Pharmaceutical Research

, Volume 30, Issue 12, pp 2976–2992 | Cite as

Lipid-Based Formulations and Drug Supersaturation: Harnessing the Unique Benefits of the Lipid Digestion/Absorption Pathway

  • Hywel D. Williams
  • Natalie L. Trevaskis
  • Yan Yan Yeap
  • Mette U. Anby
  • Colin W. Pouton
  • Christopher J. H. Porter
Expert Review


Drugs with low aqueous solubility commonly show low and erratic absorption after oral administration. Myriad approaches have therefore been developed to promote drug solubilization in the gastrointestinal (GI) fluids. Here, we offer insight into the unique manner by which lipid-based formulations (LBFs) may enhance the absorption of poorly water-soluble drugs via co-stimulation of solubilization and supersaturation. Supersaturation provides an opportunity to generate drug concentrations in the GI tract that are in excess of the equilibrium crystalline solubility and therefore higher than that achievable with traditional formulations. Incorporation of LBF into lipid digestion and absorption pathways provides multiple drivers of supersaturation generation and the potential to enhance thermodynamic activity and absorption. These drivers include 1) formulation dispersion, 2) lipid digestion, 3) interaction with bile and 4) lipid absorption. However, high supersaturation ratios may also stimulate drug precipitation and reduce exposure where re-dissolution limits absorption. The most effective formulations are likely to be those that generate moderate supersaturation and do so close to the site of absorption. LBFs are particularly well suited to these criteria since solubilization protects against high supersaturation ratios, and supersaturation initiation typically occurs in the small intestine, at the absorptive membrane.


absorption bile salt digestion lipid-based formulations polymeric precipitation inhibitors solubility supersaturation 



The colloidal aqueous phase formed on digestion of a lipid formulation


The maximum theoretical drug concentration that can be solubilized in the APDIGEST at a particular dose


Fatty acid


Lipid-based formulation




Lipid Formulation Classification System






Polymeric precipitation inhibitor


Poorly water-soluble drug


Drug solubility in the colloids formed on digestion of a lipid-based formulation


Drug solubility in the colloids formed on dispersion of a lipid-based formulation


Drug solubility in the free (non-colloidal) phase


The supersaturation promotion factor induced by digestion


Supersaturation ratio


The maximum supersaturation ratio formed on digestion




Unstirred water layer


Acknowledgments and Disclosures

The authors acknowledge funding support from the Australian Research Council (ARC), National Health and Medical Research Council (NHMRC) and Capsugel for their programs in lipid based drug delivery.


