School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland.
Pharmaceutical Engineering Group, School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland.
AAPS PharmSciTech. 2019 Dec 12;21(1):23. doi: 10.1208/s12249-019-1553-2.
The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels as possible, to keep the final tablet weight low, and, correspondingly, the dosage form size small enough to be acceptable from a patient perspective. Additionally, a multi-step batch-based manufacturing process is usually required for production of solid dosage forms. This study presents the development and production, by twin-screw melt granulation technology, of a high-dose immediate-release fixed-dose combination (FDC) product of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with drug loads of 80% w/w and 6% w/w, respectively. For an 850/63 mg dose of MET/SIT, the final weight of the caplets was approximately 1063 mg compared with 1143 mg for the equivalent dose in Janumet®, the marketed product. Mixtures of the two drugs and polymers were melt-granulated at temperatures below the individual melting temperatures of MET and SIT (231.65 and 213.89°C, respectively) but above the glass transition temperature or melting temperature of the binder(s) used. By careful selection of binders, and processing conditions, direct compressed immediate-release caplets with desired product profiles were successfully produced. The melt granule formulations before compression showed good flow properties, were larger in particle size than individual starting API materials and were easily compressible. Melt granulation is a suitable platform for developing direct compressible high-dose immediate-release solid dosage forms of FDC products.
开发含有高剂量药物的口服固体制剂，如片剂，需要尽可能将聚合物和其他添加剂的含量控制在低水平，以降低最终片剂的重量，相应地，使剂型尺寸足够小，从患者角度来看是可以接受的。此外，通常需要多步批处理制造工艺来生产固体制剂。本研究通过双螺杆熔融造粒技术，开发了盐酸二甲双胍（MET）和磷酸西他列汀（SIT）的高剂量即释固定剂量组合（FDC）产品，药物负载分别为 80%w/w 和 6%w/w。对于 850/63mg 的 MET/SIT 剂量，与市售产品 Janumet®中等效剂量的 1143mg 相比，胶囊的最终重量约为 1063mg。两种药物和聚合物的混合物在低于 MET 和 SIT 的各自熔点（分别为 231.65°C 和 213.89°C）但高于所用粘合剂的玻璃化转变温度或熔点的温度下熔融造粒。通过仔细选择粘合剂和加工条件，成功生产出具有所需产品特性的直接压片即释胶囊。压缩前的熔融颗粒制剂具有良好的流动性，粒径大于单个起始 API 材料，且易于压缩。熔融造粒是开发 FDC 产品的直接可压缩高剂量即释固体制剂的合适平台。
