Study On Lappaconitine Hydrobromide-loaded Solid Lipid Nanoparticles As Carrier For Transdermal Drug Delivery

In resent years, the transdermal drug delivery systems (TDDS) has been developed rapidly in pharmaceutical science. The uttermost advantage of TDDS is to reduce adverse side effects, to enhance therapy index and for the convenience of clinical usage. In the past, lots of research attention has been paid to transdermal delivery, topical delivery and dermal delivery in TDDS. The transdermal delivery of large molecular such as peptides and proteins, the targeting delivery of drugs for the therapy of skin diseases are major challenges in TDDS. Nowadays, with the rapid development of nanotechnology, nanoparticle drug delivery system (NDDS) is used to conquer these challenges.Solid lipid nanoparticles (SLN) is an alternative carrier system using solid biodegradable lipid as drug carriers, with the diameters ranging between 10 nanometers and 1000 nanometers, which has the advantages of high physical stability and more entrapment efficiency (EE). It can be used for controlled drug release and sustained release formulation. It offers more bioavailability comparing to other transdermal systems. It also has the advantages of low speed of leakage, low cytotoxity, large scale capability, etc. The objective of this thesis was to study thelappaconitine hydrobromide-loaded solid lipid nanoparticles (LH-SLN). The model drug employed here was a lipophilic drug lappaconite hydrobromide (LH). The present study was to assess the feasibility of high pressure homogenization technique, and the physicochemical properties of prepared LH-loaded SLN, such as particle size analysis, zeta potential measurement, drug entrapment efficiency, physical stability, in vitro drug release behavior, skin irritation testing and skin permeation studies. An HPLC method with acetonitrile: 0.02 mol·L-1NaH2PO4 solution (26:74, v/v) as mobile phase was developed for the assay of LH in formulation, its physical stability, in vitro drug release behavior and skin permeation studies. The analysis method was proven to be precise, simple and reliable.Based on the results from the pre-formulation study, the method of high pressure homogenization technique was used to prepare LH-SLN. The parameter such as morphous, particle size and entrapment efficiency (EE) were used as criterions to evaluate the effects of surfactants, lipid materials, emulsifying temperature, emulsifying time and stirring rate on the properties of LH-SLN. As a result, the lipid concentration, ratios of drug to lipid, the amount of surfactant mixture and ratios of poloxamer 188 and Tween 80 were proved to have great effect on the properties of LH-SLN. On the basis of the single factor exploration , the satisfactory formulation was selected by orthogonal design using high entrapment efficiency as standard. Three batches of LH-SLN were prepared using the optimized formulation. From photon correlation spectroscopy using Malvern Zetasizer, the particle size was determined to be 33.8nm, the entrapment efficiency was 70.48% and the zeta potential was -38mV, which met the pre-set criteria.The entrapment efficiency of LH-SLN was directly determined by ultrafiltration method using centrifugal filter tubes. The drug loading capacity and pattern were studied as well. In vitro drug release was studied by using the dialysis bag method and the drug release equation was determined by the curve fitting method. The results showed that the drug release of LH-SLN in vitro fited Higuchi kinetics model very well. The equation was Q=-0.3216 t1/2+0.1698 (r=0.9954) . The stability of LH-SLN was examined after being stored under cold conditions, and the results showed that LH-SLN was stable for two months at least.In order to assess the skin uptake and penetration of LH from SLN, the in vitro permeation ability through skins was studied using Franz-type diffusion cells. The KM rats and normal saline were selected. The results indicated that LH-SLN was more suitable as the trandermal drug delivery system.The in vitro permeation studies with various pretreated skin membranes had shown that the stratum corneum was the main barrier of percutaneous absorption. It displayed some"reservoir"effect to LH-SLN. The mechanism of LH-SLN as the penetration enhancer was discussed by using analytical means (such as DSC and SEM). The result of microscopic observation manifested the barrier-weakening action of SLN toward the epidermis. The tight conjunction of lipid membrane was destroyed after applying SLN,accompanying many crevices which facilitated the compound permeates the penetration pathway.At last, LH-SLN suspension would be made into gel to study the skin irritation. As a result, less stimulation was seen for normal skin, which indicated that LH-SLN gel was safer and caused less skin irritation.Currently, there has been no report about lappaconitine hydrobromide-loaded solid lipid nanoparticles as carriers for transdermal drug delivery in the world. In this dissertation, it was proved that solid lipid nanoparticles indeed increased the absorption of poor water solubility drugs after transdermal drug delivery. Therefore, it is a new drug delivery system with great research value and potential.