盐酸氨氯吡咪透颅吸收研究

发布时间：2019-07-02 20:48

【摘要】：目的:探讨新的给药途径,用盐酸氨氯吡咪进行大鼠在体透颅吸收的研究;给脑部疾病的治疗提供一个新的给药途径。建立盐酸氨氯吡咪高效液相色谱测定方法。探讨透颅穴位与非穴位给药之间是否存在显著性差异。研究桉叶油对盐酸氨氯吡咪的促渗作用及盐酸氨氯吡咪的透过量。方法:本专题进行盐酸氨氯吡咪生物样品高效液相色谱法测定的方法学考察;盐酸氨氯吡咪透颅给药药动学研究,并用3p97软件处理所得数据;盐酸氨氯吡咪不同年龄段大鼠透颅给药研究,考察透过率与脑颅厚度的关系;盐酸氨氯吡咪透颅穴位给药的研究,研究透颅穴位与非穴位给药是否存在差异性。制备盐酸氨氯吡咪凝胶,为体外透颅研究提供一个药物剂型。盐酸氨氯吡咪体外透颅研究及选用桉叶油为渗透剂,3%氮酮为对照进行渗透剂的筛选。结果:盐酸氨氯吡咪的标准曲线回归方程为y=70724x+1983.7,R2=0.9991,在0.02~0.32μg/ml之间呈线性关系;低(0.08μg/ml)、中(0.16μg/ml)、高(0.24μg/ml)3个浓度的日内精密度RSD为3.33%、1.73%、7.98%,日间精密度RSD为0.47%、0.72%、1.04%,均10%,符合方法学要求;常温下10小时内稳定性的RSD分别为0.61%,0.06%,1.59%,均10%,符合方法学要求;低、中、高浓度的提取回收率分别为88.2±2.08%、87.9±1.97%、90.4±2.36%,均≥70%,符合方法学要求;低、中、高浓度的相对回收率分别为105.9±1.12%、101.2±1.42%、112.0±2.78%,均在85%-115%之间,符合方法学要求。盐酸氨氯吡咪在大鼠脑中的药代动力学符合一室模型(weight=1),其药动学主要参数为:A为0.266875±0.0290μg*m L-1,Ke为0.004208±0.0002min-1,Ka为0.092585±0.0313 min-1,Lag time为50.416229±1.3574 min,T1/2(Kα)为7.486592±1.0691min,T1/2(Ke)为164.7375564±11.2555 min,Tpeak为85.39389±2.6294 min,Cmax为0.219884±0.0201μg/m L,AUC为60.544632±4.0446(μg*m L-1)*min,CL/F(s)为1.982009±0.1319 mg/kg/min/(μg*m L-1),V/F(c)为471.0563±40.2545(mg*kg-1)/(μg*m L-1)。盐酸氨氯吡咪在幼年、中年、老年大鼠脑中的浓度分别为0.30275μg/m L,0.22726μg/m L,0.06789μg/m L。所建立的分析方法无法检测出透颅穴位给药后大鼠脑组织中盐酸氨氯吡咪的含量。盐酸氨氯吡咪凝胶处方确定HPMC为主要凝胶基质,甘油为药物和HPMC的分散剂和润湿剂,其最佳处方为HPMC 0.4g,甘油1.5g,加水至10g,最后将p H调至6。加了渗透剂的凝胶透颅渗透率增加,其中4%及5%桉叶油的促渗效果较优,增透倍数分别为1.295、1.264倍;且4%和5%桉叶油的促渗作用比3%氮酮的促渗作用好。盐酸氨氯吡咪凝胶的透皮累积渗透量比透颅累积渗透量稍大,但没有显著性差异(P0.05)。结论:初步探讨了盐酸氨氯吡咪的透颅吸收研究,其药动学参数表明盐酸氨氯吡咪可渗透进入大脑。盐酸氨氯吡咪透颅给药的药物透过量与年龄成反比,表明了盐酸氨氯吡咪的透过量可能与脑颅骨的厚度有关。在透颅穴位给药的初步研究中,所建立的分析方法无法检测给药后大鼠脑组织中盐酸氨氯吡咪的含量,表明盐酸氨氯吡咪透颅穴位给药进入脑组织的含量低于检测限;其原因可能与给药面积和给药量有关。盐酸氨氯吡咪体外透皮给药与透颅给药实验中,透皮累积渗透量比透颅累积渗透量稍大,但无显著性差异;表明大鼠的脑颅可能对盐酸氨氯吡咪具有比较高的透过率。这些实验工作为透颅给药途径提供了数据支持。
[Abstract]:Objective: To study the new route of administration, and to study the absorption of the rat in the body by using the chlorprochlorid hydrochloride, and to provide a new route for the treatment of the brain diseases. A high performance liquid chromatography method was established for the determination of chlorprochlorid hydrochloride. To study whether there was a significant difference between the acupuncture point and the non-acupuncture point. The effects of eucalyptol oil on the protonic effect of p-chloroprochlorid and the transmission of ammochloride in hydrochloric acid were studied. Methods: The method of high performance liquid chromatography (HPLC) was carried out for the determination of chlorprochlorid hydrochloride by HPLC, and the pharmacokinetic study was carried out with 3 p97 software, and the data were treated with 3p97 software. The relationship between the transmission rate and the thickness of the brain and the thickness of the cranial fossa was studied. The preparation method comprises the following steps of: preparing a chlorprochlorid hydrochloride gel, and providing a pharmaceutical dosage form for the in-vitro penetrating cranium study. The study on the in vitro and the selection of the osmotic agent with the use of eucalyptus oil as the penetrating agent and 3% azone as the control. Results: The linear regression equation of the standard curve of the chlorprochlorid hydrochloride is y = 70724x + 1983.7, R2 = 0.9991, the linear relationship between 0.02 and 0.32. mu. g/ ml, low (0.08. mu.g/ ml), medium (0.16. mu.g/ ml), high (0.24. mu.g/ ml) three concentrations, the RSD is 3.33%, 1.73%, 7.98%, and the day precision RSD is 0.47%, 0.72%, 1.04% and 10%, the RSD were 