  1. 1.
    Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65:315–499.PubMedCrossRefGoogle Scholar
  2. 2.
    Porter CJH, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6:231–48.PubMedCrossRefGoogle Scholar
  3. 3.
    Porter CJH, Pouton CW, Cuine JF, Charman WN. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev. 2008;60:673–91.PubMedCrossRefGoogle Scholar
  4. 4.
    Hauss DJ. Enhancing the bioavailability of poorly water-soluble drugs. New York: Informa Healthcare; 2007.Google Scholar
  5. 5.
    Dahan A, Hoffman A. Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: correlation with in vivo data and the relationship to intra-enterocyte processes in rats. Pharm Res. 2006;23:2165–74.Google Scholar
  6. 6.
    Han SF, Yao TT, Zhang XX, Gan L, Zhu CL, Yua HZ, et al. Lipid-based formulations to enhance oral bioavailability of the poorly water-soluble drug anethol trithione: effects of lipid composition and formulation. Int J Pharm. 2009;379:18–24.PubMedCrossRefGoogle Scholar
  7. 7.
    Cuine JF, Charman WN, Pouton CW, Edwards GA, Porter CJH. Increasing the proportional content of surfactant (Cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of danazol reduces oral bioavailability in beagle dogs. Pharm Res. 2007;24:748–57.PubMedCrossRefGoogle Scholar
  8. 8.
    Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98:2549–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Gao P, Guyton ME, Huang T, Bauer JM, Stefanski KJ, Lu Q. Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations. Drug Dev Ind Pharm. 2004;30:221–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Gao P, Akrami A, Alvarez F, Hu J, Li L, Ma C, et al. Characterization and optimization of AMG 517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption. J Pharm Sci. 2009;98:516–28.PubMedCrossRefGoogle Scholar
  11. 11.
    Miller JM, Beig A, Carr RA, Spence JK, Dahan A. A win-win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability. Mol Pharm. 2012;9:2009–16.CrossRefGoogle Scholar
  12. 12.
    Ozaki S, Minamisono T, Yamashita T, Kato T, Kushida I. Supersaturation-nucleation behavior of poorly soluble drugs and its impact on the oral absorption of drugs in thermodynamically high-energy forms. J Pharm Sci. 2012;101:214–22.PubMedCrossRefGoogle Scholar
  13. 13.
    Anby MU, Williams HD, McIntosh M, Benameur H, Edwards GA, Pouton CW, et al. Lipid digestion as a trigger for supersaturation: in vitro and in vivo evaluation of the utility of polymeric precipitation inhibitors in self emulsifying drug delivery systems. Mol Pharm. 2012;9:2063–79.CrossRefGoogle Scholar
  14. 14.
    Thomas N, Holm R, Mullertz A, Rades T. In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS). J Control Release. 2012;160:25–32.PubMedCrossRefGoogle Scholar
  15. 15.
    Yeap YY, Trevaskis NL, Porter CJH. Lipid absorption triggers drug supersaturation at the intestinal unstirred water layer and promotes drug absorption from mixed micelles. Pharm Res. 2013. doi: 10.1007/s11095-013-1104-6
  16. 16.
    Gao P, Rush BD, Pfund WP, Huang TH, Bauer JM, Morozowich W, et al. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J Pharm Sci. 2003;92:2386–98.PubMedCrossRefGoogle Scholar
  17. 17.
    Williams HD, Anby MU, Sassene P, Kleberg K, Bakala N’Goma JC, Calderone M, et al. Toward the establishment of standardized in vitro tests for lipid-based formulations: 2) The effect of bile salt concentration and drug loading on the performance of Type I, II, IIIA, IIIB and IV formulations during in vitro digestion. Mol Pharm. 2012;9:3286–300.PubMedCrossRefGoogle Scholar
  18. 18.
    Yeap YY, Trevaskis NL, Quach T, Tso P, Charman WN, Porter CJH. Intestinal bile secretion promotes drug absorption from lipid colloidal phases via induction of supersaturation. Mol Pharm. 2013;10:1874–89.PubMedCrossRefGoogle Scholar
  19. 19.
    Porter CJH, Kaukonen AM, Taillardat-Bertschinger A, Boyd BJ, O’Connor JM, Edwards GA, et al. Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine. J Pharm Sci. 2004;93:1110–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Mohsin K, Long MA, Pouton CW. Design of lipid-based formulations for oral administration of poorly water-soluble drugs: precipitation of drug after dispersion of formulations in aqueous solution. J Pharm Sci. 2009;98:3582–95.PubMedCrossRefGoogle Scholar
  21. 21.
    Williams HD, Sassene P, Kleberg K, Calderone M, Igonin A, Jule E et al. Toward the establishment of standardized in vitro tests for lipid-based formulations: 3) Understanding supersaturation versus precipitation potential during the in vitro digestion of Type I, II, IIIA, IIIB and IV lipid-based formulations. Pharm Res. 2013. doi: 10.1007/s11095-013-1038-z
