Approaches to Rapid In Vivo Optimization of Hydrophilic Matrix Tablets

  • John McDermott
  • Peter Scholes
  • Wu Lin
  • Alyson Connor
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 16)


The optimisation of hydrophilic matrix tablets to balance formulation, biopharmaceutical, and physiological variables to achieve a target product profile is a complex process. Traditionally this optimisation process has relied upon application of a series of in vitro, preclinical, and clinical experimentation which extend programme timelines and increase cost to the development programme.

The purpose of this chapter is to discuss the formulation and biopharmaceutical variables that can impact the optimisation of a hydrophilic matrix tablet and describe the limitations of in vitro and preclinical models. The chapter will present strategies to overcome these limitations by designing development programmes to accelerate the in vivo optimisation process using a clinical “make-test” paradigm, termed Translational Pharmaceutics, including case studies.


Regional absorption Gamma scintigraphy Translational pharmaceutics RapidFACT Formulation development Clinical testing Formulation design space 


  1. 1.
    Hauss DJ. Oral lipid-based formulations. Adv Drug Deliv Rev. 2007;59:667–76.PubMedCrossRefGoogle Scholar
  2. 2.
    Quotient Clinical, data on file.Google Scholar
  3. 3.
    Grass GM, Sinko PJ. Physiologically-based pharmacokinetic simulation modelling. Adv Drug Deliv Rev. 2002;54:433–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Gao P, Skoug JW, Nixon PR, Ju TR, Stemm NL, Sung KC. Swelling of hydroxypropyl methylcellulose matrix tablets. 2. Mechanistic study of the influence of formulation variables on matrix performance and drug release. J Pharm Sci. 1996;85:732–40.PubMedCrossRefGoogle Scholar
  5. 5.
    Patel A, Lin W, Hyman B, Stevens LA, Kucera SU, Wagner K, Scholes PD. Development of a formulation design space to enable real-time optimisation of a Modified Release (MR) tablet composition within a flexible clinical study. In: American Association of Pharmaceutical Scientists Annual Meeting and Exposition. Chicago, IL. 2012.Google Scholar
  6. 6.
    Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15:25–35.CrossRefGoogle Scholar
  7. 7.
    Talukdar MM, Michoel A, Rombaut P, Kinget R. Comparative study on xanthan gum and hydroxypropylmethyl cellulose as matrices for controlled-release drug delivery I. Compaction and in vitro drug release behaviour. Int J Pharm. 1996;129:233–41.CrossRefGoogle Scholar
  8. 8.
    Tahara K, Yamamoto K, Nishihata T. Application of model-independent and model analysis for the investigation of effect of drug solubility on its release rate from hydroxypropyl methylcellulose sustained-release tablets. Int J Pharm. 1996;133:17–27.CrossRefGoogle Scholar
  9. 9.
    Bonderoni MC, Caramella C, Sangalli ME, Conte U, Hernandez RM, Pedraz JL. Rheological behaviour of hydrophilic polymers and drug release from erodible matrices. J Control Release. 1992;18:205–12.CrossRefGoogle Scholar
  10. 10.
    Goncalves-Araújo T, Rajabi-Siahboomi AR, Caraballoa I. Application of percolation theory in the study of an extended release erapamil hydrochloride formulation. Int J Pharm. 2008;361:112–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Levina M, Rajabi-Siahboomi A. The influence of excipients on drug release from hydroxypropyl methylcellulose matrices. J Pharm Sci. 2004;93:2746–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Williams RO, Reynolds TD, Cabelka TD, Sykora MA, Mahaguna V. Investigation of excipient type and level on drug release from controlled release tablets containing HPMC. Pharm Dev Technol. 2002;7:181–93.PubMedCrossRefGoogle Scholar
  13. 13.
    Missaghi S, Patel P, Tiwari SB, Farrell TP, Rajabi-Siahboomi A. Investigation of the influence of tablet shape, geometry and film coating on drug release from hypromellose extended-release matrices. Drug Deliv Technol. 2010;10:32–41.Google Scholar
  14. 14.
    McConnell EL, Fadda HM, Basit AW. Gut instincts: Explorations in intestinal physiology and drug delivery. Int J Pharm. 2008;364:213–26.PubMedCrossRefGoogle Scholar
  15. 15.
    Schiller C, Fröhlich C-P, Giessmann T, Siegmund W, Mönnikes H, Hosten N, Weitschies W. Intestinal fluid volumes and transit of dosage forms, as assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2005;22:971–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Zarate N, Mohammed S, O’Shaughnessy E, Newell M, Yazak E, Semler J, Scott SM. Accurate localisation of a fall in pH within the ileo-caecal region. Neurogastroenterol Motil. 2009;21 Suppl 1:43.Google Scholar
  17. 17.
