本文選題：ML4000　切入點：固體分散體　出處：《河南大學》2016年碩士論文　論文類型：學位論文

【摘要】：骨關節(jié)炎(OA)屬于臨床常見的關節(jié)炎的一種,主要治療藥物為非甾體抗炎藥(NSAIDs)。本文的模型藥ML4000是在COX/5-LOX雙重抑制劑ML3000的結構基礎上連接NO釋放基團,所制備的具有COX/5-LOX雙重抑制作用的NO供體型新型非甾體抗炎藥,ML4000抗炎活性強,同時還具有顯著的NO釋放活性,胃腸耐受性良好,無心血管不良反應。首先對ML4000進行了處方前理化性質研究,主要包括藥物的外觀性狀、熔點、晶型、溶解度、引濕性。原料藥為微黃色結晶性粉末,Tm=106.3~107.3℃;通過粉末X射線衍射與差示掃描量熱技術對ML4000的晶型加以研究,結果表明ML4000為晶態(tài)化合物;ML4000在乙腈、二甲基甲酰胺、丙酮、氯仿和二氯甲烷等有機溶劑中溶解,在乙醚中略溶,在甲醇和無水乙醇中極微溶解,在水中不溶;在不同pH緩沖溶液中均為不溶或難溶;ML4000不具有吸濕性。ML4000在水中不溶,固體分散技術在改善難溶性藥物溶解性能方面具有顯著的優(yōu)勢。本文將ML4000制備成為固體分散體(Solid Dispersions,SD),并壓制成片,旨在改善藥物的體外溶出情況,提高體內生物利用度。建立了高效液相色譜法對ML4000原料藥、SD及其片劑的含量、溶出度加以測定,并進行方法學驗證,驗證結果表明方法重現性好,準確度高。本研究還對SD及其片劑進行了質量評價與初步穩(wěn)定性考察。分別以泊洛沙姆188、聚乙二醇4000(PEG4000)、聚乙二醇6000(PEG6000)、聚維酮(PVP K30,PVP K90)、共聚維酮Co-PVP和SOLUPLUS?為載體,采用各自適宜的制備方法(熔融法、溶劑-熔融法和溶劑蒸發(fā)法)制備SD,并通過對體外溶出情況的考察進行處方與制備工藝的篩選。結果發(fā)現以上幾種載體所制備SD均可在一定程度上提高藥物的溶出速率與溶出度,泊洛沙姆188、PEG4000和PEG6000與其他輔料相比所制備SD的增溶效果不明顯。對以上三種方法加以比較,溶劑蒸發(fā)法的制備工藝以及所制備SD溶出效果明顯優(yōu)于其他兩種。PVP K90與SOLUPLUS?在制備過程中,產品粘性過大,所制備SD難以刮出或處理。Co-PVP制備成固體分散體所需藥輔比為1:5,所需載體量遠大于PVP K30(1:2)。最終確定采用溶劑蒸發(fā)法,以PVP K30為載體,藥輔比為1:2,二氯甲烷為溶劑,溶劑用量以1g ML4000加40ml二氯甲烷為優(yōu)化處方。采用差示掃描量熱技術(DSC)與傅里葉變換紅外光譜掃描技術(FT-IR)對ML4000-PVP K30固體分散體加以表征,以判斷藥物在固體分散體中的存在狀態(tài)及藥物與輔料之間的相互作用。DSC圖結果表明,ML4000具有一個明顯的吸熱峰,PVP K30空白輔料本身為無定型態(tài),物理混合物中藥物結晶峰減弱,但仍明顯存在,SD(1:2,1:3)中的藥物結晶峰基本消失,證明ML4000:PVP K30=1:2即可形成SD,且藥物在SD中以無定型狀態(tài)存在;FT-IR結果表明藥物與載體材料之間可能存在氫鍵作用;SD中藥物的質量分數與溶出重現性符合要求。固體分散體初步穩(wěn)定性考察結果表明,ML4000固體分散體在高熱與強光條件下較穩(wěn)定,溶出度及藥物質量分數無明顯變化,但SD具有一定的吸濕性,因此需密閉干燥保存;長期留樣實驗表明,SD留樣3個月穩(wěn)定,可進一步制備成片劑。在固體分散體研究的基礎上,采用粉末直壓技術將固體分散體片粉壓制成片。以片粉的流動性、可壓性和片劑的外觀、溶出情況為判定標準,對固體分散體片劑的處方及工藝因素進行單因素考察,篩選出崩解劑種類為PVPP,潤滑劑種類為硬脂酸鎂。在此基礎上,選擇崩解劑用量、潤滑劑用量以及填充劑的種類三個因素,每個因素三個水平,應用L9(34)正交實驗設計優(yōu)化處方。根據優(yōu)化處方制備3批樣品,處方的均一性和重現性良好,對其進行質量研究及穩(wěn)定性初步考察。結果表明,ML4000固體分散體片的含量均勻度、含量及溶出情況均符合要求,初步穩(wěn)定性實驗顯示,樣品在強光(4500lx±500lx)、高熱(60℃)與高濕(RH75%±5%)條件下放置10d或加速試驗條件放置1個月均穩(wěn)定。
[Abstract]:Osteoarthritis (OA) is a common clinical arthritis, the main drugs for the treatment of non steroidal anti-inflammatory drugs (NSAIDs). The model of this paper is the connection of NO ML4000 drug release groups in the structural basis of COX/5-LOX dual inhibitor of ML3000, prepared with COX/5-LOX dual inhibition of NO donor type non model steroidal anti-inflammatory drugs, ML4000 strong anti-inflammatory activity, but also has a significant release of NO activity, good gastrointestinal tolerance, cardiovascular adverse reactions. First carried out on the ML4000 of properties before the prescription, including appearance, drug melting point, crystal type, solubility, hygroscopicity. Raw materials for micro yellow crystalline powder, Tm=106.3~107.3 C; to study through the crystalline powder X ray diffraction and differential scanning calorimetry technique of ML4000, the result shows that the ML4000 is amorphous compounds; ML4000 in acetonitrile, two methyl formamide, acetone, chloroform and two chlorine Methane dissolved in organic solvents such as ether, slightly soluble in methanol and ethanol, low dissolved, insoluble in water; in different pH buffer solution were solubility; ML4000 is not hygroscopic.ML4000 can not dissolve in water, has significant advantages of solid dispersion technique to improve the solubility of insoluble drug. This paper will become the preparation of ML4000 solid dispersion (Solid Dispersions, SD), and pressed into tablets, which aims to improve the dissolution of drugs in vitro, increase the bioavailability. A HPLC method was established for the ML4000 API, SD content and its tablets, dissolution of determination, and validation, verification results show that the method has a good reproducibility and high accuracy. This study also carried out preliminary investigation and quality evaluation on the stability of SD and its tablets. With Bo Losham 188, polyethylene glycol 4000 (PEG4000), polyethylene glycol 6000 (PEG6 000), polyvinylpyrrolidone (PVP K30, PVP K90), copovidone Co-PVP