Abstract
Reduced portfolio attrition and faster development of high quality drugs that address unmet medical needs is an established imperative within the pharmaceutical industry. Given the complexity of modern drug discovery, this goal can only be achieved through well-designed pharmacology, pharmacokinetic, and toxicology studies resulting in the identification of exceptional development candidates. Pivotal to the success of these studies is the use of appropriate formulations designed to deliver the compound to the desired site via the desired route, in a consistent and acceptable manner. It is also essential that the formulations are developed with a clear understanding of the goals of the studies, future application of the formulations, and/or the data from the studies. However, the development of an appropriate discovery formulation can be challenging due to a myriad of factors that include suboptimal biopharmaceutical properties, dose, compound purity, compound availability, and aggressive timelines. This chapter will cover formulations used in the discovery setting from conventional vehicles to solubilizing systems and alternate delivery approaches. The application of the appropriate formulation approach to meet the study goals and efficient development timelines will also be discussed.
Keywords
- Solid Dispersion
- Toxicology Study
- Osmotic Pump
- Amorphous Solid Dispersion
- Discovery Setting
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Akimoto M, Nagahata N et al (2000) Gastric pH profiles of beagle dogs and their use as an alternative to human testing. Eur J Pharm Biopharm 49(2):99–102
Anderson GD, Saneto RP (2012) Current oral and non-oral routes of antiepileptic drug delivery. Adv Drug Deliv Rev 64(10):911–918
Balazs O (2011) Preclinical formulation in early drug research. In: Tihanyi K, Vastag M (eds) Solubility, delivery and ADME problems of drugs and drug candidates. Budapest, Bentham, p 22
Bernabei R, Rossini PM et al (2012) Compliance and caregiver satisfaction in Alzheimer’s disease: results from the AXEPT study. Dement Geriatr Cogn Dis Extra 2(1):418–432
Bhattachar SN, Perkins EJ et al (2011) Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus, simulations to predict absorption. J Pharm Sci 100(11):4756–4765
Bikiaris DN (2011) Solid dispersions, part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs. Expert Opin Drug Deliv 8(11):1501–1519
Bittner BG, Bravo RC, Walter I, Huwyler J (2005) Impact of oral administration of the surface-active excipient Solutol HS 15 on the pharmacokinetics of intravenously administered colchicine. Lett Drug Des Discov 2(3):3
Blagg J, Allerton CM et al (2007) Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route. Bioorg Med Chem Lett 17(24):6691–6696
Bravo González RC, Huwyler J, Boess F, Walter I, Bittner B (2004) In vitro investigation on the impact of the surface-active excipients Cremophor EL, Tween 80 and Solutol HS 15 on the metabolism of midazolam. Biopharm Drug Dispos 25(1):13
Brewster M, Claire M, Noppe M, Lampo A, Loftsson T (2007) The use of solubilizing excipients and approaches to generate toxicology vehicles for contemporary drug pipelines. In: Augustijns P, Brewster M (eds) Solvent systems and their selection in pharamceutics and biopharmaceutics. Springer, New York, pp 221–256
Buckley LA, Dorato MA (2009) High dose selection in general toxicity studies for drug development: a pharmaceutical industry perspective. Regul Toxicol Pharmacol 54(3):301–307
Buggins TR, Dickinson PA et al (2007) The effects of pharmaceutical excipients on drug disposition. Adv Drug Deliv Rev 59(15):1482–1503
Carino SR, Sperry DC et al (2006) Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model. J Pharm Sci 95(1):116–125
Carrier RL, Miller LA et al (2007) The utility of cyclodextrins for enhancing oral bioavailability. J Control Release 123(2):78–99
