本文選題：醋酸奧曲肽 + 液晶凝膠�。� 參考：《湖北中醫(yī)藥大學(xué)》2017年碩士論文

【摘要】：藥物載體作為藥物的傳遞中介,能對(duì)藥物起保護(hù)作用,并使之能夠被人體吸收,同時(shí)可實(shí)現(xiàn)藥物的靶向作用,使其釋放速率可控。隨著科學(xué)技術(shù)的不斷發(fā)展,許多新劑型逐漸被開(kāi)發(fā)出來(lái),例如微乳、亞微乳、脂質(zhì)體、醇質(zhì)體、微球、納米材料、凝膠等藥物載體的研究已取得重大進(jìn)展。溶致液晶(Lyotropic liquid crystals,LLCs)作為一種新型的藥物載體,也開(kāi)始受到關(guān)注。作為藥物載體時(shí),溶致液晶能夠提高藥物的穩(wěn)定性,防止蛋白、多肽等生物活性分子的酶解,并實(shí)現(xiàn)其在體內(nèi)的持續(xù)釋放,從而減少給藥次數(shù),給患者帶來(lái)極大的便利。胃腸胰內(nèi)分泌腫瘤(gastroenteropancreatic neuroendocrine tumors,GEP-NETs)是由胃、腸和胰腺中的神經(jīng)內(nèi)分泌細(xì)胞,在致癌因素的作用下所引發(fā)的疾病。通過(guò)藥物治療的方法,緩解腫瘤所造成的疾病癥狀,并抑制腫瘤的增長(zhǎng),控制原發(fā)病灶向周圍部位轉(zhuǎn)移,對(duì)于胃腸胰內(nèi)分泌腫瘤疾病的緩解和治療有較好的作用。醋酸奧曲肽是治療該類腫瘤的常用藥物之一。醋酸奧曲肽(octreotide acetate,OA)是一種生長(zhǎng)抑素類似物,能結(jié)合胃、腸、胰中的生長(zhǎng)抑素受體,并抑制這些部位多種激素的過(guò)度分泌,停藥后不會(huì)引起激素分泌的反彈現(xiàn)象。目前,醋酸奧曲肽上市的劑型主要為注射劑型,常通過(guò)皮下注射和靜脈滴注方式給藥,但藥物在體內(nèi)的半衰期較短,需要頻繁給藥,因此給患者帶來(lái)不便和痛苦,也造成經(jīng)濟(jì)上的負(fù)擔(dān)。為了延長(zhǎng)藥物在給藥部位的作用時(shí)間,增加其生物利用度,并降低用藥的次數(shù),本課題擬以具有良好的生物相容性的天然物質(zhì)大豆卵磷脂(soya phosphatidyl choline,SPC)和二油酸甘油酯(glycerol dioleate,GDO)為原材料,并添加乙醇以降低體系的黏度,研制出一種具有藥物緩釋作用、遇水可發(fā)生膠凝反應(yīng)的醋酸奧曲肽液晶前體制劑。本研究通過(guò)單因素實(shí)驗(yàn),考察了乙醇用量以及SPC/GDO的配比對(duì)醋酸奧曲肽液晶凝膠前體的性質(zhì)的影響。通過(guò)所形成體系的外觀性能,確定了體系中無(wú)水乙醇的用量為15wt%,并通過(guò)對(duì)體系的成膠能力、通針性、流變學(xué)性質(zhì)等進(jìn)行考察,初步篩選出SPC和GDO的質(zhì)量比的范圍在70:30至30:70之間。通過(guò)偏光顯微鏡對(duì)體系的液晶結(jié)構(gòu)進(jìn)行了表征,同時(shí)結(jié)合不同體系的體外釋放性質(zhì),對(duì)處方進(jìn)行優(yōu)化,最終確定該體系中SPC/GDO的配比為7:3(wt/wt)。經(jīng)過(guò)處方優(yōu)化得到的醋酸奧曲肽液晶凝膠前體為淡黃色、澄清透明的液體,在貯存條件下,具有良好的流動(dòng)性和注射性能,經(jīng)皮下給藥注射到體內(nèi)后,與體液接觸即可形成凝膠狀的半固體,從而延緩藥物釋放。通過(guò)旋轉(zhuǎn)流變儀測(cè)定結(jié)果發(fā)現(xiàn),加水前后該制劑的復(fù)數(shù)黏度(η~*)值具有顯著差異。在剪切應(yīng)力為20Pa、頻率為0.1Hz的條件下,加水前制劑的η~*值僅為9.86×10-2Pas,而加水相變后其η~*值可達(dá)到6.22×103Pas,表明該制劑在體內(nèi)具有較好的粘附性。建立醋酸奧曲肽液晶凝膠前體的質(zhì)量控制方法,采用HPLC方法測(cè)定制劑中的藥物含量,并對(duì)該方法的專屬性、精密度、重復(fù)性、回收率等進(jìn)行考察,經(jīng)檢驗(yàn),該方法專屬性強(qiáng),且具有較好的精密度和重復(fù)性,通過(guò)該方法測(cè)得的樣品含量符合規(guī)定。影響因素試驗(yàn)顯示,醋酸奧曲肽液晶凝膠前體受到溫度和光照的影響比較大,因此,應(yīng)將制劑在避光的條件下冷藏保存。同時(shí),為了避免空氣中的水分對(duì)制劑造成的細(xì)微影響,可將制劑置于干燥的環(huán)境中保存,使制劑能夠有更好的穩(wěn)定性。本研究通過(guò)影響因素實(shí)驗(yàn)和長(zhǎng)期穩(wěn)定性實(shí)驗(yàn),對(duì)醋酸奧曲肽液晶凝膠前體的外觀性狀和制劑中藥物的含量進(jìn)行了考察,從而考察不同因素對(duì)制劑穩(wěn)定性的影響情況。實(shí)驗(yàn)結(jié)果顯示,光照和溫度對(duì)醋酸奧曲肽液晶凝膠前體的穩(wěn)定性有較大影響,同時(shí)結(jié)合制劑本身的性質(zhì),應(yīng)將其密封避光冷藏保存在干燥的貯存環(huán)境中。綜上所述,本研究所制備的醋酸奧曲肽液晶凝膠前體具有較好的注射性能,經(jīng)皮下給藥后,形成的凝膠結(jié)構(gòu)穩(wěn)定,具有良好的藥物緩釋性能。
[Abstract]:As the mediator of drug delivery, drug carrier can protect the drug and can be absorbed by the body, and can be absorbed by the human body. At the same time, it can target the drug and make the release rate controllable. With the continuous development of science and technology, many new dosage forms have been developed gradually, such as microemulsion, microemulsion, liposomes, alcohol plastids, microspheres, nanomaterials, and coagulation. Significant progress has been made in the research of drug carriers such as glue. Lyotropic liquid crystals (LLCs), as a new drug carrier, has also been paid attention to. As a drug carrier, lyotropic liquid crystal can improve the stability of the drug, prevent the enzymatic hydrolysis of protein, polypeptide and other bioactive molecules, and realize its continuous release in the body. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is a neuroendocrine cell in the stomach, the intestines, and the pancreas, caused by the carcinogenic factors, and alleviated the symptoms of the tumor by drug treatment. Octreotide acetate (OA) is a somatostatin similar to the growth of somatostatin, which combines the growth of the stomach, the intestines, and the pancreas. Inhibin receptor, which inhibits the excessive secretion of a variety of hormones in these parts, does not cause the rebound of hormone secretion after stopping. At present, the main dosage forms of octreotide