hu YZ,Li M,Zhang TT,et al.Preparation of liposomal artesunate dry powder inhalers and the effect on the acute lung injury of rats[J].Acta Pharm Sin(药学学报),2016,51:1906-1912.
[8]Zhang WJ,Yang DX,Feng LL,et al.Modification by wheat germ agglutinin delays the ocular elimination of liposome[J].Acta Pharm Sin(药学学报),2014,49:543-549.
[9]Xu Y,Shi L,Deng YH.Effect of polyethylene glycol-lipid derivatives on the stability of grafted liposomes[J].Acta Pharm Sin(药学学报),2011,46:1178-1186.
[10]Zhang D,Xu H,Hu MN,et al.“PEG dilemma”for liposomes and its solving approaches[J].Acta Pharm Sin(药学学报),2015,50:252-260.
[11]Li WZ,Hao XL,Zhao N,et al.Propylene glycol-embodying deformable liposomes as a novel drug delivery carrier for vaginal fibrauretine delivery applications[J].J Control Release,2016,226:107-114.
[12]Li WZ,Han WX,Zhao N,et al.Studies on the preparation and transdermal drug delivery of hydrogel patches of palmatine loaded flexible nano-liposomes[J].Chin J Vet Drug(中国兽药杂志),2016,50:46-50.
[13]Mahor S,Rawat A,Dubey PK,et al.Cationic transfersomes based topical genetic vaccine against hepatitis B[J].Int J Pharm,2007,340:13-19.
[14]Fichorova RN,Mendonca K,Yamamoto HS,et al.A quantitative multiplex nuclease protection assay reveals immunotoxicity gene expression profiles in the rabbit model for vaginal drug safety evaluation[J].Toxicol Appl Pharm,2015,285:198-206.
[15]Wang HJ,Liu MF,Du S.Optimization of madecassoside liposomes using response surface methodology and evaluation of its stability[J].Int J Pharm,2014,473:280-285.
[16]Zhao Q,Li WZ,Cheng YC,et al.Studies on the transdermal delivery of palmatine by several volatile oils as penetration enhancers[J].Appl Chem Ind(应用化工),2016,45:186-189.