Skip to main content
SpringerLink
Log in

Biopharmaceutical Evaluation and CMC Aspects of Oral Modified Release Formulations

  • Review Article
  • Theme: Revisiting Drug Absorption and Elimination in the Design and Evaluation of Oral Modified Release Drug Products
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form. The quality-by-design (QbD) aspects of MR dosage form design and development are discussed with the emphasis on the regulatory view of the data required to support dosage form development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Philip A, Philip B. Colon-targeted delivery systems: a review of primary and novel approaches. Oman Medical Journal. 2010;25:70–8.

    Article  Google Scholar 

  2. Timmins P, Mathias N. Formulation technology can enable oral drug delivery of new generation medicines for inflammatory bowel disease. Industrial Pharm. 2016;52:4–18.

    Google Scholar 

  3. Zhang H, Surian JM. Biopharmaceutic consideration and assessment for oral controlled release formulations. In: Zhang, Park, editors. Oral controlled release formulation design and drug delivery. Hoboken: Wiley; 2010.

    Google Scholar 

  4. Ungell AL, Nylander S, Bergstrand S, Sjoberg A, Lennernas H. Membrane transport of drugs in different regions of the intestinal tract of the rat. J Pharm Sci. 1998;87:360–6.

    Article  CAS  PubMed  Google Scholar 

  5. Wen H, Park K. Introduction and overview of oral controlled release formulation design. In: Zhang, Park, editors. Oral controlled release formulation design and drug delivery. Hoboken: Wiley; 2010.

    Chapter  Google Scholar 

  6. Thombre AG. Assessment of the feasibility of oral controlled release in an exploratory development setting. Drug Discov Today. 2005;10:1159–66.

    Article  CAS  PubMed  Google Scholar 

  7. Davis SS. Formulation strategies for absorption windows. Drug Discov Today. 2005;10:249–57.

    Article  CAS  PubMed  Google Scholar 

  8. Dempski RE, Scholtz EC, Oberholtzer ER, Yeh KC. Pharmaceutical design and development of a Sinemet controlled release formulation. Neurology. 1989;39:20–4.

    CAS  PubMed  Google Scholar 

  9. Fagerholm U, Lindahl A, Lennernas H. Regional intestinal permeability in rats of compounds with different physicochemical properties and transport mechanisms. J Pharm Pharmacol. 1997;49:687–90.

    Article  CAS  PubMed  Google Scholar 

  10. Wilding IR. Site specific drug delivery in the gastrointestinal tract. Crit Rev Ther Drug Carrier Systems. 2000;17:557–620.

    CAS  Google Scholar 

  11. Oo C, Smell P, Barrett J, Deer A, Liu B, Wilding IR. Pharmacokinetics and delivery of the anti-influenza prodrug oseltamivir to the small intestine and colon using site-specific delivery capsules. Int J Pharm. 2003;257:257–9.

    Article  Google Scholar 

  12. Wilding IR, Prior DV. Remote controlled capsules in human drug absorption studies. Crit. Rev. Ther. Drug Carrier Systems. 2003;20:405–31.

    CAS  Google Scholar 

  13. Wilding IR, Connor AL, Carpenter P, Rordorf C, Branson J, Milosavljev S, et al. Assessment of lumiracoxib bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy. Pharm Res. 2004;21:443–6.

    Article  CAS  PubMed  Google Scholar 

  14. Hinderling PH, Karara AH, Tao B, Pawula M, et al. Systemic availability of the active metabolites hydroxyl-fasudil after administration of fasudil to different sites of the human gastrointestinal tract. J Clin Pharmacol. 2007;47:19–25.

    Article  CAS  PubMed  Google Scholar 

  15. Macha S, Yong CI, MacGregor TR, Castles M, Quinson AM, Rouyrre N, et al. Assessment of nevirapine bioavailability from targeted sites in the human gastrointestinal tract. J Clin Pharmacol. 2009;49:1417–25.

    Article  CAS  PubMed  Google Scholar 

  16. Menon R, Cefali E, Wilding I, Wray H, Connor A. The assessment of human regional drug absorption of free acid and sodium salt forms of acipimox in healthy volunteers to direct modified release formulation strategy, Biopharm. Drug Disposition. 2009;30:508–16.

    Article  CAS  Google Scholar 

  17. Stockis A, Sargentini-Maier ML, Otoul C, Connor A, Wilding I, Wray H. Assessment of levetiracetam bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy: open-label single-dose, randomized, four-way crossover study in healthy male volunteers. Clin Ther. 2010;32:1813–21.