  22. 22.
    Chiang PC, Thompson DC, Ghosh S, Heitmeier MR. A formulation-enabled preclinical efficacy assessment of a farnesoid X receptor agonist, GW4064, in hamsters and cynomolgus monkeys. J Pharm Sci. 2011;100:4722–33.PubMedCrossRefGoogle Scholar
  23. 23.
    Kossena GA, Boyd BJ, Porter CJH, Charman WN. Separation and characterization of the colloidal phases produced on digestion of common formulation lipids and assessment of their impact on the apparent solubility of selected poorly water-soluble drugs. J Pharm Sci. 2003;92:634–48.PubMedCrossRefGoogle Scholar
  24. 24.
    Kossena GA, Charman WN, Wilson CG, O’Mahony B, Lindsay B, Hempenstall JM, et al. Low dose lipid formulations: effects on gastric emptying and biliary secretion. Pharm Res. 2007;24:2084–96.PubMedCrossRefGoogle Scholar
  25. 25.
    Bakala N’Goma JC, Amara S, Dridi K, Jannin V, Carriere F. Understanding the lipid-digestion processes in the GI tract before designing lipid-based drug-delivery systems. Ther Deliv. 2012;3:105–24.PubMedCrossRefGoogle Scholar
  26. 26.
    Carey MC, Small DM, Bliss CM. Lipid digestion and absorption. Annu Rev Physiol. 1983;45:651–77.PubMedCrossRefGoogle Scholar
  27. 27.
    Armand M, Pasquier B, Andre M, Borel P, Senft M, Peyrot J, et al. Digestion and absorption of 2 fat emulsions with different droplet sizes in the human digestive tract. Am J Clin Nutr. 1999;70:1096–106.PubMedGoogle Scholar
  28. 28.
    Kleberg K, Jacobsen F, Fatouros DG, Mullertz A. Biorelevant media simulating fed state intestinal fluids: colloid phase characterization and impact on solubilization capacity. J Pharm Sci. 2010;99:3522–32.PubMedCrossRefGoogle Scholar
  29. 29.
    Kaukonen AM, Boyd BJ, Porter CJH, Charman WN. Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res. 2004;21:245–53.PubMedCrossRefGoogle Scholar
  30. 30.
    Raneand SS, Anderson BD. What determines drug solubility in lipid vehicles: is it predictable?. [Review] [144 refs][Erratum appears in Adv Drug Deliv Rev. 2008 Dec 14;60(15):1674]. Adv Drug Deliv Rev. 2008;60:638–656.Google Scholar
  31. 31.
    Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006;29:278–87.PubMedCrossRefGoogle Scholar
  32. 32.
    Porter CJH, Kaukonen AM, Boyd BJ, Edwards GA, Charman WN. Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation. Pharm Res. 2004;21:1405–12.PubMedCrossRefGoogle Scholar
  33. 33.
    Hofmann AF, Borgstrom B. The intraluminal phase of fat digestion in man: the lipid content of the micellar and oil phases of intestinal content obtained during fat digestion and absorption. J Clin Invest. 1964;43:247–57.Google Scholar
  34. 34.
    Wilson FA, Sallee VL, Dietschy JM. Unstirred water layers in intestine - rate determinant of fatty acid absorption from micellar solutions. Science. 1971;174:1031–33.PubMedCrossRefGoogle Scholar
  35. 35.
    Yeap YY, Trevaskis NL, Porter CJH. The potential for drug supersaturation during intestinal processing of lipid-based formulations may be enhanced for basic drugs. Mol Pharm. 2013. doi: 10.1021/mp400035z.Google Scholar
  36. 36.
    Williams HD, Hergaden B, Porter CJH. Drug supersaturation in digested lipid-based drug delivery systems. Aaps J. 2012;S2.Google Scholar
  37. 37.
    Lee KWY, Porter CJH, Boyd BJ. The effect of administered dose of lipid-based formulations on the in vitro and in vivo performance of cinnarizine as a model poorly water-soluble drug. J Pharm Sci. In press. 2012.Google Scholar
  38. 38.
    Shiau YF. Mechanism of intestinal fatty-acid uptake in the rat - the role of an acidic microclimate. J Physiol-Lond. 1990;421:463–74.PubMedGoogle Scholar
  39. 39.
    Shiau YF, Fernandez P, Jackson MJ, McMonagle S. Mechanisms maintaining a low-ph microclimate in the intestine. Am J Physiol. 1985;248:G608–17.PubMedGoogle Scholar
  40. 40.
    Lucas ML, Schneider W, Haberich FJ, Blair JA. Direct measurement by ph-microelectrode of ph microclimate in rat proximal jejunum. Proc R Soc B-Biol Sci. 1975;192:39–48.CrossRefGoogle Scholar
  41. 41.
    Cuine JF, McEvoy CL, Charman WN, Pouton CW, Edwards GA, Benameur H, et al. Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs. J Pharm Sci. 2008;97:995–1012.PubMedCrossRefGoogle Scholar
  42. 42.
    James PF. Kinetics of crystal nucleation in silicate-glasses. J Non-Cryst Solids. 1985;73:517–40.CrossRefGoogle Scholar
  43. 43.
    Boistelle R, Astier JP. Crystallization mechanisms in solution. J Crystal Growth. 1988;90:14–30.Google Scholar
