| Transdermal drug delivery system (TDDS) was defined that drug was absorbed and delivered to the target sites through the skin administration, then played the role as treatment or prevention of disease. Transdermal administration has a variety of advantages. It can effectively avoid the first-pass effect, overcome gastrointestinal toxicity, increase the local drug concentration, and reduce gastrointestinal side effects. However, transdermal administration is limited to the skin barrier. Currently, iontophoresis, light therapy, and ultrasound therapy have been developed to overcome the barrier. However, these tools require special equipment, methods, and professional operation. The method of pharmaceutics is more conducive to the application.In this work, the new type of microemulsion (ME) transdermal drug delivery system was studied.Ibuprofen (IBU) was selected as model drug. IBU has multiple pharmacological effects including anti-inflammatory, analgesic and antipyretic. It is used to treat rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, neuritis and so on. Since the 1970s, IBU has been widely used in clinical practice, but IBU showed severe gastrointestinal side effects after oral, like heart palpitations, nausea, dizziness, etc. Transdermal drug delivery system can effectively overcome the first-pass effect and avoid damage to the gastrointestinal tract that may be incurred after oral administration. However, domestic commercially available IBU creams in broad show low percutaneous penetration. Moreover, foreign gel products are unavailable in domestic market. On the other hand, gel formulation has a short retention. ME transdermal system shows high moisture, high permeability, good cuticle and dermal drug reservoir function. It is promising to apply ME on transdermal administration. The purpose of this study is to overcome the lack of clinical application of IBU, to develop of new ME system administration, which can enhance transdermal permeation and reduce toxicity.In the first chapter, RP-HPLC method was used to analyze IBU content in vitro samples. The linearity range was 1-200μg/ml, with a coefficient of 0.9999. Both within-and between-day precisions were less than 3%. Recovery was in the range of 95%-105%. Therefore, the analytical method is suitable for analyzing in vitro and in vivo samples.In the second chapter, optimal formulation of IBU-based ME was obtained. The proportions of different ingredients were determined with the values of flux. Firstly, the equilibrium solubility was determined. Apart from olive oil, short-chain fatty acid esters (SCT), glyceryl triacetate, the solubility of IBU in excipients were high. Secondly, the optimized ME formulation was selected with pseudo-ternary phase diagrams combining single factor screening and design-response surface method. The permeation rate from K-C diffusion cell in vitro experiments, centrifugal stability and HaCaT cytotoxicity were selected as an indicator. The optimized ME composition: IBU 5%, OA:IPM:EP (1:2:1) as an oil phase 4%, Cremophor RH40 as a surfactant, ethanol:isopropyl alcohol (2:1) as the co-surfactant, surfactant and co-surfactant, the sum of the proportion of prescriptions for the 44%, Km value was 1.42. Menthol (6%) was added to the optimized formulation to improve penetration rate. Finally, the optimized prescription from the theoretical design was verified. The results proved that designed response surface had high reliability. Physicochemical properties were characterized. Particle size was about 90 nm, zeta potential was about-17 mV and droplets were round from the image of TEM.In the third chapter, pharmacokinetics and pharmacodynamics of IBU-based ME were evaluated. Pharmacokinetics was analyzed by HPLC-MS/MS. The linearity range was 10-1000.0 ng/Ml, showing good linear relationship. Both within and between-day precisions were less than 5%. Recovery was in the range of 90-110%. The analytical method was suitable for analyzing in vitro and in vivo microdialysis samples. Firstly, both blood and dermis microdialysis probes recoveries in vitro and in vivo were determined. In vivo recovery of blood and dermal probes were 26.63±2.60% and 40.62±1.30%, respectively. Then the characteristics of pharmacokinetics were determined for ibuprofen gel, cream, ME, and oral tablet. The rank of AUC in blood shows gel≈ oral group> cream> ME and the rank of AUC in dermis shows gel> ME> cream> oral group. Hence, ME may be an ideal formulation for topical administration to improve the local concentration and reduce systemic side effects. The results from microdialysis were well correlated with CSLM and retention in vivo. Hot plate and writhing method were studied on pharmacodynamics of IBU. The threshold of analgesia in mouse from ME was improved by 87.5%,and was dosage-dependent. The safety of IBU-based ME was also examined. The impact on stratum corneum lipid was evaluated with DSC:gel> ME> cream> control group. The rank of HaCaT cytotoxicity in vitro cell model:gel> ME> cream. The rank of irritation on skin in vivo from pathological text:gel> cream> ME> control group.In the forth chapter, the integrity, dose per actuation, and less packing of the selected spray devices were measured to ensure that the devices were suitable. The influencing factors test, accelerated and long term testing for stability in accordance with the Chinese Pharmacopeia and ministerial standard were evaluated. Appearance, pH, centrifugation stability and content analysis were selected as indicators.The results from impact factors test showed that the ME was stable under high temperature, high humidity and strong light. No significant changes were observed in above indicators after accelerated stability test under the condition of 40±2℃ and RH75±5% for 6 months and long term stability test under the condition of 25±2℃ and RH40+10% for 12 months. |