Chapman CD, Frey WH 2nd et al (2013) Intranasal treatment of central nervous system dysfunction in humans. Pharm Res 30(10):2475–2484
Charman SA, Perry CS et al (2006) Alteration of the intravenous pharmacokinetics of a synthetic ozonide antimalarial in the presence of a modified cyclodextrin. J Pharm Sci 95(2):256–267
Chaubal MV (2004) Application of drug delivery technologies in lead candidate selection and optimization. Drug Discov Today 9(14):603–609
Chen XQ, Gudmundsson OS et al (2012) Application of lipid-based formulations in drug discovery. J Med Chem 55(18):7945–7956
Chien JY, Ho RJ (2011) Drug delivery trends in clinical trials and translational medicine: evaluation of pharmacokinetic properties in special populations. J Pharm Sci 100(1):53–58
Chiou WL, Barve A (1998) Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Pharm Res 15(11):1792–1795
Dafallah AA, al-Mustafa Z (1996) Investigation of the anti-inflammatory activity of Acacia nilotica and Hibiscus sabdariffa. Am J Chin Med 24(3–4):263–269
Dietrich E, Gums JG (2012) Intranasal fentanyl spray: a novel dosage form for the treatment of breakthrough cancer pain. Ann Pharmacother 46(10):1382–1391
Dimitrov NV, Meyer-Leece C et al (1996) Plasma alpha-tocopherol concentrations after supplementation with water- and fat-soluble vitamin E. Am J Clin Nutr 64(3):329–335
Dorato MA, Buckley LA (2007) Toxicology testing in drug discovery and development. Curr Protoc Toxicol Chapter 19: Unit 19 11
Dudley RE, Constantinides P (2011) Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same. WIPO, Clarus Therapeutics, Inc
Fancher RM, Zhang H et al (2011) Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds. J Pharm Sci 100(7):2979–2988
Ferguson SA, Boctor SY (2009) Use of food wafers for multiple daily oral treatments in young rats. J Am Assoc Lab Anim Sci 48(3):292–295
Foster KA, Sun H et al (2013) Utility of gastric-retained alginate gels to modulate pharmacokinetic profiles in rats. J Pharm Sci 102(8):2440–2449
Friesen DT, Shanker R et al (2008) Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: an overview. Mol Pharm 5(6):1003–1019
Gad SC, Cassidy CD et al (2006) Nonclinical vehicle use in studies by multiple routes in multiple species. Int J Toxicol 25(6):499–521
Gao P, Guyton ME et al (2004) Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations. Drug Dev Ind Pharm 30(2):221–229
Gao Y, Carr RA et al (2010) A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: application to physiologically based pharmacokinetic modeling. Mol Pharm 7(5):1516–1526
Gartner K, Buttner D et al (1980) Stress response of rats to handling and experimental procedures. Lab Anim 14(3):267–274
Gayrard V, Lacroix MZ et al (2013) High bioavailability of bisphenol A from sublingual exposure. Environ Health Perspect 121(8):951–956
Gleeson MP, Hersey A et al (2011) Probing the links between in vitro potency, ADMET and physicochemical parameters. Nat Rev Drug Discov 10(3):197–208
Goswami T, Kokate A et al (2013) In silico model of drug permeability across sublingual mucosa. Arch Oral Biol 58(5):545–551
Gullapalli R, Wong A et al (2012) Development of ALZET(R) osmotic pump compatible solvent compositions to solubilize poorly soluble compounds for preclinical studies. Drug Deliv 19(5):239–246
Hageman MJ (2006) Solubility, solubilization and dissolution in drug delivery during lead optimization. In: Borchardt RT, Kerns EH, Hageman MJ, Thakker DR, Stevens JL (eds) Optimizing the drug-like properties of leads in drug discovery, vol VI, Biotechnology: pharmaceutical aspects. Springer, New York, pp 99–103
He K, Qian M et al (2008) N-in-1 dosing pharmacokinetics in drug discovery: experience, theoretical and practical considerations. J Pharm Sci 97(7):2568–2580
Higgins J, Cartwright ME et al (2012) Progressing preclinical drug candidates: strategies on preclinical safety studies and the quest for adequate exposure. Drug Discov Today 17(15–16):828–836
Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1:727–730
