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Evaluating Oral Drug Delivery Systems: Digestion Models

  • Ragna Berthelsen
  • Philip SasseneEmail author
  • Thomas Rades
  • Anette Müllertz
Chapter
Part of the Advances in Delivery Science and Technology book series (ADST)

Abstract

In order to assess drug release from a digestible drug delivery system (DDS), it is important to simulate the relevant digestion processes as well as the dissolution process. Compared to commonly used dissolution models, digestion models are typically more complex, as they incorporate the digestive enzymes. This also renders these models suitable for the evaluation of food effects on drugs and dosage forms.

In this chapter, the human digestion processes are briefly described, followed by a description of the most commonly used digestion models including the pH-stat controlled lipolysis models, the Dynamic Gastric Model (DGM) and TNO gastrointestinal model (TIM-1). The pH-stat controlled models are examples of relatively simple digestion models commonly used to evaluate the amount of drug solubilised in the aqueous phase during digestion of lipid based DDS (LbDDS), whereas the DGM and the TIM-1 represent two of the more complex dissolution and digestion models available. Emphasis will be on the models suitability to assess LbDDS and will therefore primarily involve lipid digestion.

Keywords

Digestion In vitro GI tract Digestible drug delivery systems Lipid-based drug delivery systems Food effects pH-stat controlled lipolysis model DGM TIM-1 