acetate are injection type, often by subcutaneous injection and intravenous drip, but the drug is short in the body and needs frequent administration, thus giving the patient a bad effect. In order to prolong the action time of the drug in the drug delivery area, increase its bioavailability and reduce the number of drugs, the subject is to use natural biocompatible soybean lecithin (soya phosphatidyl choline, SPC) and two oleate (glycerol dioleate, GDO) as raw materials. With the addition of ethanol in order to reduce the viscosity of the system, a liquid crystalline precursor preparation of octreotide acetate was developed with the drug release effect and a gelation reaction in water. The effect of the amount of ethanol and the ratio of SPC/GDO on the properties of the octreotide acetate precursor of the octreotide acetate was investigated by a single factor experiment. In appearance, the amount of anhydrous ethanol in the system was determined to be 15wt%, and the quality ratio of SPC and GDO was preliminarily screened from 70:30 to 30:70 by the sizing ability of the system, the needle property and the rheological properties. The structure of the liquid crystal of the system was characterized by polarizing microscope and combined with the body of different systems. The formulation was optimized, and the ratio of SPC/GDO was determined to be 7:3 (wt/wt) in the system. The precursor of octreotide acetate liquid crystal gel obtained by prescription was light yellow, clarified transparent liquid and had good fluidity and injection performance under storage conditions. After being injected subcutaneously into the body, the liquid was exposed to body fluid. The gelatinous semisolid can be formed to delay the drug release. The results of the rotation rheometer show that the value of the complex viscosity (ETA *) of the preparation before and after water is significant difference. Under the condition of the shear stress 20Pa and the frequency of 0.1Hz, the value of the ETA ~ * of the preparation before adding water is only 9.86 x 10-2Pas, and the value of the ETA * is 6.22 * 1 after the water adding phase change. 03Pas shows that the preparation has good adhesion in the body. The quality control method of the liquid crystal gel precursor of octreotide acetate is established, the content of the drug in the preparation is determined by HPLC method, and the specificity, precision, repeatability and recovery rate of the method are investigated. The method is highly specific and has good precision and good precision. Repeatability, the sample content measured by this method accords with the regulations. The influence factor test shows that the precursor of octreotide acetate liquid crystal is more affected by temperature and light, so the preparation should be kept under the condition of avoiding light. Meanwhile, in order to avoid the subtle influence of water in the air on the preparation, the preparation can be put into dry. The effect of different factors on the stability of the preparation of octreotide acetate liquid crystal gel was investigated by the influence factor experiment and the long-term stability test, and the effect of different factors on the stability of the preparation was investigated. The temperature has a great influence on the stability of the liquid crystal gel precursor of octreotide acetate. At the same time, it should be kept in a dry storage environment with the properties of the preparation itself. In summary, the precursor of the octreotide acetate liquid crystal gel prepared in this study has good injection performance and the gel junction formed after subcutaneous administration. It is stable and has good drug release properties.
【學(xué)位授予單位】：湖北中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R943

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