引子: 共晶技術和納米沉澱技術於近年被廣泛討論能改進藥物性質和提高體內性能。本論文研究旨在將該兩種技術嘗試應用於五種模型藥物中，分別是薑黃素(CUR)，氟比洛芬(FLU)，布洛芬(IBU)，酮洛芬(KET) 和環氧洛芬(LOX)。這些藥物均難溶於水，擁有較差機械性質，相對高的親油性和潛在治療腦退化症的功用。在共晶技術中，藥物將會與煙酰胺(NCT)先溶於在溶劑中，透過蒸發以誘發共晶產生。另一方面，瞬時納米沉澱(FNP)技術會將藥物溶液(包含穩定劑)與反溶劑在封閉衝擊射流混合器(CIJM)或多入口渦旋混合器(MIVM)快速混合，生成納米藥物。 / 方法: 將藥物和NCT溶於乙醇中，應用旋轉蒸發或簡單蒸發生成共晶。透過不同的檢測方法，包括X射線衍射，差示掃描量熱法，熱重分析，吸濕分析，傅立葉變化紅外線光譜，特性溶出速率量度法和壓實分析將共晶檢定。另一方面，利用CIJM或MIVM，藥物在不同的混合速率，溶劑性質，聚乙二醇-聚乳酸(穩定劑)分子重量或藥物對聚合物比的工藝環境下載入於納米粒子中。生產出來的納米藥物會利用動態光散射測定粒徑; 電泳光散射法測定zeta電位; 掃描電子顯微鏡和原子力顯微鏡測定粒子形貌和其表面性質; X-射線光電子能譜測定表面成分; 高效液相色層分析測定載藥量和包封率。 / 結果: 利用旋轉蒸發，高純度的1:1 IBU-NCT 和FLU-NCT 的共晶能成功生成，但KET-NCT和LOX-NCT 共晶則不能獲得。低純度的CUR-NCT 共晶可根據相同技術取得。相比原來藥物而言，IBU-NCT 和FLU-NCT 共晶均有較好的機械性質，抗吸水性和溶解速度。而在FNP研究中，証實了混合速率，溶劑性質，聚乙二醇-聚乳酸(穩定劑)分子重量或藥物對聚合物比均對生產出來的納米粒子的粒徑有重要影響。另外，納米粒子的穩定性可籍添加輔助穩定劑(如PVA)大幅提高。XPS分析証實輔助穩定劑能與在粒子表面的聚乙二醇起相互作用，更佳地保護粒子。而在一系列對四種不同的洛芬藥物的實驗中，多次線性回歸分析指出三種有關藥物的溶液性質(即溶解度，分配係數和酸度系數)會對生成的納米粒子的粒徑和包封率有顯著影響。 / 結論: 將IBU和FLU與NCT結成共晶能同時提高其機械性質，抗吸水性和溶解速度。而在FNP中，優化不同工藝參數能有效控制納米藥物的粒徑，形態，表面性質和穩定性。 / Introduction: In recent years, cocrystallization and nanoprecipitation have gained increasing popularity as viable strategies for improving the pharmaceutical properties and in vivo performance of drugs. The present thesis was aimed at assessing these two approaches for potential applications in pharmaceutical formulation and manufacture with five model drugs, viz. curcumin (CUR), flurbiprofen (FLU), ibuprofen (IBU), ketoprofen (KET) and loxoprofen (LOX). Selection of these drugs for the study was guided mainly by their poor water solubility, poor compactibility, typical drug‘s lipophilicity (log P =3-5), and potential for treatment of Alzheimer‘s disease. Cocrystallization was induced by the attainment of a sufficient supersaturation level through rapid solvent removal from a solution containing the drug and the coformer, nicotinamide (NCT), while flash nanoprecipitation (FNP) was achieved by rapid and homogenous mixing of drug solution (with stabilizer and co-stabilizer if required) with antisolvent in the mixing chamber of a specially designed confined impinging jet mixer (CIJM) or multi-inlet vortex mixer (MIVM). / Methods: Cocrystals were prepared by rotary solvent evaporation or slow evaporation of a solution of drug and NCT in ethanol, and characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, moisture sorption analysis, Fourier transform infrared spectroscopy, intrinsic dissolution rate (IDR) measurement and compaction analysis. Polymer-stabilized drug nanoparticles were prepared by FNP using a two-stream CIJM or four-stream MIVM under defined conditions of varying flowrate, solvent type, molecular weight of amphiphilic diblock (PEG-PLA) copolymer (stabilizer), or drug-to-copolymer ratio. The resulting nanoparticles were characterized for particle size by dynamic light scattering; zeta potential by electrophoretic light scattering; particle morphology and surface properties by scanning electron microscopy and atomic force microscopy; surface composition by X-ray photoelectron spectroscopy (XPS); and drug loading and encapsulation efficiency (EE) by high performance liquid chromatography. / Results: Phase-pure 1:1 cocrystals of IBU and FLU with NCT were obtainable by rotary solvent evaporation, but not slow evaporation. Similar solvent removal failed to cause any cocrystal formation for KET and LOX while inducing partial cocrystal conversion for CUR. Both IBU-NCT and FLU-NCT cocrystals displayed enhanced IDR, reduced moisture sorption and improved tabletability compared with the individual profen crystals. FNP studies using the MIVM confirmed the flowrate, solvent type, molecular weight of PEG-PLA copolymer, and drug-to-copolymer mass ratio being important process variables for controlling particle size and particle stability. Particle stability could be enhanced with a hydrophilic co-stabilizer (e.g., PVA). Such co-stabilizers possibly act by binding to the PEG corona at the particle surface to reinforce the protective steric barrier, as substantiated by XPS data. Comparative studies on nanoparticle production by FNP for the four profens indicated that three structure-related intrinsic solution properties of the profens, namely, water solubility, log P and pKa, were important determinants of the particle size and EE of nanoparticles, as determined by multiple linear regression analysis. / Conclusion: Cocrystallization with NCT can simultaneously improve the tableting behavior, hygroscopicity, and dissolution performance of IBU and FLU. Proper optimization of the process variables in FNP is critical to the controlled production of polymer-stabilized drug nanoparticles with consistent properties and storage stability. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chow, Shing Fung. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 224-247). / Abstracts also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_1077685 |
| Date | January 2014 |
| Contributors | Chow, Shing Fung (author.), Chow, Hee Lum Albert , 1956- (thesis advisor.), Chinese University of Hong Kong Graduate School. Division of Pharmacy, (degree granting institution.) |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography, text |
| Format | electronic resource, electronic resource, remote, 1 online resource (xxiii, 247 leaves) : illustrations (some color), computer, online resource |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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