College of Pharmacy, University of Iowa, 115 S. Grand Avenue, Iowa City, IA 52242, USA.
Drug Product Development, Bristol Myers Squibb, 556 Morris Avenue, Summit, NJ 07901, USA.
J Pharm Sci. 2021 Sep;110(9):3276-3288. doi: 10.1016/j.xphs.2021.05.025. Epub 2021 Jun 5.
Developing solid oral drug products with good content uniformity (CU) at low doses is challenging; this challenge further aggravates when the tablet size decreases from a conventional tablet to a micro/mini-tablet (1.2-3 mm diameter). To alleviate the CU issues, we present a novel use of nanocrystalline suspension combined with high shear wet granulation for the first time. In this approach, nanomilled drug in the form of nanocrystalline suspension is sprayed onto the powder bed to ensure uniform distribution. The resulting granules had adequate particle size distribution and flow characteristics to enable manufacturing of micro-tablets with good weight uniformity and tensile strength. Nanomilled drug resulted in excellent content uniformity among individual micro-tablets even at a dose strength as low as 0.16 mcg, whereas micronized drug resulted in unacceptable CU even at 5x higher dose strength (0.8 mcg). Besides, the use of nanomilled drug has enhanced the dosing flexibility of micro-tablets and showed superior dissolution performance in comparison with micronized drug with no impact of storage conditions (40 °C/75%RH for six months) on their dissolution performance. The proposed approach is simple and can be easily incorporated into traditional high shear wet granulation process to develop sub-microgram dose solid oral drug products.
开发低剂量、具有良好含量均一性（CU）的固体制剂具有挑战性；当片剂尺寸从常规片剂减小到微/迷你片剂（直径 1.2-3 毫米）时，这一挑战会进一步加剧。为了缓解 CU 问题，我们首次提出了将纳米晶体混悬液与高剪切湿法制粒结合使用的新方法。在这种方法中，纳米研磨药物以纳米晶体混悬液的形式喷雾到粉末床上，以确保均匀分布。得到的颗粒具有适当的粒径分布和流动特性，能够制造出重量均匀性和拉伸强度良好的微片剂。即使在剂量强度低至 0.16 微克的情况下，纳米研磨药物也能使各个微片剂的 CU 达到极好的均匀度，而微米化药物即使在 5 倍更高的剂量强度（0.8 微克）下也会导致不可接受的 CU。此外，纳米研磨药物的使用增强了微片剂的剂量灵活性，并显示出优于微米化药物的溶解性能，而不会影响其溶解性能（在 40°C/75%RH 条件下储存六个月）。该方法简单，可轻松集成到传统的高剪切湿法制粒工艺中，开发亚微克剂量的固体制剂。