    Evans DE, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut. 1988;29:1035–41.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Connor A, Evans P, Church A, McDermott J, Yamaguch S, Yamashita K, Tagashira M, Morimoto S. A phase I study to investigate the impact of gastrointestinal site of delivery, gastrointestinal pH and formulation composition, on the bioavailability of AK106-001616 in healthy subjects. In: American Association of Pharmaceutical Scientists Annual Meeting and Exposition, San Antonio, TX. 2013.Google Scholar
  19. 19.
    Beaumont K. The importance of gut wall metabolism in determining drug bioavailability. In: van de Waterbeemd H, Lennernäs H, Artursson P, editors. Drug bioavailability. 1st ed. Weinheim, Germany: Wiley-VCH; 2003. p. 311–28.CrossRefGoogle Scholar
  20. 20.
    Tubic-Grozdanis M, Hilfinger JM, Amidon GL, Kim JS, Kijek P, Staubach P, Langguth P. Pharmacokinetics of the CYP 3A substrate simvastatin following administration of delayed versus immediate release oral dosage forms. Pharm Res. 2008;25(7):1591–600.PubMedCrossRefGoogle Scholar
  21. 21.
    Jones K, Connor A, Paterson M. Development of oral formulations to overcome gut wall metabolism. In: 10th Annual American Association of Pharmaceutical Scientists North East Regional Discussion Group (NERDG) Conference, Connecticut. 2007.Google Scholar
  22. 22.
    Martin NE, Collison KR, Martin LL, Tardif SJ, Wilding IR, Wray H, Barrett JS. Pharmacoscintigraphic assessment of the regional drug absorption of the dual angiotension-converting enzyme/neutral endopeptidase inhibitor, M100240, in healthy volunteers. J Clin Pharm. 2003;43:529–38.CrossRefGoogle Scholar
  23. 23.
    Connor A, Evans P, Doto J, Ellis C, Martin DE. An oral human drug absorption study to assess the impact of site of delivery on the bioavailability of bervirimat. J Clin Pharm. 2009;49:606–12.CrossRefGoogle Scholar
  24. 24.
    Hinderling PH, Karara AH, Tao B, Pawula M, Wilding IR, Lu M. Systemic availability of the active metabolite hydroxyl-fasudil after administration of fasudil to different sites of the human gastrointestinal tract. J Clin Pharm. 2007;47:19–25.CrossRefGoogle Scholar
  25. 25.
    Limb MC, Starling RD, Connor A, Stevens LA, Evans P, Church A, Paterson M, RobargeMJ, Harrington JJ. Absorption of ATHX-105 phosphate from the human gastrointestinal tract. In: American Association of Pharmaceutical Scientists Annual Meeting and Exposition, Los Angeles, CA. 2009.Google Scholar
  26. 26.
    Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986;27:886–92.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Davis SS, Washington N, Parr GD, Short AH, John VA, Lloyd P, Walker SM. Relationship between the rate of appearance of oxprenolol in the systemic circulation and the location of an oxprenolol Oros 16/260 drug delivery system within the gastrointestinal tract as determined by scintigraphy. Br J Clin Pharmacol. 1988;26:435–43.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Davis J, Burton J, Connor AL, Macrae R, Wilding IR. Scintigraphic study to investigate the effect of food on a HPMC modified release formulation of UK-294,315. J Pharm Sci. 2009;98(4):1568–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Brown J, Crison J, Timmins P. Predicting feasibility and characterizing performance of extended-release formulations using physiologically based pharmacokinetic modelling. Ther Deliv. 2012;3(9):1047–59.PubMedCrossRefGoogle Scholar
  30. 30.
    Dressman JB. Comparison of canine and human gastrointestinal physiology. Pharm Res. 1986;3(3):123–30.PubMedCrossRefGoogle Scholar
  31. 31.
    Abrahamsson B, Poulin P, Sun D, Mager D. Extrapolation preclinical data to predict human pharmacokinetics: Understanding and practice. In: Symposium at: American Association of Pharmaceutical Scientists Annual Meeting and Exposition, Los Angeles, CA. 2009.Google Scholar
  32. 32.
    Reddy MB, Connor A, Brennan BJ, Morcos PN, Zhou A, McLawhon P, Fretland A, Evans P, Smith P, Tran JQ. Physiological modeling and assessments of regional drug bioavailability of danoprevir to determine whether a controlled release formulation is feasible. Biopharm Drug Dispos. 2011;32(5):261–75.PubMedCrossRefGoogle Scholar
  33. 33.
    Brown J, Chien C, Timmins P, Dennis A, Doll W, Sandefer E, Page R, Nettles RE, Zhu L, Grasela D. Compartmental absorption modeling and site of absorption studies to determine feasibility of an extended-release formulation of an HIV-1 attachment inhibitor phosphate ester prodrug. J Pharm Sci. 2013;102(6):1742–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Sutton SC. The use of gastrointestinal intubation studies for controlled release development. Br J Clin Pharmacol. 2009;68(3):342–54.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Wilding I, Hirst P, Connor A. Development of an engineering based capsule for human drug absorption studies. Pharm Sci Technol Today. 2000;3(11):385–92.PubMedCrossRefGoogle Scholar
