研究目的
在药物发现过程中，制剂在评估分子的生物学特性中起着关键作用。提升受试化合物在体内的暴露量是早期动物实验的主要目标之一 [16, 17]，只有这样，药代动力学、药效学和毒理学才能与特定目标的生物反应联系起来。选择合适的临床前制剂不但可以优化体内暴露量，还可以促进化合物的优化、选择和进行开发性评估，从而更好地为临床制剂的设计与开发提供数据支持 [18]。早期筛选阶段的受试化合物，通常会遇到理化性质不理想，化合物量不充足和时间紧等问题，针对这些挑战，药明康德药性评价部成立了为药代动力学研究，药效和毒理研究进行临床前制剂筛选的团队，团队具有 10 多年的技术与经验积累，能够为大小动物实验进行快速的筛选与配制服务，每周为临床前动物实验提供的制剂超过近千瓶，而且能够利用毫克级别化合物在 24 小时内为临床前动物实验提供合适的溶媒处方。
研究方法
制剂团队可以在一个工作日内筛选出符合药代动力学研究的溶剂和溶媒。溶媒筛选过程中，增溶技术（如 pH 调节和助溶剂）是常用的技术手段，对于一些难溶性化合物，通常选用助溶剂加表面活性剂，或络合剂加 pH 调节这样的联合方式。另外，药性评价部制剂组可以根据差异化的项目需求，不同的给药剂量和途径定制化地设计试药策略。
策略 [19]
助溶剂
表面活性剂
环糖
粒径减少
盐型
无定形固体分散体
以脂类为主的制剂
设备
渗透压仪
理化性质检测仪
SPEX®SAMPLEPREP 研磨仪
小动物植入式渗透压泵
粒径检测仪
偏光显微镜
Retsch 湿法球磨仪
Covaris®E200x 超级超声分散仪
小动物胶囊
冻干仪
Retsch 球磨仪
实验流程
制剂团队不但可以为从筛选阶段到 IND 申报阶段的药代动力学研究提供制剂筛选与配制服务，同时也可以为药效试验及临床前毒理实验提供制剂筛选服务。该类制剂筛选可根据每个特定原料药的理化性质（如解离常数pKa，油水分布系数，溶解度）选择制剂的溶解及辅料添加配方。 通过体外溶解度评估、均一性和粒径分析为原料药选择最合适的制剂。从符合条件的候选制剂中进一步筛选，以确保得到体内生物利用度最好的或满足实验目的的制剂。
参考文献
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14. Liu X, et al. (2009) Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. Drug Metab Dispos 37:787-793
15. Gilberto DB, Zeoli AH, Szczerba PJ, Gehret JR, Holahan MA, Sitko GR, Johnson CA, Cook JJ, Motzel SL. Contemp Top Lab Anim Sci. 2003 Jul; 42 (4): 53-9
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19. Hywel D. Williams, Natalie L. Strategies to Address Low Drug Solubility in Discovery and Development. Pharmacol Rev 65:315 499, January 2013
2. Oh, Luke, et al. In Vitro Skin Permeation Methodology for Over-The-Counter Topical Dermatologic Products." Therapeutic Innovation & regulatory science 54.3 (2020): 693-700
3. Haq, Anika, et al. Strat-M ® synthetic membrane: Permeability comparison to human cadaver skin.' International journal of pharmaceutics547.1-2 (2018): 432-437
4. Kim, J.S., Mitchell, S., Kijek, P., Tsume, Y., Hilfinger, J. and Amidon, G.L., 2006. The suitability of an in-situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests. Molecular Pharmaceutics, 3 (6), pp.686-694
5. Chiou, W.L. and Barve, A., 1998. Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Pharmaceutical Research, 15 (11), p.1792
6. Cao, X., Gibbs, S.T., Fang, L., Miller, H.A., Landowski, C.P., Shin, H.C., Lennernas, H., Zhong, Y., Amidon, G.L., Lawrence, X.Y. and Sun, D., 2006. Why is it challenging to predict intestinal drug absorption and oral bioavailability in humans using the rat model. Pharmaceutical Research, 23 (8), pp.1675-168
7. Salphati, L., Childers, K., Pan, L., Tsutsui, K. and Takahashi, L., 2001. Evaluation of a single-pass intestinal perfusion method in rats for the prediction of absorption in man. Journal of pharmacy and pharmacology, 53 (7), pp.1007-1013
8. Dahlgren, D., Roos, C., Sjögren, E. and Lennernäs, H., 2015. Direct in vivo human intestinal permeability (Peff) determination with different clinical perfusion and intubation methods. Journal of pharmaceutical sciences, 104 (9), pp.2702-2726
9. Technical Guidelines for Non-clinical Kinetic Studies of Chemical Drugs
10. Diehl. K et al. " A Good Practice Guide to the Administration of Substances and Removal of Blood, Including Routes and Volume. " Journal of Applied Toxicology. 21: 15-23. 2001
11. Turner P.V., Brabb T. Pekow C., and Vasbinder M.A ". Administration of Substances to Laboratory Animals: Routes of Administration and Factors to Consider. " JAALAS. 50 (5): 600-613. 2011
12. Rollin B.E., Kesel M.L., The experimental animal in biomedical research, Vol. 2. Care, husbandry, and well-being, an overview by species
13. Maurer TS, DeBartolo DB, Tess DA, Scott DO (2005) Relationship between exposure and non-specific thirty-binding of three central nervous system drugs in mice. Drug Metab Dispos 33:175-181
14. Liu X, et al. (2009) Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. Drug Metab Dispos 37:787-793
15. Gilberto DB, Zeoli AH, Szczerba PJ, Gehret JR, Holahan MA, Sitko GR, Johnson CA, Cook JJ, Motzel SL. Contemp Top Lab Anim Sci. 2003 Jul; 42 (4): 53-9
16. Seshadri Neer Vannan. Preclinical formulations for discovery and toxicology: physicochemical challenges. Expert Opin. Drug Metab. Toxicol. (2006) 2 (5): 715-731
17. Michael J Waring. Lipophilicity in drug discovery. Expert Opin. Drug Discov. (2010) 5 (3)
18. Dai W -G, Pollock-Dove C, Dong L C, Li S. Advanced screening assays to rapidly identify solubility-enhancing formulations: high throughput, miniaturization, and automation. Adv Drug Deliv Rev. 2008; 60 (6): 657 72
19. Hywel D. Williams, Natalie L. Strategies to Address Low Drug Solubility in Discovery and Development. Pharmacol Rev 65:315 499, January 2013
