The Skin Permeation Study Of Imperatorin Via Charged Ultradeformable Lipid Vesicles For Transdermal Delivery

Imperatorin has a wide range of pharmacological activities.Thus the potential for formulation development and clinical application is possible.However,the bioavailability through the oral route in the human body is low.With the numerous metabolic pathways,the further utilization of imperatorin was limited.The purpose of this project is to develop a novel nano-liposome vesicles,which called ultradeformable liposomes with high deformability,have the ability to squeeze themselves through intercellular sealing lipids of the stratum corneum.It can increase the penetration ability of imperatorin through the skin.Meanwhile,the surface charge modification of the ultradeformable liposomes were investigated to evaluate the in vitro transdermal performance of different imperatorin-loaded nano-liposome vesicles.The first chapter gives an overview of human skin structure.Most drug molecules are difficult to effectively penetrate the stratum corneum of the skin.Imperatorin should be prepared into ultradeformable liposomes by means of formulation to promote its diffusion and release in the skin.In chapter two,HPLC method for the determination of imperatorin was established.The solubility of imperatorin and the apparent oil-water partition coefficient were investigated.The results showed that imperatorin is a poorly soluble drug,and Tween-80 can be used as an accepted media for in vitro release tests.In Chapter 3,the soy phosphatidylcholine,cholesterol were used as the prescription ingredients.The ultradeformable liposomes were prepared by the thin film hydration method and dispersed by the probe ultrasonic method.The particle size,encapsulation efficiency and stability were used as indicators to evaluate the optimization of liposome formulation and preparation.Tween-20 was used as a“bilayer softening compound”for ultradeformable liposomes in final optimization formulation.And the ratio between phosphatidylcholine and Tween-20was 85:15,while the amount of cholesterol used in a ratio of 10:1.And the ratio of drug content of imperatorin is 0.1%.The entrapment efficiency of the ultradeformable liposomes in this system are highest of57.60±2.06%with the particle size of 73.5±1.75nm.The different ion surfactant were added to the formulation to prepare surface-charge modified ultradeformable liposomes with the same preparation method.The evaluation of physicochemical properties and in vitro transdermal diffusion capabilities with different imperatorin-loaded nano-liposome vesicles would be demonstrated in subsequent chapters.In the fourth chapter,the morphology,particle size,polymer dispersity index,zeta potential,entrapment efficiency and deformability of different imperatorin nano-lippsome vesicles were investigated.The results showed that the morphological characteristics observed under transmission electron microscope were spherical.And the particle size range were all within 100nm.The polymer dispersity index meet the requirements.The zeta potential of the cationic ultradeformable liposomes was 20.22±0.96mv,and the anionic ultradeformable liposomes was-42.63±0.80mv,which revealed that the surface charge of ultradeformable liposomeswas were successfully modified.Among them,the cationic ultradeformable liposomes have the highest entrapment efficiency of 60.32±2.82%tested by dialysis method.And the highest deformability coefficient of 135.08±5.74mg/sec^-1/cm² calculated with extrusion method.The above indicators indicated that cationic ultradeformable liposomes was beneficial to improve the transdermal penetration efficiency of imperatorin.Chapter 5 showed the Franz diffusion of in vitro transdermal permeability of different imperatorin-loaded nano-liposome vesicles.The results demonstrated that the transdermal permeability of cationic ultradeformable liposomes was significantly improved.The permeation coefficient was 3.45 times higher than that of imperatorin aqueous suspension.The cumulative amount of permeation accumulated within 24hours was 330.50±9.68μg/cm².It was found that the fluorescence intensity at the skin depth of 64μm was the strongest,which was2399.97±248.62 AU.With the differentially scanning calorimetry and infrared spectroscopy analysis of the skin after in vitro transdermal skin tests,it was shown that the lipid structures of the stratum corneum in the skin were not seriously damaged,and the interactions between cationic ultradeformable liposomes and the stratum corneum lipids increased the lipid fluidity,which promoted the transdermal permeation of drugs.In this paper,the imperatorin-loaded cationic ultradeformable liposomes were prepared,which significantly increased the percutaneous cumulative penetration in vitro.The positive charge of the surface could be attracted to the negatively charged lipid in the skin to promote the diffusion through the deeper region in epidermis.The stratum corneum lipids was diffused by the vesicle formulations without serious structural changes.Our results provide useful fundamental information for further development of imperatorin for cutaneous penetration.