and SOLUPLUS? As the carrier, using their own suitable preparation method (melting method, solvent melting method and solvent evaporation method) the preparation of SD, and through the investigation on the dissolution in vitro screening prescription and preparation technology the results showed that these carriers prepared SD can improve the dissolution rate and solubility in a certain extent, poloxamer 188, PEG4000 and PEG6000 compared with other materials for preparation of SD solubilization effect is not obvious. Compared to the above three methods, preparation process and solvent evaporation method the preparation of SD dissolution effect was better than that of the other two kinds of.PVP K90 and SOLUPLUS? In the preparation process, the product viscosity is too large, the preparation of SD is difficult to scrape or.Co-PVP solid dispersions prepared for medicine auxiliary ratio is 1:5 and the required carrier amount is far greater than the PVP K30 (1:2). The final solution Agent evaporation method, with PVP K30 as the carrier, the auxiliary drug is 1:2, dichloromethane as solvent, solvent dosage to 1g ML4000 and 40ml dichloromethane as the optimum formulation. By differential scanning calorimetry (DSC) and Fu Liye transform infrared spectroscopy scanning technology (FT-IR) to the characterization of ML4000-PVP K30 solid dispersions to determine drug in the solid dispersion in the presence of interaction between the state and the results of.DSC drug and excipients showed that ML4000 has an obvious endothermic peak, PVP K30 itself is amorphous excipients, physical mixture drug crystallization peak weakened, but still exists, SD (1:2,1:3) crystal peak in basic drugs that ML4000:PVP K30=1:2 can disappear, the formation of SD, and the drug in SD in the amorphous state; FT-IR results shows that there are hydrogen bond interaction between drug and carrier materials; the mass fraction of SD in drug dissolution and reproducibility of Fu The requirements. The solid dispersion of the preliminary stability test results show that the dispersion is stable in high temperature and light conditions ML4000 solid, dissolution and drug concentration had no obvious change, but SD has a certain amount of moisture, therefore closed dry; long-term observation experiments show that the SD sample was stable in 3 months. Can be further prepared into tablets. Based on solid dispersions on straight by powder press technology solid dispersion powder pressed into tablets. The tablets fluidity powder, compressibility and tablet appearance, dissolution as criterion, formulation and technology factors on solid dispersion tablets were the single factor investigation, screening for PVPP type disintegrating agent, lubricant type for magnesium stearate. On this basis, choose the disintegrating agent, lubricant dosage and filler type three factors, three levels of each factor, the application of L9 (34) orthogonal experimental design Optimization prescription. According to the optimization of the prescription of preparation of 3 batches of samples, the prescription of uniformity and good reproducibility, evaluate the quality and stability of the research. The results showed that the content uniformity of ML4000 solid dispersion tablets, content and dissolution conditions are in line with the requirements of preliminary stability test, the samples in the light (4500lx + 500lx), high temperature (60 DEG C) and high humidity (RH75% + 5%) under the condition of placing 10d or accelerated test conditions were stable for 1 months.

【學位授予單位】：河南大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R943;R927

【相似文獻】

相關期刊論文 前10條

1 劉其媛;張振海;蔣艷榮;金鑫;陳小云;賈曉斌;;基于殼聚糖的丹參酮Ⅱ_A固體分散體的研究[J];中草藥;2013年04期

2 張赫然;宋麗明;王彥竹;王杏林;;熱熔擠出技術制備固體分散體的輔料研究進展[J];現代藥物與臨床;2014年05期

3 肖玉秀,程偉,梅潔,陳曉槞,張麗娜;VA丙嗪固體分散體的制備[J];中國醫(yī)院藥學雜志;2005年08期

4 楊彩琴;林玉龍;王偉;吳海燕;賈梅;;桂利嗪-聚乙二醇固體分散體的制備及體外溶出實驗[J];中國醫(yī)院藥學雜志;2006年06期

5 朱靜;楊照罡;陳曉梅;孫葭北;古麗斯坦·阿吾提;張p，

本文編號：1611651