低溶性药物立即释放口服剂型纳米制剂的开发和评价
获得学士学位的博士学位论文。作者:Zun Huang，作者:Zun Huang，作者:Zun Huang，作者:Zun Huang
溶解度和溶出速率对于口服吸收是必不可少的，因此可溶性药物的生物利用度是必不可少的。目前，有各种配方方法可用于克服溶解度和溶出速率的问题。但是，单一的配方方法始终有其缺点。该作品的目的是通过组合Cocrystal和纳米晶体制剂技术来探讨纳米聚晶制剂，并通过研究其溶解机制来优化制剂。还探讨了下游工艺研究以将纳米聚晶制剂转化为最终的口服固体剂型。用不同的实验室湿磨方法制备和优化纳米晶体制剂的不同实验室级纳米晶体制备方法与铣削效率和工艺属性进行比较。双离心铣削被认为是具有更高铣削效率，制剂筛选效率和更广泛的可控过程属性的最有前途的方法。施加双离心铣削方法以有效地筛选稳定剂并调节工艺参数，用泊洛沙姆407稳定的优化的伊唑康唑纳米晶体，其平均粒度为200nm和PDI 0.2。纳米血管术在4,25和40℃下稳定一个月。优化的纳米晶体制剂表现出比在体外溶解研究中的水槽或非水槽条件下的物理混合物和原料药物更快的溶解速率。 While compared with commercial product Sporanox®, nanocrystal formulation exhibited faster drug release under sink conditions but lower and limited solubility increment under non-sink conditions. Itraconazole nanocrystal formulation might not exhibit advantageous in vivo behavior compared to the commercial product. A selection of a suitable in vitro dissolution test to evaluate nanocrystal formulation was crucial. In addition, nanocrystalline formulation significantly improved the dissolution rate of poorly soluble APIs, while its increases in solubility were limited. Finally, some other solubilization methods like cocrystal or amorphization could be combined with the nanocrystal approach and utilized to offer a practical approach for delivering orally poorly soluble drugs. Combination of cocrystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs Four itraconazole and indomethacin nano-cocrystals with mean particle diameters of around 450 nm were successfully prepared. Solid-state characterization suggested that by transforming raw drug powder into its cocrystal form is a new strategy for the preparation of nano-formulations which are physically or chemically unstable during wet milling. Furthermore, in situ solubility studies indicated that nano-cocrystals showed remarkably higher solubility and dissolution rate compared to nanocrystals and cocrystals. The maximum kinetic solubility of nano-cocrystals increased with excess conditions until reaches a plateau. The highest increase was obtained with itraconazole-succinic acid nano-cocrystals with a solubility of 263.5 ± 3.9 µg/mL which is 51.5 and 6.6 times higher than the solubility of itraconazole crystalline and itraconazole-succinic acid cocrystal. The combination of cocrystals and nanocrystals could potentially overcome the limitation of nanocrystals in solubility improvement and the limitation of cocrystal in dissolution rate improvement. Nanocrystal technique efficiently promotes the potential of cocrystal solubilization effect by its superior dissolution rate. This nano-cocrystal formulation expands the drug development strategies of poorly soluble drugs. Itraconazole-succinic acid nano-cocrystals: Kinetic solubility improvement and influence of polymers on controlled supersaturation A systematic experimental investigation was conducted to explore the precipitation inhibition capacity of a range of commonly used precipitation inhibitors (HPMC E5, HPMC E50, HPMCAS, HPC-SSL, PVPK30 and PVPVA64) in itraconazole-succinic acid nano-cocrystal formulation. HPMC E5 achieved greatest extended nano-cocrystals dissolution and maintenance of supersaturation based on specific drug/polymer intermolecular interaction. Dissolved polymer not only increased maximum achievable supersaturation, but also maintained supersaturation for prolonged times, resulting in significantly