本文選題：和厚樸酚 + 自微乳化給藥系統(tǒng)��； 參考：《重慶醫(yī)科大學(xué)》2014年碩士論文

【摘要】：厚樸屬木蘭科，為我國傳統(tǒng)中藥，已用于多種疾病的治療，和厚樸酚是其主要活性成分之一，但其在水中的溶解度極低，因此目前未見上市產(chǎn)品。 自微乳化給藥系統(tǒng)（Self-microemulsifying drug delivery systems，SMEDDS）由四種組分構(gòu)成，表面活性劑、助表面活性劑、油相與藥物，輕微攪拌，即可在水中自發(fā)形成細(xì)小的乳滴。SMEDDS能夠增加水難溶性藥物在胃腸道的溶出度，利于藥物的吸收。 目前可以通過不同的方法和手段將自微乳制劑同固體材料結(jié)合，形成固體自乳化片，微丸和微球等，跟傳統(tǒng)自微乳制劑相比，固體自微乳制劑攜帶更方便，穩(wěn)定性更高，患者順應(yīng)性更好。 本課題為了提高和厚樸酚的溶解度和口服生物利用度，將和厚樸酚制備成自微乳化給藥系統(tǒng)，對(duì)處方進(jìn)行了優(yōu)化，對(duì)其質(zhì)量進(jìn)行了初步評(píng)價(jià)，并研究它在大鼠體內(nèi)的藥動(dòng)學(xué)特征，再進(jìn)一步探索與多糖類高分子材料結(jié)合制成固體制劑，為開發(fā)難溶性藥物的臨床應(yīng)用提供一定的理論基礎(chǔ)。具體研究?jī)?nèi)容包括以下兩個(gè)部分： 第一部分和厚樸酚自微乳化給藥系統(tǒng)的研究 1建立紫外分光光度法測(cè)定和厚樸酚的含量，和厚樸酚的最大紫外檢測(cè)波長(zhǎng)為294nm，和厚樸酚在4.0～28.0μg/ml濃度范圍內(nèi)，吸光度與濃度線性關(guān)系良好，標(biāo)準(zhǔn)曲線方程為A=0.0292C-0.0038，r=0.9996。同時(shí)，精密度、回收率均滿足方法學(xué)要求。 2考察和厚樸酚在各輔料中的溶解度，篩選對(duì)和厚樸酚溶解度較大的輔料，初步確定油相、表面活性劑、助表面活性劑；然后通過處方配伍實(shí)驗(yàn)選擇乳化效果較好且處方穩(wěn)定的輔料，再采用水滴定法繪制偽三元相圖，以微乳區(qū)域大小為指標(biāo)，確定以MCT作為油相，Cremophor RH40為表面活性劑，Transcutol P為助表面活性劑，表面活性劑與助表面活性劑的比值（Km）為2，最后以體外釋放及粒徑考察結(jié)果得到各組分的最佳比例為MCT∶Cremophor RH40∶Transcutol P=20.0∶53.3∶26.7。 3采用染色法鑒別和厚樸酚自微乳制劑乳化后的微乳類型，并對(duì)制劑的自乳化速率和初步穩(wěn)定性進(jìn)行考察。結(jié)果表明和厚樸酚自微乳制劑乳化后為O/W型微乳，自乳化時(shí)間短且穩(wěn)定性好。 4建立HPLC方法測(cè)定和厚樸酚在體內(nèi)的藥物濃度，血漿中和厚樸酚在0.0355～9.0909μg/ml濃度范圍內(nèi)，線性關(guān)系良好，其回歸方程為：Y=0.3890C+0.0249，r=0.9996，，該方法準(zhǔn)確度高，專屬性強(qiáng)且重現(xiàn)性好，滿足血藥濃度分析的要求。大鼠口服灌胃和厚樸酚SMEDDS和混懸液后，前者生物利用度是后者的1.25倍，因此和厚樸酚SMEDDS對(duì)提高和厚樸酚的生物利用度有效果。 第二部分和厚樸酚自微乳化給藥系統(tǒng)結(jié)冷膠鈣微丸的制備及特性研究 1采用離子凝膠法制備載和厚樸酚SMEDDS的結(jié)冷膠鈣微丸(calcium-gellan beads containing honokiol self-microemulsifying drugdelivery system, GB-HSMEDDS)，以結(jié)冷膠濃度，氯化鈣濃度，交聯(lián)時(shí)間，自微乳與結(jié)冷膠溶液質(zhì)量比值(g/g)為變量，采用單因素實(shí)驗(yàn)設(shè)計(jì)，以GB-HSMEDDS的包封率作為考察指標(biāo)，當(dāng)結(jié)冷膠濃度為1.25%，CaCl2濃度為8%，和厚樸酚SMEDDS與結(jié)冷膠溶液質(zhì)量比為0.15，交聯(lián)時(shí)間15min為制備條件時(shí)，GB-HSMEDDS包封率和形態(tài)較好。 2對(duì)優(yōu)化后的GB-HSMEDDS在pH1.2HCl溶液及pH6.8PBS中的溶脹及釋放特性進(jìn)行研究。結(jié)果表明GB-HSMEDDS在pH6.8PBS中的溶脹度顯著大于在pH1.2HCl溶液中的(p＜0.01)，藥物在HCl溶液中2h的累積釋放超過50%，而在PBS中的不足20%。
[Abstract]:Magnoliaceae, Magnolia, is a traditional Chinese medicine which has been applied to many kinds of diseases. Honokiol is one of its main active components, but its solubility in water is very low. Therefore, it has not been listed at present.
Self microemulsifying drug delivery system (Self-microemulsifying drug delivery systems, SMEDDS) consists of four components, surfactant, CO surfactant, oil and drugs, mild mixing, can spontaneously in water droplet formation of small.SMEDDS can increase the water insoluble drugs in the gastrointestinal tract of the dissolution, to the absorption of the drug.
At present, self microemulsifying agents can be combined with solid materials by different ways and means to form solid self emulsifying tablets, pellets and microspheres. Compared with traditional self microemulsifying agents, solid self microemulsion formulations are more convenient, stable and patient compliant.
This subject is to improve the solubility and bioavailability of honokiol and magnolol will use, preparation of self microemulsifying drug delivery system, the formulation was optimized on a preliminary evaluation of its quality, and study its pharmacokinetic characteristics in rats, to further explore the combined with polysaccharide polymer made of solid preparation, to provide a theoretical basis for the clinical application of insoluble drugs. The research contents include the following two parts:
Study on the first part and the self microemulsification system of magnolol
1 the content of a UV spectrophotometric method for the determination of honokiol, the maximum UV detection wavelength of honokiol and magnolol in 294nm, 4 ~ 28 g/ml concentration range, a good linear relationship between absorbance and concentration, the standard curve equation was A=0.0292C-0.0038, r=0.9996. at the same time, precision and recovery rate are satisfied learn the requirements.
The solubility of 2 investigated honokiol in various excipients, screening of honokiol higher solubility materials, preliminary determination of oil phase, surfactant, cosurfactant; and then through the prescription experiment, better emulsifying effect and stability of prescription accessories, then using drip method of drawing the pseudo three component phase diagram, in microemulsion the size of the region as the index to determine the MCT as oil phase, Cremophor RH40 as surfactant, Transcutol P as cosurfactant, ratio of surfactant and co surfactant (Km) was 2, the in vitro release and particle size examination results obtained the best proportion of each component is MCT: Cremophor RH40 Transcutol: P=20.0: 53.3: 26.7.
3 Identification of honokiol self microemulsion after microemulsification and identification of the self emulsifying rate and initial stability of the prepared self emulsifying microemulsion. The results showed that after emulsification, honokiol self microemulsifying agent was O/W microemulsion with short self emulsifying time and good stability.
4 to establish a HPLC method for the determination of magnolol and plasma drug concentration in vivo, honokiol in 0.0355 ~ 9.0909 g/ml concentration range, good linear relationship, the regression equation is: Y=0.3890C+0.0249, r=0.9996, the method has high accuracy, strong specificity and good reproducibility, meet the requirements of blood drug concentration analysis. Rat oral Honokiol and SMEDDS suspension, the bioavailability is 1.25 times of the latter. Therefore, honokiol and magnolol SMEDDS to improve the bioavailability of the effect.
Preparation and characterization of colder calcium pellets in the second part and the self microemulsification system of magnolol
1 by ion gel preparation containing honokiol SMEDDS calcium gellan gum pellets (calcium-gellan beads containing honokiol self-microemulsifying drugdelivery system, GB-HSMEDDS), with gellan gum concentration, calcium chloride concentration, crosslinking time, self microemulsion and gellan gum solution quality ratio (g/g) as a variable, the single factor experiment GB-HSMEDDS, the entrapment efficiency as indexes, when the gellan gum concentration was 1.25%, the concentration of CaCl2 was 8%, and the junction of magnolol SMEDDS gellan gum solution quality ratio is 0.15, crosslinking time of preparation conditions for 15min system, GB-HSMEDDS encapsulation efficiency and good morphology.
On the 2 and release properties of the optimized GB-HSMEDDS in pH1.2HCl solution and pH6.8PBS of the swelling were studied. The results showed that GB-HSMEDDS in pH6.8PBS in the degree of swelling was significantly higher than that in pH1.2HCl solution (P < 0.01), the cumulative drug release in HCl solution 2h of more than 50%, while in PBS 20%.

