| Tripterygium wilfordiiHook f.(TWHF), a traditional Chinese medicine grown in the east and south of China, Japan, and Korea, has potent anti-inflammatory properties and it has been used to treat a variety of immune-related diseases, especially rheumatoid arthritis, with promising clinical results. Nevertheless, its long-term and large-dosing administration was restricted by the low solubility of its useful components and its toxicity, especially on gastrointestinal, cardiovascular and reproductive system. Furthermore, its therapeutic dose is close to its toxic dose, resulting in a low therapeutic index. Hereby, a drug delivery system which is able to maximize the anti-inflammatory properties and minimize the toxicity of TWHF is supposed to be developed in the clinical trials.Transdermal drug delivery systemis gaining ground on account of its advantages to minimize gastrointestinal side effects and first pass metabolism when compared to other administration routes. Moreover, transdermal drug delivery system could provide a stable plasma blood concentration different from oral administration, solving the low therapeutic index problem of TWHF. Thus, we use the transdermal drug delivery system as our delivery system for TWHF in this study, However, in order to reach therapeutic concentrations in the epidermis and/or in the dermis or even in the systemic circulation, the skin barrier has to be overcome. Microemulsions are considered efficient carriers in the transdermal drug delivery system and effective vehicles of the solubilization of both hydrophilic and lipophilic drugs. Their excellent drug delivery potential as well as the solubilization capacity is caused by a variety of factors depending on the composition and the resulting microstructures, but mainly, the continuously and spontaneously fluctuating interfaces of microemulsion enable high drug mobility and might enhance the drug diffusion process. Therefore, we try to prepare a novel TWHF transdermal microemulsion drug delivery system (TMDDS) here to get a more potent efficacy and lower toxicity on the administration of TWHF.In light of the evaluation indexes of transdermal accumulation and4h suppression ratio of inflammation, the optimum formula was ascertained by the central composite design-response surface methodology. When the correspondent percentage of oleic acid as oil phase was0.12, the percentage of surfactants (Labrasol) and cosurfactants (Transcutol P and Pharmasolve) was0.59, and the percentage of water was0.29, respectively, it was the optimum formula. The transdermal accumulation was35.87mg/ml and the4h suppression ratio of inflammation was61.56%. After that, we verified the optimum formula and found that the optimum formula of Tripteryglum. wilfordii. Hook.f METDDS was acquired swiftly and simply by the central composite design-response surface methodology. Meanwhile, a reliable predictability can be seen.Pharmacodynamic study was conducted by complete Freund adjuvant arthritis rat model, TWHF and TWHF-ME were continuously administrated24days at dose30,60,120mg/kg. Rats were observed during the administration of the general status, weekly monitoring of body weight.The volumes of the swelling were measured at0,4,8,12,18,24,28,36and42days. After the last administration, blood biochemistry, organ coefficient, and prostaglandin (PG) level in sera were checked and tissue histopathology were evaluated in animal model of rheumatoid arthritis. The results showed that anti-inflammatory activities of TWHF-ME are stronger than those of free TWHF. TWHF-ME can enhanced inhibition effect of the rat paw swelling and serum prostaglandin, and has a protective effect on the damage of the ankle joint and the synovial membrane by pathology. Meanwhile, TWHF-ME reduced liver toxicity and reproductive toxicity which induced by TWHF. And there was a slight pathological injury of the testis and epididymis.We assessed the integrity, dose per actuation, and other requirements listed in the Chinese Pharmacopeia of the spray devices, and the devices passed all the tests. We performed the influencing factors test, accelerated and long term testing for stability in accordance with the Chinese Pharmacopeia and ministerial standard. Quality assessment criteria include appearance, pH, TLC and LC-MS-MS, and a quality specification protocol were developed. Results from influencing factors test showed instability under high temperature, high humidity and strong light, and hence the transdermal spray should be stored in a cool dry place, and away from light. Accelerated and long term stability testing showed no significant changes in quality after storing under the condition of40℃±2℃and RH75%±5%, as well as25℃±2℃and RH40%±10%for3months. Results at6months for accelerated testing, and results at6,9,12,18,24and36months for long term testing are under way.Based on the above results, it can be concluded that TWHF transdermal microemulsion spray has successfully achieved the objectives of the research project. Not only did the transdermal spray increase the efficacy, reduce the toxicity but also provide a stable plasma concentration of the TWHF. Quality control was effective, and stability test also demonstrated satisfactory results. |
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