0.61%, 0.06%, 1.59% and 10%, respectively. The recoveries were 88.2% 2.08%, 87.9% 1.97%, 90.4% 2.36% and 70%, respectively. The relative recovery rates of low, medium and high concentrations were 105.9% 1.12%, 101.2% 1.42%, 112.0% 2.78%, and all were between 85% and 115%, and met the methodological requirements. The pharmacokinetics of ambroxol hydrochloride in the brain of rats was in accordance with the one-compartment model (weight = 1). The main parameters were: A is 0.266875, 0.0290. mu. g * m L-1, Ke is 0.004208-0.0002 min-1, Ka is 0.092585-0.0313min-1, Lag time is 50.416229-1.357min, T1/2 (Ke) is 7.486592-1.357min, T1/2 (Ke) is 164.7375564-11.2555min, Tpeak is 85.39389-2.6294min, The Cmax was 0.2219884 to 0.0201. m u.g/ m L, the AUC was 60.554 4632-4.0446 (. mu.g * m L-1) * min, CL/ F (s) was 1.982009, 0.1319 mg/ kg/ min/ (. mu.g * m L-1), and V/ F (c) was 471.0563-40.2545 (mg * kg-1)/ (. mu.g * m L-1). The concentration of ambroxol hydrochloride in the brain of young, middle-aged and old rats was 0.30275 & mu; g/ m L, 0.222726 & mu; g/ m L, and 0.06789 & mu; g/ m L respectively. The established analytical method was unable to detect the content of ambroxol hydrochloride in the brain tissue of rats after the administration of the through-cranial acupuncture point. HPMC is the main gel matrix, glycerol is the dispersing agent and wetting agent of the drug and HPMC, the best formulation is HPMC 0.4 g, glycerin 1.5 g, water to 10g, and finally the p H is adjusted to 6. The penetration rate of the gel penetrating through the penetrating agent increased, and the permeability of 4% and 5% of the eucalyptus oil was better, the penetration multiple was 1.295 and 1.264 times, and the growth-promoting effect of 4% and 5% of the eucalyptus oil was better than that of 3% azone. The amount of the transdermal cumulative penetration of the chlorprochlorid hydrochloride gel was slightly larger than that of the penetrating cranium, but there was no significant difference (P0.05). Conclusion: The study of the trans-cranial absorption of chlorprochlorid hydrochloride is discussed. The pharmacokinetic parameters show that the chlorprochlorid hydrochloride is permeable to the brain. The amount of the drug to be administered to the mprochlorid hydrochloride is inversely proportional to the age, indicating that the amount of the chlorprochlorid hydrochloride may be related to the thickness of the skull of the brain. In the preliminary study of the administration of the through-cranial acupuncture point, the established analytical method was unable to detect the content of the ambroxol hydrochloride in the brain tissue of the rat after administration, indicating that the content of the ammochlorid hydrochloride in the brain tissue was lower than that of the detection limit; the cause may be related to the area of administration and the amount of administration. In the experiment of transdermally and transdermal administration of ammochlorid hydrochloride in vitro, the amount of transdermal cumulative penetration was slightly larger than that of the through-cranial, but there was no significant difference; it was shown that the brain of the rat might have a relatively high transmission rate to the chlorprochlorid hydrochloride. These experiments provide data support for the transcranial route of administration.
【学位授予单位】：广东药科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R96

【相似文献】