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 林桂蕓,謝生發(fā),謝鴻,鷗俊;和厚樸酚抑菌作用的研究[J];成都大學(xué)學(xué)報(bào)(自然科學(xué)版);2003年02期

2 閔玲;朱小牧;胡麗娜;;和厚樸酚在腫瘤治療中的研究進(jìn)展[J];華西藥學(xué)雜志;2010年01期

3 王金鈴;孫進(jìn);何仲貴;;微乳及其在藥學(xué)中應(yīng)用[J];中國藥劑學(xué)雜志(網(wǎng)絡(luò)版);2009年04期

4 王海燕;朱希強(qiáng);郭學(xué)平;;結(jié)冷膠在醫(yī)藥領(lǐng)域的應(yīng)用[J];中國生化藥物雜志;2012年02期

5 劉華,李三鳴,袁悅,馮明芳,吳瓊;酮洛芬自乳化制劑處方及化學(xué)穩(wěn)定性研究[J];沈陽藥科大學(xué)學(xué)報(bào);2005年01期

6 劉琳婕;逄秀娟;張偉;高雪峰;段江瑛;王思玲;;水飛薊素自微乳的研制[J];沈陽藥科大學(xué)學(xué)報(bào);2007年09期

7 宦娣;易濤;劉穎;肖璐;何吉奎;;微粉硅膠對(duì)固體自微乳化給藥系統(tǒng)小腸吸收的影響[J];藥學(xué)學(xué)報(bào);2011年04期

8 李t

本文編號(hào)：1741713