【摘要】：目的:探討新的給藥途徑,用鹽酸氨氯吡咪進行大鼠在體透顱吸收的研究;給腦部疾病的治療提供一個新的給藥途徑。建立鹽酸氨氯吡咪高效液相色譜測定方法。探討透顱穴位與非穴位給藥之間是否存在顯著性差異。研究桉葉油對鹽酸氨氯吡咪的促滲作用及鹽酸氨氯吡咪的透過量。方法:本專題進行鹽酸氨氯吡咪生物樣品高效液相色譜法測定的方法學考察;鹽酸氨氯吡咪透顱給藥藥動學研究,并用3p97軟件處理所得數(shù)據(jù);鹽酸氨氯吡咪不同年齡段大鼠透顱給藥研究,考察透過率與腦顱厚度的關(guān)系;鹽酸氨氯吡咪透顱穴位給藥的研究,研究透顱穴位與非穴位給藥是否存在差異性。制備鹽酸氨氯吡咪凝膠,為體外透顱研究提供一個藥物劑型。鹽酸氨氯吡咪體外透顱研究及選用桉葉油為滲透劑,3%氮酮為對照進行滲透劑的篩選。結(jié)果:鹽酸氨氯吡咪的標準曲線回歸方程為y=70724x+1983.7,R2=0.9991,在0.02~0.32μg/ml之間呈線性關(guān)系;低(0.08μg/ml)、中(0.16μg/ml)、高(0.24μg/ml)3個濃度的日內(nèi)精密度RSD為3.33%、1.73%、7.98%,日間精密度RSD為0.47%、0.72%、1.04%,均10%,符合方法學要求;常溫下10小時內(nèi)穩(wěn)定性的RSD分別為0.61%,0.06%,1.59%,均10%,符合方法學要求;低、中、高濃度的提取回收率分別為88.2±2.08%、87.9±1.97%、90.4±2.36%,均≥70%,符合方法學要求;低、中、高濃度的相對回收率分別為105.9±1.12%、101.2±1.42%、112.0±2.78%,均在85%-115%之間,符合方法學要求。鹽酸氨氯吡咪在大鼠腦中的藥代動力學符合一室模型(weight=1),其藥動學主要參數(shù)為:A為0.266875±0.0290μg*m L-1,Ke為0.004208±0.0002min-1,Ka為0.092585±0.0313 min-1,Lag time為50.416229±1.3574 min,T1/2(Kα)為7.486592±1.0691min,T1/2(Ke)為164.7375564±11.2555 min,Tpeak為85.39389±2.6294 min,Cmax為0.219884±0.0201μg/m L,AUC為60.544632±4.0446(μg*m L-1)*min,CL/F(s)為1.982009±0.1319 mg/kg/min/(μg*m L-1),V/F(c)為471.0563±40.2545(mg*kg-1)/(μg*m L-1)。鹽酸氨氯吡咪在幼年、中年、老年大鼠腦中的濃度分別為0.30275μg/m L,0.22726μg/m L,0.06789μg/m L。所建立的分析方法無法檢測出透顱穴位給藥后大鼠腦組織中鹽酸氨氯吡咪的含量。鹽酸氨氯吡咪凝膠處方確定HPMC為主要凝膠基質(zhì),甘油為藥物和HPMC的分散劑和潤濕劑,其最佳處方為HPMC 0.4g,甘油1.5g,加水至10g,最后將p H調(diào)至6。加了滲透劑的凝膠透顱滲透率增加,其中4%及5%桉葉油的促滲效果較優(yōu),增透倍數(shù)分別為1.295、1.264倍;且4%和5%桉葉油的促滲作用比3%氮酮的促滲作用好。鹽酸氨氯吡咪凝膠的透皮累積滲透量比透顱累積滲透量稍大,但沒有顯著性差異(P0.05)。結(jié)論:初步探討了鹽酸氨氯吡咪的透顱吸收研究,其藥動學參數(shù)表明鹽酸氨氯吡咪可滲透進入大腦。鹽酸氨氯吡咪透顱給藥的藥物透過量與年齡成反比,表明了鹽酸氨氯吡咪的透過量可能與腦顱骨的厚度有關(guān)。在透顱穴位給藥的初步研究中,所建立的分析方法無法檢測給藥后大鼠腦組織中鹽酸氨氯吡咪的含量,表明鹽酸氨氯吡咪透顱穴位給藥進入腦組織的含量低于檢測限;其原因可能與給藥面積和給藥量有關(guān)。鹽酸氨氯吡咪體外透皮給藥與透顱給藥實驗中,透皮累積滲透量比透顱累積滲透量稍大,但無顯著性差異;表明大鼠的腦顱可能對鹽酸氨氯吡咪具有比較高的透過率。這些實驗工作為透顱給藥途徑提供了數(shù)據(jù)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.
【學位授予單位】：廣東藥科大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R96

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