鹽酸多西環(huán)素論文鹽酸多西環(huán)素殼聚糖微囊的制備及其在家兔體內(nèi)的藥動學研究

1、鹽酸多西環(huán)素論文：鹽酸多西環(huán)素殼聚糖微囊的制備及其在家兔體內(nèi)的藥動學研究【中文摘要】鹽酸多西環(huán)素(Doxycycline Hyclate)為廣譜抗生素,獸醫(yī)臨床應(yīng)用廣泛。但其性質(zhì)不穩(wěn)定性.口服和注射刺激性較大,因而在一定程度上限制了鹽酸多西環(huán)素的應(yīng)用。藥物微囊化后不但可以提高藥物的穩(wěn)定性,延緩藥物釋放從而延長藥物在體內(nèi)的作用時間,減少對胃的刺激,還可進一步制成其它劑型,如散劑、片劑、顆粒劑、注射劑等以方便臨床應(yīng)用。目前,有關(guān)鹽酸多西環(huán)素微囊的制備國內(nèi)外尚未見報道。因此,本實驗采用乳化交聯(lián)法制備鹽酸多西環(huán)素殼聚糖微囊,并對所得微囊的各項性質(zhì)及其在家兔體內(nèi)的藥動學進行了研究。建立反相高效液相色譜法

2、(RP-HPLC)測定微囊中鹽酸多西環(huán)素的載藥量和包封率。色譜條件為：色譜柱KromasilC18柱(4.6mm×150mm,5um),流動相：0.05mol·L-1草酸銨溶液-二甲基甲酰胺-0.2mol/L磷酸氫二銨溶液-甲醇(53：33：4：10),流速：1.0 mL/min,檢測波長：280 nm,柱溫：35g/mL濃度范圍內(nèi)與峰面積呈良好線性關(guān)系,回歸方程為：A=18503.14C-9789.27,r=0.9997(n=7),回收率在98.81%-100.10%之間,日內(nèi)RSD及日間RSD均小于2%(n=5)。證明該方法準確可靠、方便快捷,可用于鹽酸多西環(huán)素微囊中藥

3、物含量及包封率的測定。以包封率和載藥量為主要考察指標,在單因素實驗基礎(chǔ)上結(jié)合正交實驗設(shè)計法優(yōu)選出鹽酸多西環(huán)素殼聚糖微囊的最佳制備處方,即：殼聚糖濃度：2%,司盤-80：5,藥物與殼聚糖質(zhì)量比：2：5,甲醛：1.5%。按以上處方制得微囊平均載藥量和包封率分別為20.60%,85.54%。本實驗對鹽酸多西環(huán)素殼聚糖微囊的形態(tài)、粒徑、包封率、載藥量、體外釋藥特性及穩(wěn)定性等藥劑學特性進行了考察和評價。掃描電鏡下可見微囊呈較規(guī)整的球形,平均粒徑為10um,分布均勻,分散性較好。體外釋放實驗表明鹽酸多西環(huán)素原料藥3h釋放達到90%以上,而微囊在48h后僅約釋放出80%。可見,微囊化后具有明顯的緩釋效應(yīng)。穩(wěn)

4、定性實驗表明,藥物微囊化后能顯著提高其穩(wěn)定性。通過給家兔分別灌服鹽酸多西環(huán)素水溶液(A組)和其殼聚糖微囊的水分散液(B組)研究鹽酸多西環(huán)素殼聚糖微囊在家兔體內(nèi)的藥動學特征。以HPLC法測定血漿中鹽酸多西環(huán)素含量.所得數(shù)據(jù)以DAS2.0藥動學軟件處理,進行房室模型擬合,以AIC值最小,R2值最大為判斷依據(jù),結(jié)果表明兩組藥時數(shù)據(jù)均符合一級吸收二室模型(權(quán)重=1),計算藥代動力學參數(shù)如下：A組：Ka為(1.256±0.708)1/h,T1/2為(1.157±0.526)h,T1/2為(2.189±0.377)h, AUC(0-)為(11.834±0.194)m