Jacquemin E, Hermeziu B et al (2009) Bioavailability of oral vitamin E formulations in adult volunteers and children with chronic cholestasis or cystic fibrosis. J Clin Pharm Ther 34(5):515–522
Kesisoglou F, Mitra A (2012) Crystalline nanosuspensions as potential toxicology and clinical oral formulations for BCS II/IV compounds. AAPS J 14(4):677–687
Kesisoglou F, Panmai S et al (2007) Nanosizing—oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev 59(7):631–644
Kumar R, Knick VB et al (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6(7):2012–2021
Kurkov SV, Loftsson T (2013) Cyclodextrins. Int J Pharm 453(1):167–180
Kurkov SV, Madden DE et al (2012) The effect of parenterally administered cyclodextrins on the pharmacokinetics of coadministered drugs. J Pharm Sci 101(12):4402–4408
Kwong E, Higgins J et al (2011) Strategies for bringing drug delivery tools into discovery. Int J Pharm 412(1–2):1–7
Lam JK, Xu Y et al (2013) Oral transmucosal drug delivery for pediatric use. Adv Drug Deliv Rev 73C:50–62
Larger PJ, Breda M et al (2005) Ion-suppression effects in liquid chromatography-tandem mass spectrometry due to a formulation agent, a case study in drug discovery bioanalysis. J Pharm Biomed Anal 39(1–2):206–216
Lee YC, Zocharski PD et al (2003) An intravenous formulation decision tree for discovery compound formulation development. Int J Pharm 253(1–2):111–119
Lee PH, Conradi R et al (2010) Development of an in silico model for human skin permeation based on a Franz cell skin permeability assay. Bioorg Med Chem Lett 20(1):69–73
Lehman PA, Raney SG (2012) In vitro percutaneous absorption of ketoprofen and testosterone: comparison of pluronic lecithin organogel vs. pentravan cream. Int J Pharm Compd 16(3):248–252
Li P, Zhao L (2007) Developing early formulations: practice and perspective. Int J Pharm 341(1–2):1–19
Li S, Pollock-Dove C et al (2012) Enhanced bioavailability of a poorly water-soluble weakly basic compound using a combination approach of solubilization agents and precipitation inhibitors: a case study. Mol Pharm 9(5):1100–1108
Loftsson T, Brewster ME (2010) Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Pharmacol 62(11):1607–1621
Loftsson T, Brewster ME (2011) Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes. J Pharm Pharmacol 63(9):1119–1135
Long G, Works J (2013). Innovation in the biopharmaceutical pipeline: a multidimensional view. www.pharma.org
Lorenz W, Reimann HJ et al (1977) Histamine release in dogs by Cremophor E1 and its derivatives: oxethylated oleic acid is the most effective constituent. Agents Actions 7(1):63–67
Lorenz W, Schmal A et al (1982) Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: analysis of various components in cremophor El and development of a compound with reduced toxicity. Agents Actions 12(1–2):64–80
Lui CY, Amidon GL et al (1986) Comparison of gastrointestinal pH in dogs and humans: implications on the use of the beagle dog as a model for oral absorption in humans. J Pharm Sci 75(3):271–274
Lukas G, Brindle SD et al (1971) The route of absorption of intraperitoneally administered compounds. J Pharmacol Exp Ther 178(3):562–564
Luke DR, Tomaszewski K et al (2010) Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD). J Pharm Sci 99(8):3291–3301
M3(R2) Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. I. C. o. Harmonization
Maas J, Kamm W et al (2007) An integrated early formulation strategy—from hit evaluation to preclinical candidate profiling. Eur J Pharm Biopharm 66(1):1–10
Mactier RA, Khanna R et al (1987) Role of peritoneal cavity lymphatic absorption in peritoneal dialysis. Kidney Int 32(2):165–172
Mathias NR, Hussain MA (2010) Non-invasive systemic drug delivery: developability considerations for alternate routes of administration. J Pharm Sci 99(1):1–20
Merisko-Liversidge EM, Liversidge GG (2008) Drug nanoparticles: formulating poorly water-soluble compounds. Toxicol Pathol 36(1):43–48