References

  1. Ali H, Nazzal M, Zaghloul AA, Nazzal S (2008) Comparison between lipolysis and compendial dissolution as alternative techniques for the in vitro characterization of alpha-tocopherol self-emulsified drug delivery systems (SEDDS). Int J Pharm 352(1–2):104–114. doi: 10.1016/j.ijpharm.2007.10.023 PubMedCrossRefGoogle Scholar
  2. Alvarez FJ, Stella VJ (1989) The role of calcium ions and bile salts on the pancreatic lipase-catalyzed hydrolysis of triglyceride emulsions stabilized with lecithin. Pharm Res 6(6):449–457PubMedCrossRefGoogle Scholar
  3. Armand M (2007) Lipases and lipolysis in the human digestive tract: where do we stand? Curr Opin Clin Nutr Metab Care 10(2):156–164. doi: 10.1097/MCO.0b013e3280177687 PubMedCrossRefGoogle Scholar
  4. Armand M, Borel P, Dubois C, Senft M, Peyrot J, Salducci J, Lafont H, Lairon D (1994) Characterization of emulsions and lipolysis of dietary lipids in the human stomach. Am J Physiol 266(3):G372–G381PubMedGoogle Scholar
  5. Armand M, Borel P, Pasquier B, Dubois C, Senft M, Andre M, Peyrot J, Salducci J, Lairon D (1996) Physicochemical characteristics of emulsions during fat digestion in human stomach and duodenum. Am J Physiol 271(1):G172–G183PubMedGoogle Scholar
  6. Armand M, Pasquier B, Andre M, Borel P, Senft M, Peyrot J, Salducci J, Portugal H, Jaussan V, Lairon D (1999) Digestion and absorption of 2 fat emulsions with different droplet sizes in the human digestive tract. Am J Clin Nutr 70(6):1096–1106PubMedGoogle Scholar
  7. Barker R, Abrahamsson B, Kruusmagi M (2014) Application and validation of an advanced gastrointestinal in vitro model for the evaluation of drug product performance in pharmaceutical development. J Pharm Sci 103(11):3704–3712. doi: 10.1002/Jps.24177 PubMedCrossRefGoogle Scholar
  8. Bates TR, Gibaldi M, Kanig JL (1966) Solubilizing properties of bile salt solutions. II. Effect of inorganic electrolyte lipids and a mixed bile salt system on solubilization of glutethimide griseofulvin and hexestrol. J Pharm Sci 55(9):901–906. doi: 10.1002/jps.2600550906 PubMedCrossRefGoogle Scholar
  9. Berthelsen R, Holm R, Jacobsen J, Kristensen J, Abrahamsson B, Mullertz A (2015) Kolliphor surfactants affect solubilization and bioavailability of fenofibrate. Studies of in vitro digestion and absorption in rats 12(4):1062–1071. doi: 10.1021/mp500545k Google Scholar
  10. Blanquet S, Zeijdner E, Beyssac E, Meunier JP, Denis S, Havenaar R, Alric M (2004) A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions. Pharm Res 21(4):585–591. doi: 10.1023/B:Pham.0000022404.70478.4b PubMedCrossRefGoogle Scholar
  11. Carey MC, Small DM, Bliss CM (1983) Lipid digestion and absorption. Annu Rev Physiol 45:651–677. doi: 10.1146/annurev.ph.45.030183.003251 PubMedCrossRefGoogle Scholar
  12. Carriere F, Barrowman JA, Verger R, Laugier R (1993) Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. Gastroenterology 105(3):876–888PubMedCrossRefGoogle Scholar
  13. Charman WN, Porter CJH, Mithani S, Dressman JB (1997) Physicochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci 86(3):269–282. doi: 10.1021/Js960085v PubMedCrossRefGoogle Scholar
  14. Christophersen PC, Christiansen ML, Holm R, Kristensen J, Jacobsen J, Abrahamsson B, Mullertz A (2014) Fed and fasted state gastro-intestinal in vitro lipolysis: In vitro in vivo relations of a conventional tablet, a SNEDDS and a solidified SNEDDS. Eur J Pharm Sci 57:232–239. doi: 10.1016/j.ejps.2013.09.007 PubMedCrossRefGoogle Scholar
  15. Constantinides PP, Wasan KM (2007) 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 96(2):235–248. doi: 10.1002/jps.20780 PubMedCrossRefGoogle Scholar
  16. Cuine JF, McEvoy CL, Charman WN, Pouton CW, Edwards GA, Benameur H, Porter CJ (2008) 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 97(2):995–1012. doi: 10.1002/jps.21246 PubMedCrossRefGoogle Scholar
  17. Dahan A, Hoffman A (2006) 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 23(9):2165–2174. doi: 10.1007/s11095-006-9054-x PubMedCrossRefGoogle Scholar
  18. Dahan A, Hoffman A (2007) The effect of different lipid based formulations on the oral absorption of lipophilic drugs: the ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats. Eur J Pharm Biopharm 67(1):96–105. doi: 10.1016/j.ejpb.2007.01.017 PubMedCrossRefGoogle Scholar
