Cyclodextrin inclusion complex enhances solubility and antimicrobial activity of chlortetracycline hydrochloride
Chao Zhang, Lankun Yi, Yubin Bai, Xiaorong Yang, Jianhua He, Yuting Bai, Yong Zhang, Bing Li, Jiyu Zhang
Abstract
Chlortetracycline hydrochloride (CTC) is a broad-spectrum tetracycline antibiotic used to prevent or resist different bacterial infections. However, due to its poor aqueous stability and physicochemical instability, its clinical development is limited. To improve such properties, CTC complexation with β-cyclodextrin (β-CD) and 2-hydroxypropanol-β-cyclodextrin (HP-β-CD) was performed using different preparation techniques (Freeze drying and ball milling). Inclusion complexes were comprehensively characterized using different analytical techniques and showed different properties distinct to pure CTC. In the presence of both CDs, CTC solubility was significantly improved. After ratio optimization, the optimal molar ratio after freeze-drying was determined to be 1:5. Compared to pure CTC powder (4 mg/mL), the solubility of CTC/HP-β-CD improved approximately 9 times (36 mg/mL), and a new CTC injection was successfully prepared. The antibacterial activity (in vivo and in vitro) of the CTC/HP-β-CD injection was then examined in natural infection chickens. Pathological tissue images showed that a 20 mg/kg CTC/HP-β-CD dose increased antibacterial activity and therapeutic effects. Additionally, we determined five clinical strains and statistically verified that CTC/HP-β-CD exhibits stronger antibacterial activity compared to CTC and other tetracycline drugs, with the most significant effect observed against Pseudomonas aeruginosa (MIC value of 2 μg/mL). Thus, these findings suggest that CTC/HP-β-CD inclusion complexes could be promising for pharmaceutical development, warranting further clinical evaluation, as solubility was significantly increased, and enhanced antibacterial activity was recorded in vivo and in vitro. Compared with the bulk drug, the CTC/HP-β-CD prepared by freeze-drying was significantly increased by about 9 times, and a new CTC/HP-β-CD injection preparation was successfully developed. The in vivo and in vitro antibacterial activity of injection was studied for the first time, and the high biological activity of the preparation was proved by experiments. • The CTC/HP-β-CD inclusion complex prepared by freeze-drying showed the highest encapsulation rates. • CTC/HP-β-CD injection had a better therapeutic effect than florfenicol injection at the same dose. • Chlortetracycline hydrochloride had the most obvious effect on P. aeruginosa (MIC-2 μg/mL).