Miller JM, Dahan A (2012) Predicting the solubility-permeability interplay when using cyclodextrins in solubility-enabling formulations: model validation. Int J Pharm 430(1–2):388–391
Morphy R (2010) Selectively nonselective kinase inhibition: striking the right balance. J Med Chem 53(4):1413–1437
Mu J, Woods J et al (2006) Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes 55(6):1695–1704
Mu J, Petrov A et al (2009) Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol 623(1–3):148–154
Muramatsu RS, Litzinger MH et al (2010) Alternative formulations, delivery methods, and administration options for psychotropic medications in elderly patients with behavioral and psychological symptoms of dementia. Am J Geriatr Pharmacother 8(2):98–114
Musther H, Olivares-Morales A et al (2013) Animal versus human oral drug bioavailability: do they correlate? Eur J Pharm Sci 57:280–291
Nagapudi KJ, Jona J (2008) Amorphous active pharmaceutical ingredients in preclinical studies: preparation, characterization, and formulation. Curr Bioactive Compd 4(4):213–224
Nagilla R, Nord M et al (2011) Cassette dosing for pharmacokinetic screening in drug discovery: comparison of clearance, volume of distribution, half-life, mean residence time, and oral bioavailability obtained by cassette and discrete dosing in rats. J Pharm Sci 100(9):3862–3874
Neely BJ, Madihally SV et al (2009) Nonlinear quantitative structure-property relationship modeling of skin permeation coefficient. J Pharm Sci 98(11):4069–4084
Neervannan S (2006) Preclinical formulations for discovery and toxicology: physicochemical challenges. Expert Opin Drug Metab Toxicol 2(5):715–731
Oh DM, Curl RL et al (1993) Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: a mathematical model. Pharm Res 10(2):264–270
Pammolli F, Magazzini L et al (2011) The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov 10(6):428–438
Paudel KS, Milewski M et al (2010) Challenges and opportunities in dermal/transdermal delivery. Ther Deliv 1(1):109–131
Pfeil E, Dobs AS (2008) Current and future testosterone delivery systems for treatment of the hypogonadal male. Expert Opin Drug Deliv 5(4):471–481
Pole DL (2008) Physical and biological considerations for the use of nonaqueous solvents in oral bioavailability enhancement. J Pharm Sci 97(3):1071–1088
Porter CJ, Pouton CW et al (2008) Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev 60(6):673–691
Pouton CW, Porter CJ (2008) Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Adv Drug Deliv Rev 60(6):625–637
Qian F, Huang J et al (2010) Drug-polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci 99(7):2941–2947
Rabinow BE (2004) Nanosuspensions in drug delivery. Nat Rev Drug Discov 3(9):785–796
Rao VM, Stella VJ (2003) When can cyclodextrins be considered for solubilization purposes? J Pharm Sci 92(5):927–932
Reed KW, Yalkowsky SH (1985) Lysis of human red blood cells in the presence of various cosolvents. J Parenter Sci Technol 39(2):64–69
Roth BL, Sheffler DJ et al (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov 3(4):353–359
Saxena V, Panicucci R et al (2009) Developability assessment in pharmaceutical industry: an integrated group approach for selecting developable candidates. J Pharm Sci 98(6):1962–1979
Scannell JW, Blanckley A et al (2012) Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 11(3):191–200
Shah AK, Agnihotri SA (2011) Recent advances and novel strategies in pre-clinical formulation development: an overview. J Control Release 156(3):281–296
Sheth AR (2011) In vitro screening methods to assess the potential of in vivo precipitation of injectable formulations upon intravenous administration. PDA J Pharm Sci Technol 65(1):71–80
Shiotani K, Uehata K et al (1995) Differential effects of sulfate and sulfobutyl ether of beta-cyclodextrin on erythrocyte membranes in vitro. Pharm Res 12(1):78–84
Six K, Verreck G et al (2004) Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J Pharm Sci 93(1):124–131