  19. Deat E, Blanquet-Diot S, Jarrige JF, Denis S, Beyssac E, Alric M (2009) Combining the dynamic TNO-gastrointestinal tract system with a Caco-2 cell culture model: application to the assessment of lycopene and alpha-tocopherol bioavailability from a whole food. J Agric Food Chem 57(23):11314–11320. doi: 10.1021/jf902392a PubMedCrossRefGoogle Scholar
  20. DeSesso JM, Jacobson CF (2001) Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats. Food Chem Toxicol 39(3):209–228. doi: 10.1016/S0278-6915(00)00136-8 PubMedCrossRefGoogle Scholar
  21. Dickinson PA, Abu Rmaileh R, Ashworth L, Barker RA, Burke WM, Patterson CM, Stainforth N, Yasin M (2012) An investigation into the utility of a multi-compartmental, dynamic, system of the upper gastrointestinal tract to support formulation development and establish bioequivalence of poorly soluble drugs. AAPS J 14(2):196–205. doi: 10.1208/s12248-012-9333-x PubMedPubMedCentralCrossRefGoogle Scholar
  22. Dressman JB, Berardi RR, Dermentzoglou LC, Russell TL, Schmaltz SP, Barnett JL, Jarvenpaa KM (1990) Upper gastrointestinal (Gi) pH in young, healthy-men and women. Pharm Res 7(7):756–761. doi: 10.1023/A:1015827908309 PubMedCrossRefGoogle Scholar
  23. Fatouros DG, Bergenstahl B, Mullertz A (2007a) Morphological observations on a lipid-based drug delivery system during in vitro digestion. Eur J Pharm Sci 31(2):85–94. doi: 10.1016/j.ejps.2007.02.009 PubMedCrossRefGoogle Scholar
  24. Fatouros DG, Deen GR, Arleth L, Bergenstahl B, Nielsen FS, Pedersen JS, Mullertz A (2007b) Structural development of self nano emulsifying drug delivery systems (SNEDDS) during in vitro lipid digestion monitored by small-angle X-ray scattering. Pharm Res 24(10):1844–1853. doi: 10.1007/s11095-007-9304-6 PubMedCrossRefGoogle Scholar
  25. Fernandez S, Jannin V, Rodier JD, Ritter N, Mahler B, Carriere F (2007) Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol, medium chain glycerides and PEG esters. Biochim Biophys Acta 1771(5):633–640. doi: 10.1016/j.bbalip.2007.02.009 PubMedCrossRefGoogle Scholar
  26. Fernandez S, Chevrier S, Ritter N, Mahler B, Demarne F, Carriere F, Jannin V (2009) In vitro gastrointestinal lipolysis of four formulations of piroxicam and cinnarizine with the self emulsifying excipients Labrasol and Gelucire 44/14. Pharm Res 26(8):1901–1910. doi: 10.1007/s11095-009-9906-2 PubMedCrossRefGoogle Scholar
  27. Griffin BT, Kuentz M, Vertzoni M, Kostewicz ES, Fei Y, Faisal W, Stillhart C, O’Driscoll CM, Reppas C, Dressman JB (2014) Comparison of in vitro tests at various levels of complexity for the prediction of in vivo performance of lipid-based formulations: case studies with fenofibrate. Eur J Pharm Biopharm 86(3):427–437. doi: 10.1016/j.ejpb.2013.10.016 PubMedCrossRefGoogle Scholar
  28. Hamosh M, Burns WA (1977) Lipolytic-activity of human lingual glands (Ebner). Lab Invest 37(6):603–608PubMedGoogle Scholar
  29. Han SF, Yao TT, Zhang XX, Gan L, Zhu C, Yu HZ, Gan Y (2009) Lipid-based formulations to enhance oral bioavailability of the poorly water-soluble drug anethol trithione: effects of lipid composition and formulation. Int J Pharm 379(1):18–24. doi: 10.1016/j.ijpharm.2009.06.001 PubMedCrossRefGoogle Scholar
  30. Hauss DJ (2007) Oral lipid-based formulations. Adv Drug Deliv Rev 59(7):667–676. doi: 10.1016/j.addr.2007.05.006 PubMedCrossRefGoogle Scholar
  31. Heshmati N, Cheng X, Dapat E, Sassene P, Eisenbrand G, Fricker G, Mullertz A (2014) In vitro and in vivo evaluations of the performance of an indirubin derivative, formulated in four different self-emulsifying drug delivery systems. J Pharm Pharmacol 66(11):1567–1575. doi: 10.1111/jphp.12286 PubMedCrossRefGoogle Scholar
  32. Holm R, Porter CJ, Edwards GA, Mullertz A, Kristensen HG, Charman WN (2003) Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. Eur J Pharm Sci 20(1):91–97PubMedCrossRefGoogle Scholar
  33. Kaukonen AM, Boyd BJ, Charman WN, Porter CJ (2004) Drug solubilization behavior during in vitro digestion of suspension formulations of poorly water-soluble drugs in triglyceride lipids. Pharm Res 21(2):254–260PubMedCrossRefGoogle Scholar
  34. Keller PJ, Allan BJ (1967) Protein composition of human pancreatic juice. J Biol Chem 242(2):281–287PubMedGoogle Scholar
  35. Kossena GA, Charman WN, Wilson CG, O’Mahony B, Lindsay B, Hempenstall JM, Davison CL, Crowley PJ, Porter CJH (2007) Low dose lipid formulations: effects on gastric emptying and biliary secretion. Pharm Res 24(11):2084–2096. doi: 10.1007/s11095-007-9363-8 PubMedCrossRefGoogle Scholar
