单一药物与氨基酸的共非晶化是一种改善用于吸入治疗的可吸入喷雾干燥制剂雾化的技术。然而，尚未探索将第二药物分子掺入药物-氨基酸共无定形颗粒以制备组合制剂。在这里，我们使用两种模型药物头孢他啶和罗氟司特制备了组合粉末，同时使用它们可以通过抵消感染和炎症来改善非囊性纤维化支气管扩张的治疗结果。该研究采用两步法进行。第一步涉及鉴定氨基酸及其浓度（% w / w) 通过改变亮氨酸和色氨酸的组合比例 (0–25 % w / w )来实现头孢他啶的最佳雾化增强。在第二步中，罗氟司特 (5–20 % w / w) 被纳入含有选定浓度氨基酸的制剂中，以了解将第二种药物引入头孢他啶-氨基酸共无定形颗粒中的影响。总共制备了 10 种制剂，并根据固态和气溶胶性能对其进行了表征。亮氨酸引入了表面粗糙度，这与改进的颗粒雾化作用密切相关。使用 25% 的亮氨酸可获得最佳细颗粒分数 (FPF) (75%)；因此，选择亮氨酸作为给定浓度下的理想氨基酸，以了解罗氟司特包合物对头孢他啶-亮氨酸系统的影响。头孢他啶-罗氟司特粉末在配制后保留了它们的抗菌和抗炎特性。然而，包含 5% 的罗氟司特将 FPF 显着降低至 55%，而较高的罗氟司特浓度对 FPF 没有太大影响。FPF 的降低归因于颗粒表面的变化，因为发现罗氟司特降低了表面粗糙度。此外，亮氨酸结晶并包含罗氟司特。该研究表明，将第二种药物包含到药物-氨基酸无定形基质颗粒中会影响其固态动力学和气溶胶性能；因此，在进行类似的准备组合制剂的努力时，应谨慎考虑这些参数。亮氨酸结晶并包含罗氟司特。该研究表明，将第二种药物包含到药物-氨基酸无定形基质颗粒中会影响其固态动力学和气溶胶性能；因此，在进行类似的准备组合制剂的努力时，应谨慎考虑这些参数。亮氨酸结晶并包含罗氟司特。该研究表明，将第二种药物包含到药物-氨基酸无定形基质颗粒中会影响其固态动力学和气溶胶性能；因此，在进行类似的准备组合制剂的努力时，应谨慎考虑这些参数。
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Inhalable ceftazidime-roflumilast powder targeting infection and inflammation: Influence of incorporating roflumilast into ceftazidime-leucine co-amorphous formulation
Co-amorphization of a single drug with amino acid is a technique to improve aerosolization of inhalable spray-dried formulation for inhalation therapy. However, the incorporation of a second drug molecule into drug-amino acid co-amorphous particles to prepare combination formulations has not been explored. Here, we prepared combination powders using two model drugs, ceftazidime and roflumilast, which when concurrently used can potentially improve therapeutic outcome in non-cystic fibrosis bronchiectasis by counteracting both infection and inflammation. The study was performed using a two-step approach. The first step involved the identification of an amino acid and its concentration (% w/w) for the best aerosolization enhancement of ceftazidime by varying the ratios of leucine and tryptophan in combination (0–25 % w/w). In the second step, roflumilast (5–20 % w/w) was incorporated into the formulation containing the selected concentration of the amino acid to understand the impact of introducing a second drug into ceftazidime-amino acid(s) co-amorphous particles. In total, 10 formulations were prepared and characterized in terms of solid-state and aerosol performance. Leucine introduced surface asperity which correlated well with improved aerosolization of the particles. The best fine particle fraction (FPF) (75 %) was achieved with 25 % leucine; hence, leucine was selected as the ideal amino acid at the given concentration to understand the impact of roflumilast inclusion on ceftazidime-leucine system. The ceftazidime-roflumilast powder retained their anti-bacterial and anti-inflammatory properties following formulation. However, inclusion of roflumilast at 5 % dramatically decreased the FPF to 55 % and higher roflumilast concentration did not have much effect on FPF. The decrease in FPF ascribed to the change in particle surface as roflumilast was found to decrease surface asperity. In addition, leucine crystallized with inclusion of roflumilast. This study indicates that inclusion of a second drug into drug-amino acid amorphous matrix particles can affect its solid-state dynamics and aerosol performance; hence, such parameters should be cautiously considered while undertaking similar endeavors of preparing combination formulations.
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