broadened AUC maxima. The maximum achievable supersaturation was proportional to the dissolution rate which can be modulated by the rate of supersaturation generation (i.e., addition rate or dose). Supersaturation could be prolonged significantly resulting in 2-5-fold increased area under the dissolution curves compared to nano-cocrystals alone. This effect was however limited by a critical excess of undissolved particles with high specific surface area which acted as crystallization seeds resulting in faster precipitation. To achieve higher and sustained supersaturation from nano-cocrystal formulation during dissolution, faster dissolution rate and proper application of precipitation inhibitors were two driving factors. The relationship between particle size, dose and polymer ratio and their synergic impact on the supersaturation must be considered. Generally, these insights and findings would contribute to the design of optimally performing oral solid dosage formulations with incorporated nano-cocrystals. Incorporation of itraconazole nano-cocrystal into granulated or bead-layered solid dosage forms Three downstream processes (wet granulation, spray granulation, and bead layering) were evaluated on the performance of itraconazole-succinic acid nano-cocrystal suspension. Limited by low drug loading and slow dissolution profile, traditional wet granulation was not suitable for downstream processing of nano-cocrystal formulation. Spray granulation and bead layering could increase the drug loading without significantly compromising the rapid dissolution behavior of nano-cocrystal. However, the type of substrate used for spray granulation impacted the dissolution performance from the granules containing nano-cocrystals. Faster dissolution profiles and higher maximum solubility were obtained when the water-soluble substrate was used. While the type of substrate has no impact on the dissolution behavior of beads layered with nano-cocrystals. Furthermore, during the accelerated stability studies, the nano-cocrystal processed by spray granulation was less stable than nano-cocrystal processed by bead layering upon 3 months storage at 40 °C/75% RH in non-blistered condition. Overall, bead layering was the most suitable method for the downstream process of nano-cocrystal suspensions with the overall performance of a solid product.
综上所述，共晶与纳米晶的结合有可能克服纳米晶在提高溶解度方面的局限性和共晶在提高溶解速率方面的局限性。通过添加特定的沉淀抑制剂，可以优化纳米共晶配方。珠层是将纳米共晶体合并到口服固体剂型而不影响释放的一种优越的下游工艺方法。
材料
药物:伊曲康唑(BASF AG, Ludwigshafen, Germany)， Sporanox®100 mg胶囊(Janssen GmbH, Neuss, Germany)，吲哚美辛(Fluka Chemie AG, Buchs, Switzerland)
稳定剂：188年泊咯沙姆，407年泊咯沙姆， Tween 80, D-α-生育酚聚乙二醇1000琥珀酸酯(TPGS) (BASF SE，路德维希港，德国)，十二烷基硫酸钠(SDS) (Carl Roth GmbH & Co.， Karlsruhe，德国)
聚合物:羟丙基甲基纤维素E5/E50 (HPMC E5/E50)，羟丙基甲基纤维素醋酸琥珀酸酯(HPMCAS) (Colorcon Ltd, Dartford Kent, UK)，羟丙基纤维素(HPC-SSL) (Nisso Chemical Europe, Düsseldorf，德国)，聚乙烯吡啶酮(PVP K30)、聚乙烯吡咯烷酮醋酸乙烯共聚物(PVPVA64)(德国路德维希港巴斯夫SE)
溶剂:甲醇、乙醇、氯仿、四氢呋喃、乙酸乙酯、二甲基亚砜(DMSO) (Carl Roth GmbH & Co.， Karlsruhe, Germany)，用Millipore GmbH, Darmstadt, Germany) Millipore - q装置纯化的水(Millipore GmbH, Darmstadt, Germany)
其他化学物质:延胡索酸、琥珀酸、糖精、烟酰胺(Merck KGaA, Darmstadt, Germany)、乳糖(Granulac®200， Meggle AG, Wasserburg，德国)，微晶纤维素(Avicel®PH102)、糖珠(Suglets®25-30目，600-710 μm直径，NP Pharm S.A，巴赞维尔，法国)、MCC珠(Celphere®cp - 507盐酸(HCl)，氢氧化钠(NaOH)，氯化钠(NaCl) (Sigma Aldrich Chemie GmbH, Steinheim，德国)