  36. Kostewicz ES, Abrahamsson B, Brewster M, Brouwers J, Butler J, Carlert S, Dickinson PA, Dressman J, Holm R, Klein S, Mann J, McAllister M, Minekus M, Muenster U, Mullertz A, Verwei M, Vertzoni M, Weitschies W, Augustijns P (2014) In vitro models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci 57:342–366. doi: 10.1016/j.ejps.2013.08.024 PubMedCrossRefGoogle Scholar
  37. Larsen A, Holm R, Pedersen ML, Mullertz A (2008) Lipid-based formulations for danazol containing a digestible surfactant, Labrafil M2125CS: in vivo bioavailability and dynamic in vitro lipolysis. Pharm Res 25(12):2769–2777. doi: 10.1007/s11095-008-9641-0 PubMedCrossRefGoogle Scholar
  38. Larsen AT, Sassene P, Mullertz A (2011) In vitro lipolysis models as a tool for the characterization of oral lipid and surfactant based drug delivery systems. Int J Pharm 417(1–2):245–255. doi: 10.1016/j.ijpharm.2011.03.002 PubMedCrossRefGoogle Scholar
  39. Li Y, McClements DJ (2010) New mathematical model for interpreting pH-stat digestion profiles: impact of lipid droplet characteristics on in vitro digestibility. J Agric Food Chem 58(13):8085–8092. doi: 10.1021/jf101325m PubMedCrossRefGoogle Scholar
  40. Mercuri A, Lo Curto A, Wickham MSJ, Craig DQM, Barker SA (2008) Dynamic gastric model (DGM): a novel in vitro apparatus to assess the impact of gastric digestion on the droplet size of self-emulsifying drug-delivery systems. J Pharm Pharmacol 60:4CrossRefGoogle Scholar
  41. Mercuri A, Passalacqua A, Wickham MSJ, Faulks RM, Craig DQM, Barker SA (2011) The effect of composition and gastric conditions on the self-emulsification process of ibuprofen-loaded self-emulsifying drug delivery systems: a microscopic and dynamic gastric model study. Pharm Res 28(7):1540–1551. doi: 10.1007/s11095-011-0387-8 PubMedCrossRefGoogle Scholar
  42. Minekus M, Marteau P, Havenaar R, Huisintveld JHJ (1995) A multicompartmental dynamic computer-controlled model simulating the stomach and small-intestine. Altern Lab Anim 23(2):197–209Google Scholar
  43. Moreau H, Laugier R, Gargouri Y, Ferrato F, Verger R (1988) Human preduodenal lipase is entirely of gastric fundic origin. Gastroenterology 95(5):1221–1226PubMedCrossRefGoogle Scholar
  44. Naylor TA, Connolly PC, Martini LG, Elder DP, Minekus M, Havenaar R, Zeijdner E (2006) Use of a gastrointestinal model and Gastroplus for the prediction of in vivo performance. Ind Pharm 12:9–12Google Scholar
  45. Pafumi Y, Lairon D, de la Porte PL, Juhel C, Storch J, Hamosh M, Armand M (2002) Mechanisms of inhibition of triacylglycerol hydrolysis by human gastric lipase. J Biol Chem 277(31):28070–28079. doi: 10.1074/jbc.M202839200 PubMedCrossRefGoogle Scholar
  46. Palin KJ, Wilson CG (1984) The effect of different oils on the absorption of probucol in the rat. J Pharm Pharmacol 36(9):641–643PubMedCrossRefGoogle Scholar
  47. Patton JS, Carey MC (1981) Inhibition of human pancreatic lipase-colipase activity by mixed bile salt-phospholipid micelles. Am J Physiol 241(4):G328–G336PubMedGoogle Scholar
  48. Porter CJ, Kaukonen AM, Boyd BJ, Edwards GA, Charman WN (2004a) Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation. Pharm Res 21(8):1405–1412PubMedCrossRefGoogle Scholar
  49. Porter CJ, Kaukonen AM, Taillardat-Bertschinger A, Boyd BJ, O’Connor JM, Edwards GA, Charman WN (2004b) 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 93(5):1110–1121. doi: 10.1002/jps.20039 PubMedCrossRefGoogle Scholar
  50. Porter CJH, Trevaskis NL, Charman WN (2007) Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov 6(3):231–248. doi: 10.1038/Nrd2197 PubMedCrossRefGoogle Scholar
  51. Reymond JP, Sucker H, Vonderscher J (1988) In vivo model for ciclosporin intestinal absorption in lipid vehicles. Pharm Res 5(10):677–679PubMedCrossRefGoogle Scholar
  52. Sassene PJ, Knopp MM, Hesselkilde JZ, Koradia V, Larsen A, Rades T, Mullertz A (2010) Precipitation of a poorly soluble model drug during in vitro lipolysis: characterization and dissolution of the precipitate. J Pharm Sci 99(12):4982–4991. doi: 10.1002/jps.22226 PubMedCrossRefGoogle Scholar
  53. Schulze K (2006) Imaging and modelling of digestion in the stomach and the duodenum. Neurogastroenterol Motil 18(3):172–183. doi: 10.1111/j.1365-2982.2006.00759.x PubMedCrossRefGoogle Scholar
