Study Purpose
In the drug discovery process, formulation plays a crucial role in assessing the biological characteristics of molecules. Increasing the exposure of the test compound in studies in vivo is one of the main goals of early in vivo experiments [16, 17]. Choosing a suitable preclinical formulation not only optimizes in vivo PK exposure but also promotes the optimization, selection, and development evaluation of compounds to provide data support for the design and development of clinical formulations [18]. For the test compounds in the early screening stage, the unsatisfactory physical and chemical properties, the insufficient compound amount, and the tight time are commonly encountered. In response to these challenges, the DMPK of WuXi AppTec established a team for preclinical formulation screening for PK studies, pharmacodynamic and toxicological studies. The team has more than ten years of experience and can perform rapid formulation screening and preparation services for large and small animal experiments. They also provide more than nearly 1,000 arms of formulations for preclinical in vivo experiments every week. They can use limited (milligram) compounds to offer a suitable formulation for preclinical animal experiments within 24 hours.
Study Methods
The formulation team can select vehicles that meet the requirements of the PK study within one working day. In formulation screening, solubilization technology (such as pH adjustment and cosolvent) is a commonly used technical means. For some poorly soluble compounds, a cosolvent plus surfactant or complexing agent plus pH adjustment are typically used in combination. In addition, the DMPK formulation team can customize the formulation screening strategy according to differentiated project needs.
Strategy [19]
Co-solvent
Surfactant
Cyclodextrins
Particle size reduction
Salt
Amorphous solid dispersion
Lipid-Based Formulation
Instrument
Osmometer
Siri T3 for The pKa Measurement
SPEX®SAMPLEPREP Mill
Small Animal Implantable Osmotic Pump
Malvern-3000 Particle Size Tester
Polarized Light Microscope
Retsch Wet Ball Mill
Covaris®E200x ULtra Ultrasonic Disperser
Rodents Capsule
Lyophilizer
Retsch Ball Mill
Experimental Flow
The formulation team provides formulation screening and formulation services for pharmacokinetic studies from the screening stage to the IND application stage. It provides formulation screening services for pharmacodynamic tests and preclinical toxicological experiments. The team can select suitable excipients to dissolve the compound to tackle the solubility issue according to the physical and chemical properties of each specific drug substance (such as dissociation constant pKa, lipophilicity, aqueous solubility). The most appropriate formulation for a drug substance is selected by in vitro solubility assessment, homogeneity, and particle size analysis. Further screening is performed from eligible candidates to ensure the formulation with the best in vivo bioavailability or experimental objectives is achieved.
References
1. Guideline, O. E. C. D. 428-Guideline f or the Testing of Chemicals-Skin Absorption: in vitro Method." Organization for Economic Cooperation and Development, Paris (2004)
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
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
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