Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
Int J Pharm. 2018 Dec 20;553(1-2):238-260. doi: 10.1016/j.ijpharm.2018.10.046. Epub 2018 Oct 22.
Most of the recent drug compounds coming out of the drug discovery pipeline are labile (multiple polymorphs), and need to be developed into robust marketed oral drug formulations. There are only 22 oral macroamorphous drug products approved by FDA and till date none approved oral nanoamorphous drug products. However, there are several oral nanoamorphous drug formulations (including both labile and non-labile drugs) being researched and a few of these are in the clinical trials. Due to the labile nature of these drug compounds, there is a need to utilize a controlled strategy for design and development of robust nanoamorphous drug formulations in order to prevent any physicochemical instability. The present research focuses on the use of a novel integrated critical process parameters and critical formulation parameters (iCPP-CFPs) DoE approach for the design and development of stable nanoamorphous spironolactone (BCS class II compound with eight polymorphic forms). There are possibilities of the interconversion of these polymorphic forms during processing (manufacturing nanoamorphous particles) and during storage. In the present study, polymorphic transitions (amorphous to crystalline and anhydrous to hydrate) were carefully monitored via orthogonal solid-state characterization tools. Significant polymorphic transitions were observed in the formulations stored at 40 °C/75% RH over six months, however the formulations stored at 4 °C were stable. The significant iCPP-CFPs (solvent-to-antisolvent ratio, drug concentration and inlet temperature of the spray dryer) were critically investigated for their influence on different CQAs (critical quality attributes). Solvent-to-antisolvent ratio and inlet temperature were identified to be the significant iCPP-CFPs. Particle size and total product yield were identified to be the significant CQAs. Lab-scale manufacturing of the spray dried nanoamorphous spironolactone resulted in a remarkably high total product yield (82.4 ± 3.91% w/w) with a uniform and homogenous particle size (244.2 ± 23.32 nm). Furthermore, the physicochemical attributes and the drug release criteria of the nanoamorphous spironolactone were compared with two marketed products (spironolactone tablets, USP 100 mg (Pfizer and Mylan)) and other in-house formulations. In addition, nanoamorphous spironolactone showed a significantly superior kinetic solubility/dissolution rate (10-fold) with a longer supersaturation time (∼6h) compared to the in-house formulations.
大多数来自药物发现管道的新型药物化合物都是不稳定的（存在多种多晶型），需要开发成稳定的上市口服药物制剂。FDA 仅批准了 22 种口服大分子无定形药物产品，迄今为止，尚无批准的口服纳米无定形药物产品。然而，有几种口服纳米无定形药物制剂（包括不稳定和稳定的药物）正在研究中，其中一些已进入临床试验阶段。由于这些药物化合物的不稳定性，需要利用控制策略来设计和开发稳定的纳米无定形药物制剂，以防止任何物理化学不稳定性。本研究重点使用一种新颖的综合关键工艺参数和关键制剂参数（iCPP-CFPs）设计和开发稳定的纳米螺内酯（BCS 类 II 化合物，具有八种多晶型形式）。在加工（制造纳米无定形颗粒）和储存过程中，这些多晶型形式可能会相互转化。在本研究中，通过正交固态特征工具仔细监测了多晶型转变（无定形到结晶和无水到水合）。在六个月的时间里，在 40°C/75%相对湿度下储存的制剂中观察到显著的多晶型转变，然而在 4°C 下储存的制剂是稳定的。对关键工艺参数（溶剂-反溶剂比、药物浓度和喷雾干燥器的入口温度）进行了严格的考察，以研究其对不同关键质量属性（CQAs）的影响。溶剂-反溶剂比和入口温度被确定为关键工艺参数。粒径和总产率被确定为关键质量属性。喷雾干燥纳米无定形螺内酯的实验室规模生产得到了非常高的总产率（82.4±3.91%w/w），粒径均匀且均匀（244.2±23.32nm）。此外，纳米无定形螺内酯的物理化学性质和药物释放标准与两种市售产品（螺内酯片剂，USP 100mg（辉瑞和迈兰））和其他内部制剂进行了比较。此外，纳米无定形螺内酯的动力学溶解度/溶解速率（提高 10 倍）显著提高，过饱和度时间（约 6h）比内部制剂更长。
