Studies On Brucine Transdermal Patch

Strychnos nux-vomica L is commonly used toxiferous Chinese medicine. In traditional clinical medication, Strychnos nux-vomica L and its compound medicine exhibit excellent therapeutic effect, particularly in dredging collaterals, causing analgesia, eliminating stagnation, and subsiding swelling. However, the narrow oral therapeutic window seriously restricts its clinical application. As a matter of fact, the reason is that Strychnine and Brucine are the main toxiferous components as well as the principal bioactive ingredients. In the modern research studies, Strychnine has great toxicity but little curative effect; therefore, in general, the analgesic effect is closely related to Brucine. Consequently, it possesses very important clinical significance to develop Brucine into safe transdermal delivery dosage forms with convenient and accurate medication and persistent therapeutic effect.Thus, this paper conducts a detailed research study on the properties of Brucine, including oil-water partition coefficient, transdermal absorption capacities in vitro and its plasma protein binding rate at different PH values. Also, it explores and optimizes lipophilic and hydrophilic ground substances respectively in the patch preparation technology, and compares their transdermal absorption capacities in vitro. Besides, it adopts hot-plate test and acetic acid-induced writhing test in mice to examine the analgesic effect of patches, and on this basis, it selects effective dose to research pharmacokinetics in different ways of intravenous injection and transdermal medication. In short, this paper provides powerful scientific evidence for a successful production of Brucine hereafter.The research study on Brucine's transdermal absorption capacities in vitro indicates that at PH of 5,6,7.4,8 and 9 individually, the respective oil-water partition coefficient of Brucine is 0.04, 025,3.59,11.02 and 26.05; the respective accumulated permeation volume dose per unit area of transdermal absorption in vitro is (125.08±11.29), (156.957±12.086), (140.442±18.011), (154.696±12.612) and (166.412±5.469)μg·cm-2; the respective accumulated permeation percent is (56.785±7.825)%, (71.258±5.46)%, (63.760±8.176)%, (70.232±5.72)% and (75.551±2.48)%; and the respective transdermal rate is 29.505,29.245,25.674,30.261 and 45.147μg·cm-2·h-1. Therefore, as the PH value rises, oil-water partition coefficient, accumulated permeation volume dose per unit area, accumulated permeation percent and permeation rate generally increase. In addition, it is noteworthy that at a PH of 9, oil-water partition coefficient and permeation rate have significant differences (p<0.01), while the accumulated permeation percent shows no difference. In fact, when PH value is greater than the dissociation constant of drugs (Brucine pka value is 8.20), oil-water partition coefficient increased remarkably and permeation rate also become faster because the drugs permeate the lipophilic horny layer on the surface of human skin more easily. Nevertheless, in the same circumstances, accumulated permeation volume dose has no significant increase probably because of the concentration gradient on two sides of the skin.The plasma protein binding rate of Brucine presents non-quality concentration dependency in high, medium and low plasma quality concentration and the binding rate is moderate, about 59%.This paper investigates how oleic acid, tween-80, Azone, dimethyl sulfoxide and ethanol promote the permeation capacities of Brucine solutions individually. The results demonstrate that most of them can promote permeation capacities in vitro to some extent and the order of promoting degree is Azone> ethanol> dimethyl sulfoxide> tween-80> oleic acid, among which, Azone has the most significant effect, compared with the control group, permeation rate (J) increases nearly four times and permeation volume dose per unit area (Q) 2.58 times.In this paper, the formulation of transdermal patches is optimized by means of L9 (34) orthogonal design, which takes the characteristics of patches and accumulated permeation amount as indexes. Characteristics, including homogeneity,extensibility, viscosity and peeling strength are all taken into consideration. As a result, optimized lipophilic patch is acrylate Pressure-Sensitive Adhesive (E100):Plasticiser (Dibutyl Sebacate):Cross Linking Agent (Succinic Acid)= 10:4:1, plus 25% Tackifier (PEG400) and 3% Azone; while optimized hydrophilic patch is CMC-Na:PVA:PVP K30:Glycerol= 2:3:1:1.5, plus 3% Azone (The respective matrical concentration are CMC-Na:6.67%, PVA:20%, PVP:100%). The comparison between transdermal capacities of these two patches shows that lipophilic patches release quickly at first and later slowly, and basically complete releasing after 6 hours. According to the tangent line on the transdermal curve, the releasing rate Q=59.626t-0.436, and the process of releasing is in accordance with Higuchi equation (R2=0.902). Nonetheless, hydrophilic patches release at constant speed during the 24 hours, and Q=5.2504t-0.6844 (R2=0.994), which is more conform to the process of zero level releasing. Therefore, hydrophilic patches can release persistently and slowly at constant speed and guarantee stable blood drug level in vivo, which is Analgesic effect of hydrophilic patches has been examined by hot-plate test. The results reveal that medication group shows good dose dependent when given the dose of 60,120 and 240 mg·kg-1 respectively. From the hour-effect diagram, it can be seen that the analgesic effect of each group reached the maximum after 6 hours. Specifically, with high-dose given, the percent of analgesic effect was about 120%, which is almost equal to that of YunNanBaiYao patch. Besides, in the acetic acid-induced writhing test, compared with excipient group, medium dose and high does exhibit good writhing depressant effect in the dose of 60,120 and 240 mg·kg-1, and the percent of analgesic effect is more than 50%(P＜0.01), however, low dose does not have significant depressant effect (p>0.05).In the end, this paper also has carried out pharmacokinetic research on Brucine solutions intravenous injection and Brucine patches. By the DAS2.0 data processing software, it can be seen that MRT of Brucine transdemal patches has extended nearly tenfold, with MRT 49.12min and 451.89min individually, besides, its absolute bioavailability has achieved 34.76%. Apparently, Brucine transdermal patches can extend clearance time. Therefore, compared with intravenous injection, transdermal medication can remarkably lower the peak of the blood drug level, make it more stable and maintain for longer time, which is beneficial to develop its curative effects and reduce its toxicity significantly in the mean time, and to some extent, confirms the hypothesis that transdermal medication is an efficient method to avoid toxic reaction of Brucine.