Stella VJ, He Q (2008) Cyclodextrins. Toxicol Pathol 36(1):30–42
Stella VJ, Rao VM et al (1999) Mechanisms of drug release from cyclodextrin complexes. Adv Drug Deliv Rev 36(1):3–16
Strickley RG (2008) Formulation in drug discovery (chapter 24). Annu Rep Med Chem 43:419–451
Sutton SC, Engle K et al (1993) Intranasal delivery of the bisphosphonate alendronate in the rat and dog. Pharm Res 10(6):924–926
ten Tije AJ, Verweij J et al (2003) Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet 42(7):665–685
Tong WQ, Whitesell G (1998) In situ salt screening—a useful technique for discovery support and preformulation studies. Pharm Dev Technol 3(2):215–223
Traber MG, Kayden HJ et al (1986) Absorption of water-miscible forms of vitamin E in a patient with cholestasis and in thoracic duct-cannulated rats. Am J Clin Nutr 44(6):914–923
Turner PV, Brabb T et al (2011) Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci 50(5):600–613
Van Eerdenbrugh B, Van den Mooter G et al (2008) Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm 364(1):64–75
Vandecruys R, Peeters J et al (2007) Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design. Int J Pharm 342(1–2):168–175
Vasconcelos T, Sarmento B, Costa P (2007) Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today 12(23–24):8
Venkatesh S, Lipper RA (2000) Role of the development scientist in compound lead selection and optimization. J Pharm Sci 89(2):145–154
Verreck G, Six K et al (2003) Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion—part I. Int J Pharm 251(1–2):165–174
Vitic Nexus. Lhasa Limited, Leeds, UK. http://www.lhasalimited.org/products/vitic-nexus.html
Vo CL, Park C et al (2013) Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm 85(3):799–813
Warren DB, Benameur H et al (2010) Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target 18(10):704–731
Waters C (2013) The development of the rotigotine transdermal patch: a historical perspective. Neurol Clin 31(3 Suppl):S37–S50
Watkinson AC (2013) A commentary on transdermal drug delivery systems in clinical trials. J Pharm Sci 102(9):3082–3088
Weiss RB, Donehower RC et al (1990) Hypersensitivity reactions from taxol. J Clin Oncol 8(7):1263–1268
Williams HD, Trevaskis NL et al (2013) Strategies to address low drug solubility in discovery and development. Pharmacol Rev 65(1):315–499
Willmann S, Schmitt W et al (2004) A physiological model for the estimation of the fraction dose absorbed in humans. J Med Chem 47(16):4022–4031
Woodburn K, Kessel D (1994) The alteration of plasma lipoproteins by cremophor EL. J Photochem Photobiol B 22(3):197–201
Wright BA, Waters CH (2013) Continuous dopaminergic delivery to minimize motor complications in Parkinson's disease. Expert Rev Neurother 13(6):719–729
Xu S, Dai WG (2013) Drug precipitation inhibitors in supersaturable formulations. Int J Pharm 453(1):36–43
Yalkowsky SH (1999) Solubility and solubilization in aqueous media. American Chemical Society, New York
Yamada I, Haga K (1990) Measurement of gastric pH during digestion of a solid meal in dogs. Chem Pharm Bull (Tokyo) 38(6):1755–1756
Yin AY, Htun M et al (2012) Reexamination of pharmacokinetics of oral testosterone undecanoate in hypogonadal men with a new self-emulsifying formulation. J Androl 33(2):190–201
Zhang H, Zhang J et al (2002) Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet 41(9):661–680
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Bhattachar, S.N., Bender, D.M., Sweetana, S.A., Wesley, J.A. (2015). Discovery Formulations: Approaches and Practices in Early Preclinical Development. In: Templeton, A., Byrn, S., Haskell, R., Prisinzano, T. (eds) Discovering and Developing Molecules with Optimal Drug-Like Properties. AAPS Advances in the Pharmaceutical Sciences Series, vol 15. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1399-2_2
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