  54. Sek L, Porter CJ, Charman WN (2001) Characterisation and quantification of medium chain and long chain triglycerides and their in vitro digestion products, by HPTLC coupled with in situ densitometric analysis. J Pharm Biomed Anal 25(3–4):651–661PubMedCrossRefGoogle Scholar
  55. Sjogren E, Westergren J, Grant I, Hanisch G, Lindfors L, Lennernas H, Abrahamsson B, Tannergren C (2013) In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. Eur J Pharm Sci 49(4):679–698. doi: 10.1016/j.ejps.2013.05.019 PubMedCrossRefGoogle Scholar
  56. Souliman S, Blanquet S, Beyssac E, Cardot JM (2006) A level A in vitro/in vivo correlation in fasted and fed states using different methods: applied to solid immediate release oral dosage form. Eur J Pharm Sci 27(1):72–79. doi: 10.1016/j.ejps.2005.08.006 PubMedCrossRefGoogle Scholar
  57. Stillhart C, Durr D, Kuentz M (2014) Toward an improved understanding of the precipitation behavior of weakly basic drugs from oral lipid-based formulations. J Pharm Sci 103(4):1194–1203. doi: 10.1002/Jps.23892 PubMedCrossRefGoogle Scholar
  58. Thomas N, Holm R, Mullertz A, Rades T (2012a) In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (Super-SNEDDS). J Control Release 160(1):25–32. doi: 10.1016/j.jconrel.2012.02.027 PubMedCrossRefGoogle Scholar
  59. Thomas N, Holm R, Rades T, Mullertz A (2012b) Characterising lipid lipolysis and its implication in lipid-based formulation development. AAPS J 14(4):860–871. doi: 10.1208/s12248-012-9398-6 PubMedPubMedCentralCrossRefGoogle Scholar
  60. Thomas N, Holm R, Garmer M, Karlsson JJ, Mullertz A, Rades T (2013) Supersaturated self-nanoemulsifying drug delivery systems (Super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug simvastatin in dogs. AAPS J 15(1):219–227. doi: 10.1208/s12248-012-9433-7 PubMedCrossRefGoogle Scholar
  61. Thomas N, Richter K, Pedersen TB, Holm R, Mullertz A, Rades T (2014) In vitro lipolysis data does not adequately predict the in vivo performance of lipid-based drug delivery systems containing fenofibrate. AAPS J 16(3):539–549. doi: 10.1208/s12248-014-9589-4 PubMedPubMedCentralCrossRefGoogle Scholar
  62. Vardakou M, Mercuri A, Barker SA, Craig DQM, Faulks RM, Wickham MSJ (2011a) Achieving antral grinding forces in biorelevant in vitro models: comparing the USP dissolution apparatus II and the dynamic gastric model with human in vivo data. AAPS PharmSciTech 12(2):620–626. doi: 10.1208/s12249-011-9616-z PubMedPubMedCentralCrossRefGoogle Scholar
  63. Vardakou M, Mercuri A, Naylor TA, Rizzo D, Butler JM, Connolly PC, Wickham MSJ, Faulks RM (2011b) Predicting the human in vivo performance of different oral capsule shell types using a novel in vitro dynamic gastric model. Int J Pharm 419(1–2):192–199. doi: 10.1016/j.ijpharm.2011.07.046 PubMedCrossRefGoogle Scholar
  64. Wickham MJS, Faulks RM, Mann J, Mandalari G (2012) The design, operation, and application of a dynamic gastric model. Dissolution Technol 19(3):15–22CrossRefGoogle Scholar
  65. Williams HD, Sassene P, Kleberg K, Bakala-N’Goma JC, Calderone M, Jannin V, Igonin A, Partheil A, Marchaud D, Jule E, Vertommen J, Maio M, Blundell R, Benameur H, Carriere F, Mullertz A, Porter CJ, Pouton CW (2012) Toward the establishment of standardized in vitro tests for lipid-based formulations, Part 1: Method parameterization and comparison of in vitro digestion profiles across a range of representative formulations. J Pharm Sci 101(9):3360–3380. doi: 10.1002/jps.23205 PubMedCrossRefGoogle Scholar
  66. Zangenberg NH, Mullertz A, Kristensen HG, Hovgaard L (2001a) A dynamic in vitro lipolysis model. I. Controlling the rate of lipolysis by continuous addition of calcium. Eur J Pharm Sci 14(2):115–122PubMedCrossRefGoogle Scholar
  67. Zangenberg NH, Mullertz A, Kristensen HG, Hovgaard L (2001b) A dynamic in vitro lipolysis model. II: Evaluation of the model. Eur J Pharm Sci 14(3):237–244PubMedCrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2016

Authors and Affiliations

  • Ragna Berthelsen
    • 1
  • Philip Sassene
    • 1
    Email author
  • Thomas Rades
    • 1
  • Anette Müllertz
    • 2
  1. 1.Department of PharmacyUniversity of CopenhagenCopenhagenDenmark
  2. 2.Bioneer:FARMA, Department of PharmacyUniversity of CopenhagenCopenhagenDenmark

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