  44. 44.
    Devraj R, Williams HD, Warren DB, Porter CJH, Pouton CW. Effect of different nonionic surfactants in self-emulsifying lipid formulations on supersaturation during in vitro digestion. Submitted. 2013.Google Scholar
  45. 45.
    Khoo SM, Humberstone AJ, Porter CJH, Edwards GA, Charman WN. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int J Pharm. 1998;167:155–64.CrossRefGoogle Scholar
  46. 46.
    Gao ZG, Choi HG, Shin HJ, Park KM, Lim SJ, Hwang KJ, et al. Physicochemical characterization and evaluation of a microemulsion system for oral delivery of cyclosporin A. Int J Pharm. 1998;161:75–86.CrossRefGoogle Scholar
  47. 47.
    Shi Y, Gao P, Gong Y, Ping H. Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption. Mol Pharm. 2010;7:1458–65.PubMedCrossRefGoogle Scholar
  48. 48.
    Bevernage J, Brouwers J, Annaert P, Augustijns P. Drug precipitation-permeation interplay: supersaturation in an absorptive environment. Eur J Pharm Biopharm. 2012;82:424–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Kataoka M, Sugano K, da Costa Mathews C, Wong JW, Jones KL, Masaoka Y, et al. Application of dissolution/permeation system for evaluation of formulation effect on oral absorption of poorly water-soluble drugs in drug development. Pharm Res. 2012;29:1485–94.PubMedCrossRefGoogle Scholar
  50. 50.
    Miller DA, DiNunzio JC, Yang W, McGinity JW, Williams RO. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug Dev Ind Pharm. 2008;34:890–902.PubMedCrossRefGoogle Scholar
  51. 51.
    Bevernage J, Brouwers J, Brewster ME, Augustijns P. Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues. Int J Pharm. In press. 2012.Google Scholar
  52. 52.
    Constantinides PP, Wasan KM. Lipid formulation strategies for enhancing intestinal transport and absorption of P-glycoprotein (P-gp) substrate drugs: in vitro/in vivo case studies. J Pharm Sci. 2007;96:235–48.Google Scholar
  53. 53.
    Bevernage J, Forier T, Brouwers J, Tack J, Annaert P, Augustijns P. Excipient-mediated supersaturation stabilization in human intestinal fluids. Mol Pharm. 2011;8:564–70.PubMedCrossRefGoogle Scholar
  54. 54.
    Warren DB, Benameur H, Porter CJH, Pouton CW. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target. 2010;18:704–31.Google Scholar
  55. 55.
    Wei Y, Ye X, Shang X, Peng X, Bao Q, Liu M, et al. Enhanced oral bioavailability of silybin by a supersaturatable self-emulsifying drug delivery system (S-SEDDS). Colloids Surf A-Physicochem Eng Aspects. 2012;396:22–8.CrossRefGoogle Scholar
  56. 56.
    Gosangari S, Dyakonov T. Enhanced dissolution performance of curcumin with the use of supersaturatable formulations. Pharm Dev Technol. in press. 2012.Google Scholar
  57. 57.
    Anby MU, Williams HD, Feeney O, Benameur H, Edwards GA, Pouton CW, Porter CJH. Non-linear increases in danazol exposure with dose in older vs. younger beagle dogs: the potential role of differences in intestinal bile salt concentration, thermodynamic activity and formulation digestion In submission. 2013.Google Scholar
  58. 58.
    Alonzo DE, Raina S, Zhou D, Gao Y, Zhang GGZ, Taylor LS. Characterizing the impact of hydroxypropylmethyl cellulose on the growth and nucleation kinetics of felodipine from supersaturated solutions. Cryst Growth Des. 2012;12:1538–47.CrossRefGoogle Scholar
  59. 59.
    Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Inhibition of solution crystal growth of ritonavir by cellulose polymers - factors influencing polymer effectiveness. CrystEngComm. 2012;14:6503–14.CrossRefGoogle Scholar
  60. 60.
    Williams HD, Sassene P, Kleberg K, Bakala N’Goma JC, Calderone M, Jannin V, et al. Toward the establishment of standardized in vitro tests for lipid-based formulations: 1) Method parameterization and comparison of in vitro digestion profiles across a range of representative formulations. J Pharm Sci. 2012;101:3360–80.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hywel D. Williams
    • 1
    • 3
  • Natalie L. Trevaskis
    • 1
  • Yan Yan Yeap
    • 1
    • 4
  • Mette U. Anby
    • 1
    • 5
  • Colin W. Pouton
    • 2
  • Christopher J. H. Porter
    • 1
  1. 1.Drug Delivery Disposition and DynamicsMonash University (Parkville campus)MelbourneAustralia
  2. 2.Drug Discovery BiologyMonash Institute of Pharmaceutical Sciences, Monash University (Parkville campus)MelbourneAustralia
  3. 3.Capsugel R &DStrasbourgFrance
  4. 4.Department of Chemical EngineeringNortheastern UniversityBostonUSA
  5. 5.Technologie ServierOrleansFrance

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