Table 1_A high content (30%) stable doxycycline hyclate drinking-water solution for broilers: preparation, stability, and bioequivalence.docx

IntroductionDoxycycline is a semi-synthetic tetracycline antibiotic with broad-spectrum antimicrobial activity. Under intensive animal husbandry, commercially available doxycycline drinking-water formulations often show several drawbacks in solubility, stability and homogeneous distribution under farm conditions. To overcome these limitations, we developed a high content (30%, w/v), pilot-scale, stable doxycycline hyclate solution (DOX·HCl solution) specifically designed for drinking-water administration. A comprehensive quality assessment of this system was performed, followed by a bioequivalence evaluation of its application in broilers.
MethodPrescription selection through high-temperature testing was combined with preparation process study via single-factor screening to prepare DOX·HCl solution. Quality assessment included assay of DOX, the dilutability and dilution stability testing, evaluation of mixed performance, and the stability studies. Bioequivalence study was conducted in a randomized, parallel, and blinded design to compare the DOX·HCl solution with two commercially available doxycycline hyclate drinking-water products.
ResultsThree pilot-scale batches of the 30% DOX·HCl solution (mean content 100.14 ± 0.37%) were successfully manufactured under controlled conditions of 400 rpm stirring and 60 °C. These pilot samples remained stable in appearance and content when diluted with water for up to 24 h. Affecting factor testing, accelerated testing and long-term testing all showed good stability, with an expiration date exceeding 24 months. In broilers, the DOX·HCl solution achieved a Tmax of 3.19 ± 0.86 h, t1/2 of 6.47 ± 2.77 h, Cmax of 7.69 ± 2.27 μg/mL, and AUC0-t of 79.48 ± 23.88 h·μg/mL. There was no significant difference (p > 0.05) in the main pharmacokinetic parameters among the experimental broiler groups, and 90% CI values were within 80–125%, indicating that the 30% DOX·HCl solution was bioequivalent to the commercially available drinking-water formulations.
ConclusionThe 30% DOX·HCl solution represents a high-content, industrially scalable drinking-water concentrate that combines long-term physicochemical stability with bioequivalence to existing products. This formulation offers a more convenient and highly efficient reliable option that could be a potential alternative to commercial products for mixed drinking-water medication of livestock and poultry, particularly under high-density, centralized management conditions.

引言
多西环素是一种半合成四环素类抗生素，具备广谱抗菌活性。在集约化畜牧业生产中，市售多西环素饮水制剂在养殖现场常存在溶解性、稳定性及分布均匀性方面的缺陷。为克服上述局限性，本研究开发了一种高含量（30%，w/v）、适用于饮水给药的中试规模稳定盐酸多西环素（doxycycline hyclate）溶液（DOX·HCl溶液）。针对该制剂开展了全面质量评价，并对其在肉鸡中的应用进行了生物等效性评估。

材料与方法
通过高温试验筛选处方，结合单因素筛选法开展DOX·HCl溶液的制备工艺研究。质量评价内容包括多西环素（DOX）含量测定、溶解性与稀释稳定性试验、混合性能评价及稳定性考察。采用随机、平行、盲法设计开展生物等效性研究，将本研究制备的DOX·HCl溶液与2款市售盐酸多西环素饮水制剂进行对比。

结果
在400 rpm搅拌、60℃的可控条件下，成功制备3批30% DOX·HCl溶液中试批次，平均含量为100.14±0.37%。该中试样品经水稀释后24 h内外观与含量均保持稳定。影响因素试验、加速试验及长期试验均显示其具备良好稳定性，有效期可超过24个月。
在肉鸡体内，DOX·HCl溶液的达峰时间（Tmax）为3.19±0.86 h，消除半衰期（t1/2）为6.47±2.77 h，峰浓度（Cmax）为7.69±2.27 μg/mL，零到t时间点药时曲线下面积（AUC0-t）为79.48±23.88 h·μg/mL。试验肉鸡组的主要药代动力学参数无显著性差异（p>0.05），且90%置信区间（CI）均处于80%~125%范围内，表明30% DOX·HCl溶液与市售饮水制剂具备生物等效性。

结论
30% DOX·HCl溶液是一款高含量、可工业化放大的饮水浓制剂，兼具长期理化稳定性与市售产品的生物等效性。该制剂为畜禽饮水给药提供了一种更便捷、高效可靠的选择，有望在高密度集中化养殖管理条件下替代市售商用制剂。