5、g/L*h, Cmax為(1.74±0.002)mg/L, Tmax為(3±0.000)h,其擬合方程為：C=13.709e-1.256t+7.876e-0.703t-21.585e-0.323t。B組：Ka為(0.204±0.11)1/h,T1/2為(7.51±2.87)h,T1/2為(9.004±1.596)h, AUC(0-)為(35.201±0.353)mg/L*h. Cmax為(1.102±0.004)mg/L, Tmax為(12±0.000)h.擬合方程為：C=12.705e-0.204t+12.879

6、e-0.100t-25.584e-0.078t。研究結(jié)果表明,乳化交聯(lián)法制備鹽酸多西環(huán)素殼聚糖微囊工藝簡單,質(zhì)量可控,重現(xiàn)性好。所得微囊各項特性符合制劑要求,且具有很好的緩釋效果和穩(wěn)定性,有利于延長藥物作用時間,提高藥物穩(wěn)定性,減少給藥次數(shù),因此,將鹽酸多西環(huán)素微囊化具有良好的開發(fā)應(yīng)用前景。【英文摘要】As a broad-spectrum antibiotic Doxycycline hyclate is widely used in the veterinary clinic. Because of its instability, oral dosage forms and inject

7、ion of doxycycline usually have great intimulation.and its storage and application were limited in a certain extent. Microencapsulation could not only enhance pharmacal stability, prolonged drugs release time, but also lessen harm to stomach. Microcapsules can also further be made into other dosage

8、forms for clinical application convenient, such as pulveres, tablet, granules, injection et al. At present, there has no report about doxycycline hyclate microcapsules at home and abroad.,In this study, biodegradable chitosan was selected as the membrane material and doxycycline hyclate microcapsule

9、s were prepared by emulsifying crosslinking method.Characters of doxycycline hyclate-chitosan microcapsules and its pharmacokinetics in health rabbits were evaluated.An RP-HPLC method of higher specialty was used to detect the content and entrapment efficiency. The analysis was performed on a Kromas

10、il Cig (4.6mmx 150mm, Sum) analytical column. The mobile phase was composed of a mixture of 0.05 mol/Lammonium oxalate solution-N.N-dimethyl fomamide-0.2 mol/Lammonium monohydric phosphate solution-methanol (53:33:4:10) at a flow rate of 0.8mL/min. Doxycycline hyclate was detected at 280nm and at a

11、35column temperature. The results indicated that the excipients and solvent in the microcapsule could be well separated from the drug under such a designated chromatogram condition. A good linear relationship was found between peak area and the concentration of doxycycline hyclate in the range of 10

12、.0-120.0ug/mL. Linear regression equation was A=18503.14C-9789.27, (r=0.9997.n=7), the average recoveries were between 98.81%and 100.10%(n=5).RSD values of intra-day and inter-day were less than 2%(n=5).It had showed that this method were specific, accurate, reliable, sensitive and applicable for th

13、e content and entrapment efficiency determination of doxycycline hyclate microcapsules.Encapsulation efficiency and drug loading were used as the main index of examination, and the orthogonal design was used to optimize the prescripton of doxycycline hyclate-chitosan microcapsules on the base of sin

14、gle factor experiments. Under the optimal prescripton.20.60%and 85.54%were got as the mean drug loading and entrapment efficiency of doxycycline hyclate-chitosan microcapsules.In this work, surface morphology, particle size and particle size distribution, drug encapsulation efficiency, drug loading.

