Controlled Precipitation and Agglomeration of Itraconazole Nanoparticles for Pulmonary Delivery

• Other Authors: Wan, Ka Yee (author.)
• Format: Others
• Language: English; Chinese
• Published: 2016
• Online Access: http://repository.lib.cuhk.edu.hk/en/item/cuhk-1292227

研究目的:本論文旨在利用一種低水溶解度的抗真菌藥伊曲康唑(ITZ)作模型藥物，開發出一種可重現和穩定的納米粒子聚團製劑，將藥物遞送於肺深部。我們利用瞬時納米沉澱技術(FNP)生產出ITZ納米粒子，並深入探究其形成過程和相應的穩定機制。此外，我們嘗試了三種不同的製備方法，使納米粒子在受控的環境下聚集成納米粒子聚團。通過研究生產出來的納米粒子聚團，我們從而優化出納米粒子聚團的工藝。 === 方法: 我們利用了不同的檢測方法以考察從多入口渦旋混合器(MIVM)生產出來的ITZ納米粒子(納米懸浮液)的性質，包括利用動態光散射儀(DLS)去檢測粒子的粒徑和粒徑分佈; Zeta電位測量法去檢測粒子表面的電位;高效液相色譜去檢測粒子中ITZ的載量和包封率; X射線光電子能譜(XPS)去檢測粒子表面的化學成份;和原子力顯微鏡去檢測粒子的形態和相位圖像。及後，我們透過冷凍乾燥，噴霧乾燥，或凝膠化-噴霧乾燥結合法使納米懸浮液成為固態的納米粒子聚團。針對這些納米粒子聚團，我們利用DLS考察了其分散性;掃描電子顯微鏡去檢測其物理形態; 雷射粒徑分析儀去檢測其幾何平均粒徑; 和新一代藥用撞擊器(NGI)去評估其體外表現。 === 結果:我們可利用MIVM和穩定劑/輔助穩定劑生產出少於100納米和多分散性指數少於0.2的ITZ納米粒子。我們亦証明加入膽固醇(CLT)於配方中，可以生產出更穩定的ITZ納米粒子。透過分析XPS之數據，我們得知這一穩定機制源自CLT能更有效將兩性穩定劑中的親水和親油部分在粒子中重排，從而令兩性穩定劑與ITZ有更強的相互作用。我們發現利用甲基纖維素(MC)於凝膠化-噴霧乾燥結合法(ITZ: MC = 1:10)最有效製備出可輕易分散回水中的ITZ納米粒子聚團。此聚團在NGI 的測試下亦顯示出適合用於肺深部藥物傳遞的微粒分數和質量中數氣動粒徑。 === 結論: FNP是一種有效且重現性高的製備方法，生產少於100納米的ITZ納米粒子。加入CLT於配方中可大幅增加ITZ納米粒子的穩定性。而利用MC 於凝膠化-噴霧乾燥結合法中即可生產出適合用於肺深部藥物傳遞的納米粒子聚團。 === Objectives: The present thesis was aimed at developing a consistent and stable nanoparticle agglomerate formulation for deep lung delivery using the model drug, itraconazole (ITZ). ITZ is a BCS Class II antifungal antibiotic exhibiting dissolution-limited bioavailability problem. The particle formation process and associated stabilization mechanism of ITZ nanoparticles produced by flash nanoprecipitation (FNP) were investigated through in-depth nanoparticle characterization. To develop and optimize an ITZ nanoparticle agglomerate formulation with desired characteristics for deep lung delivery and acceptable stability for long-term storage, three agglomeration methods have been assessed and resulting nanoparticle agglomerates were characterized for agglomerate size and nanoparticle redispersibility. === Methods: ITZ nanosuspensions with stabilizers/costabilizers were produced under various defined conditions by FNP using a four-stream multi-inlet vortex mixer (MIVM), and characterized for particle size and size distribution by dynamic light scattering (DLS); surface charges by zeta potential measurement; drug loading and encapsulation efficiency by high performance liquid chromatography; surface composition by X-ray photoelectron spectroscopy (XPS); and nanoparticle morphology and phase imaging by atomic force microscopy. Nanoparticles in suspensions were agglomerated under defined conditions by freeze drying, spray drying, or combined gelation and spray drying with protectants where appropriate. Resulting dried agglomerates were characterized for nanoparticle redispersibility by DLS particle sizing; morphology by scanning electron microscopy; and geometric mean diameter and in vitro aerosol performance using a laser-diffraction particle sizer and a next generation impactor, respectively. === Results: ITZ nanoparticles could be reproducibly generated with a mean particle size < 100 nm and a polydispersity index < 0.2 with the aid of stabilizer/costabilizer. XPS analysis of freshly formed nanoparticles revealed initially a disordered packing structure and subsequently a time-dependent molecular rearrangement of the amphiphilic stabilizer (AS) towards a micelle-like structure on the particle surface. Cholesterol (CLT) facilitates such rearrangement and orientation of the AS molecules, producing the most stable formulation. This unique capability of CLT can be linked to its similarity in solubility parameter to, or strong association with, the hydrophobic moiety of the AS. Among the three agglomeration methods, combined gelation and spray drying was superior and the agglomerates with methylcellulose (MC) obtained could be readily redispersed back into nanoparticles in water without any apparent change in particle size (final particle size/initial particle size ratio, Sf/Si = 1.02±0.03 at ITZ:MC ratio of 1:10 w/w). The agglomerates appeared as buckling and dimpled spheres under an electron microscope, indicative of a hollow structure. The majority of the nanoparticle agglomerates generated displayed superior in vitro aerosol performance, as reflected by their high fine particle fractions (FPFs; >50%) and mass median aerodynamic diameters (MMADs) being within the optimal aerodynamic size range (i.e., 2-3 µm) for deep lung delivery. === Conclusion: FNP technology is capable of reproducibly generating ITZ nanoparticles with initial particle size < 100 nm. CLT improves particle stability by promoting rearrangement of AS molecules in nanoparticles towards a stable micelle-like structure. Spray drying in conjunction with gelation using methylcellulose has been shown to be most effective for producing redispersible nanoparticle agglomerates with the desired aerodynamic particle size range for deep lung delivery. === Wan, Ka Yee. === Thesis Ph.D. Chinese University of Hong Kong 2016. === Includes bibliographical references (leaves ). === Abstracts also in Chinese. === Title from PDF title page (viewed on …). === Detailed summary in vernacular field only. === Detailed summary in vernacular field only. === Detailed summary in vernacular field only. === Detailed summary in vernacular field only.