  36. 36.
    Hodges LA, Connolly SM, Band J, O'Mahony B, Ugurlu T, Turkoglu M, Wilson CG, Stevens HN. Scintigraphic evaluation of colon targeting pectin-HPMC tablets in healthy volunteers. Int J Pharm. 2009;370(1–2):144–50.PubMedCrossRefGoogle Scholar
  37. 37.
    Connor A. Location, location, location: Gastrointestinal delivery site and its impact on absorption. Ther Deliv. 2012;3(5):575–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Wilding A, Coupe J, Davis S. The role of γ-scintigraphy in oral drug delivery. Adv Drug Deliv Rev. 2001;46(1–3):103–24.PubMedCrossRefGoogle Scholar
  39. 39.
    Connor AL, Wray H, Cottrell J, Wilding IR. A scintigraphic study to investigate the potential for altered gut distribution of loperamide from a loperamide-simethicone formulation in man. Eur J Pharm Sci. 2001;13:369–74.PubMedCrossRefGoogle Scholar
  40. 40.
    Katsuma M, Watanabe S, Takemura S, Sako K, Sawada T, Masuda Y, Nakamura K, Fukui M, Connor AL, Wilding IR. Scintigraphic evaluation of novel colon-targeted delivery system (CODESTM) in healthy volunteers. J Pharm Sci. 2004;93(5):1287–99.PubMedCrossRefGoogle Scholar
  41. 41.
    Cole E, Scott R, Connor A, Wilding I, Petereit H, Schminke C, Beckert T, Cadé D. Enteric coated HPMC capsules designed to achieve intestinal targeting. Int J Pharm. 2002;231(1):83–95.PubMedCrossRefGoogle Scholar
  42. 42.
    Basit AW, Podczeck F, Newton JM, Waddington WA, Ell PJ, Lacey LF. The use of formulation technology to assess regional gastrointestinal drug absorption in humans. Eur J Pharm Sci. 2004;21:179–89.PubMedCrossRefGoogle Scholar
  43. 43.
    Nicholson SJ, Timmins P, Dockens RC, Connor A, Croop R, Ferrie P, Zeng J, Dennis AB, Wilding I. Development of oral extended release formulations of 6-hydroxybuspirone. Biopharm Drug Dispos. 2012;33(9):522–35.PubMedCrossRefGoogle Scholar
  44. 44.
    Lobo ED, Argentine MD, Sperry DC, Connor A, McDermott J, Stevens L, Almaya A. Optimization of LY545694 tosylate controlled release tablets through pharmacoscintigraphy. Pharm Res. 2012;29:2912–25.PubMedCrossRefGoogle Scholar
  45. 45.
    Scholes PD, Stevens LA, Paterson M, Egerton M. Translational pharmaceutics—Interactive drug development to enable rapid optimisation of drug products in early development. American Association of Pharmaceutical Scientists Annual Meeting and Exposition. Los Angeles, CA. Poster #2869. 2009.Google Scholar
  46. 46.
    Haskell RJ, Rades T, Dobry DE, Kress MH. Translational pharmaceutics: Connecting preclinical and clinical enabled formulations. In: Symposium at: American Association of Pharmaceutical Scientists Annual Meeting and Exposition, San Antonio, TX. 2013Google Scholar
  47. 47.
    International Conference on Harmonization. ICH Q8 (R2) Pharmaceutical Development. 2009. Accessed 27 May 2014.
  48. 48.
    International Conference on Harmonization. ICH Q8 (R2) ICH Q1D Bracketing and matrixing designs for stability testing of drug substances and drug products. 2002. Accessed 27 May 2014.
  49. 49.
    Prince WT, Stewart-Campbell A, Tong W, Sweetnam P, Rosen R, Goldstein I, Willett MS, Roesch BG, Garcia WD. SLx-2010, a new long-acting PDE5 inhibitor: Preliminary safety, tolerability, pharmacokinetics and endothelial function effects in healthy subjects. In: Sexual Medicine Society of North America Fall Meeting, New York, NY. 2005.Google Scholar
  50. 50.
    Lin W, Schueller O, Patel A, McDermott J, Sweetnam P, Scholes P. Formulation design space for SLx-2101 modified release tablets to enable a flexible phase I pharmacokinetic study. In: Controlled Release Society Annual Meeting and Exposition. Portland, OR. 2010.Google Scholar
  51. 51.
    Food and Drug Administration. FDA guidance for industry extended release oral dosage forms: Development, evaluation, and application of in vitro/in vivo correlations. 1997. Accessed 27 May 2014.
  52. 52.
    European Medicines Agency. Guideline on quality of oral modified release products, EMA/492713/2012. 2012.
  53. 53.
    Kane Z, Stevens LA, McDermott J, Scholes P. Impact of differences in regional bioavailability on IVIVC development for modified release drug products. In: American Association of Pharmaceutical Scientists Annual Meeting and Exposition, San Antonio, TX. 2013.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • John McDermott
    • 1
  • Peter Scholes
    • 2
  • Wu Lin
    • 2
  • Alyson Connor
    • 2
  1. 1.Drug Product OptimizationQuotient ClinicalNottinghamUK
  2. 2.Quotient ClinicalNottinghamUK

Personalised recommendations