15、stability, drug release kinetics in vitro of drug-loaded microparticles were investigated. SEM observation showed the drug-loaded microparticles exhibited sphere-like shape and average particle size was about l0um with narrow particle size distribution. In vitro release studies revealed that the dru

16、g-loaded microparticles substantially improved the sustained-release property. It can be seen that the free doxycycline hyclate rapidly release up to 90%in 3h, drug-loaded microparticles exhibited an accumulative release of 80%after 48h.The results indicated that microencapsulation could highlighted

17、 extend release property. And the stability study showed that microencapsulation could enhanced stability of doxycycline hyclate.Doxycycline hyclate solution (A group) and microcapsule suspension liquid (B group)were administrated on health rabbits orally to study the pharmacokinetic of doxycycline

18、hyclate microcapsule. Using doxycycline hyclate solution as a reference, their pharmacokinetic differences were compared. Plasma drug concentration was determined by RP-HPLC. and the pharmacokinetic parameters were analyzed by DAS2.0 pharmacokinetic program. The results showed that data of A, B grou

19、p was in line with a two-compartment model (weight=1). The main pharmacokinetic parameters and the fitting equation were as follows:A group:Ka was (1.256±0.708)1/h, T1/2a was (1.157±0.526)h. T1/2p was (2.189±0.377)h, AUC(0-) was (11.834±0.194)mg/L*h, Cmax was (1.74±0.002)mg/

20、L, Tmax was (3±0.000)h, the fitting equation was C=13.709e-1.256t+7.876e-0.703t-21.585e-0.323t .B group:Ka was (0.204±0.11)1/h. T1/2a was (7.51±2.87)h. T1/2was (9.004±1.596)h, AUC(0-) was (35.201±0.353)mg/L*h. Cmax was (1.102±0.004)mg/L. Tmax was (12±0.000)h. the f

21、itting equation was C=12.705e-0.204t+12.879e-0.100t-25.584e-0.078tcStudies on the preparation and pharmacokinetics of doxycycline hyclate microcapsules showed the emulsifying crosslinking method was simple and of good reproducibility. and the quality was adjustable. The characteristics of microcapsu

22、les were live up to the preparations requirements and had preferable sustained-release, stability, being in favor of prolonging the action time.improving doxycycline hyclates stability in microcapsule, reduing the administration times. So microcapsulating the doxycycline hyclate has good development

23、 and application prospects.【關(guān)鍵詞】鹽酸多西環(huán)素 殼聚糖微囊 質(zhì)量評價 藥物動力學【英文關(guān)鍵詞】Doxycycline hyclate Chitosan microcapsules Quality evaluation Pharmacokinetic【目錄】鹽酸多西環(huán)素殼聚糖微囊的制備及其在家兔體內(nèi)的藥動學研究 摘要 4-6 ABSTRACT 6-8 英文縮寫詞表 9-12 第一章 文獻綜述 12-29 1. 微囊研究進展及在藥物新制劑研發(fā)中的應(yīng)用 12-18 1.1. 微囊的定義 12 1.2. 藥物微囊化的優(yōu)點及其應(yīng)用 12-13 1.3. 微囊的制備方法 13

24、-16 1.4. 藥物微囊化的應(yīng)用 16-17 1.5. 微囊化技術(shù)存在的問題及發(fā)展方向 17-18 2. 殼聚糖及其在藥物傳遞系統(tǒng)中的應(yīng)用 18-23 2.1. 殼聚糖的性質(zhì) 18-19 2.2. 殼聚糖在藥物傳遞系統(tǒng)中的應(yīng)用 19-21 2.3. 殼聚糖微囊的制備研究 21-22 2.4. 殼聚糖微囊存在的問題及應(yīng)用前景 22-23 3. 鹽酸多西環(huán)素研究進展 23-29 3.1. 理化性質(zhì) 23 3.2. 鹽酸多西環(huán)素藥效學研究進展 23-24 3.3. 鹽酸多西環(huán)素的耐藥性 24 3.4. 鹽酸多西環(huán)素藥動學研究 24-26 3.5. 鹽酸多西環(huán)素毒副作用相關(guān)研究 26 3.6. 鹽酸多西環(huán)素新制劑研究 26-29 第二章 選題背景和研究目的與意義 29-31 1. 選題背景 29-30 2. 研究目的與意義 30-31 第三章 鹽酸多西環(huán)素殼聚糖微囊的制備 31-39 1. 實驗材料 31 1.1. 儀器 31 1.2. 試劑 31 2. 實驗方法 31-