    Article  CAS  PubMed  Google Scholar 

  18. Parasrampuria DA, Kanamaru T, Connor A, Wilding I, Ogala K, Simoto Y, et al. Evaluation of regional gastrointestinal absorption of edoxaban using the enterion capsules. J Clin Pharmacol. 2015;55:1286–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eudragit Technical Brochure. Evonik Industries AG, Germany. http://healthcare.evonik.com/sites/lists/NC/DocumentsHC/Evonik-Eudragit_brochure.pdf

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. Buch A, Barr WH. Absorption of propranolol in humans following oral, jejunal, ileal administration. Pharm Res. 1998;15:953–7.

    Article  CAS  PubMed  Google Scholar 

  22. Skelly JP, Barr WH. In: Robinson JR, Lee VHL, editors. Regulatory assessment, in controlled drug delivery, fundamentals and applications. 2nd ed. New York: CRC Press; 1987. p. 293–334.

    Chapter  Google Scholar 

  23. Lee L, Hossain M, Wang Y, Sedek G. Absorption of rivastigmine form different regions of the gastrointestinal tract in humans. J Clin Pharmacol. 2004;44:599–604.

    Article  CAS  PubMed  Google Scholar 

  24. Petri NM, Borga O, Nyberg L, Hedeland M, Bondesson U, Lennernas H. Effect of erythromycin on the absorption of fexofenadine in the jejunum, ileum, and colon determined using local intubation in healthy volunteers. Int J Clin Pharmacol Ther. 2006;44:71–9.

    Article  CAS  PubMed  Google Scholar 

  25. Tsunashima D, Kawamura A, Murakami M, Sawamoto T, Undre N, Brown M, et al. Assessment of tacrolimus absorption form the human intestinal tract: open-label, randomized, 4-way crossover study. Clin Ther. 2014;36:748–59.

    Article  CAS  PubMed  Google Scholar 

  26. Olivares-Morales A, Ghosh A, Aarons L, Rostami-Hodjegan A. Development of a novel simplified PBPK absorption model to explain the higher relative bioavailability of the OROS® formulation of oxybutynin. AAPS J. 2016;18:1532–49.

    Article  CAS  PubMed  Google Scholar 

  27. Reddy MB, Connor A, Brennan BJ, Morcos PN, Zhou A, McLawhon P, et al. Physiological modeling and assessment of regional drug bioavailability of danoprevir to determine whether a controlled release formulation is feasible. Biopharm Drug Dispos. 2011;32:261–75.

    Article  CAS  PubMed  Google Scholar 

  28. Klein S. Predicting food-effects on drug release from extended release oral dosage forms containing a narrow-therapeutic index drug. Dissolution Tech. 2009:28–38.

  29. Lukacova V, Woltosz WS, Bolger MB. Prediction of modified release pharmacokinetics and pharmacodynamics from in vitro, immediate release, and intravenous data. AAPS J. 2009;11:323–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Good DJ, Hartley R, Mathias N, Crison J, Tirucherai G, Timmins P, et al. Mitigation of adverse clinical events of a narrow target therapeutic index compound through modified release formulation design: an in vitro, in vivo, in silico and clinical pharmacokinetic analysis. Mol Pharm. 2015;12:4434–44.

    Article  CAS  PubMed  Google Scholar 

  31. Guidance for industry, extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. 1997. https://www.fda.gov/downloads/drugs/guidances/ucm070239.pdf

  32. Chen ML, Shah VP, Ganes D, Midha KK, Caro J, Nambiar P, et al. Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified release products: workshop summary report. AAPS J. 2010;12:371–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Davis SS, Wilding EA, Wilding IW. Gastrointestinal transit of a matrix tablet formulation: comparison of canine and human data. Int J Pharm. 1993;94:235–8.

    Article  CAS  Google Scholar 

  34. Sutton S. Companion animal physiology and dosage form performance. Advanced Drug Deliv Reviews. 2004;56:1383–98.

    Article  CAS  Google Scholar 

  35. Brown J, Crison J, Timmins P. Predicting feasibility and characterizing performance of extended-release formulations using physiologically based pharmacokinetic modeling. Ther Deliv. 2012;3:1047–59.

    Article  CAS  PubMed  Google Scholar 

  36. FDA guidance for the industry: exposure response relationships—study design, data analysis and regulatory applications, 2003, http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072109.pdf

  37. Fleisher D, Li C, Zhou Y, Pao KH, Karim A. Drug, meal, and formulation interactions influencing drug absorption after oral administration: clinical implications. Clin Pharmacokinet. 1999;36:233–5.

    Article  CAS  PubMed  Google Scholar 

  38. Singh BN. Effects of food on clinical pharmacokinetics. Clin Pharmacokinet. 1999;37:213–55.

    Article  CAS  PubMed  Google Scholar 

  39. Benet LZ. The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development. J Pharm Sci. 2013;102:34–42.

    Article  CAS  PubMed  Google Scholar 

  40. Varum FJO, Hatton GB, Basit AW. Food, physiology and drug delivery. Int J Pharm. 2013;457:446–60.

    Article  CAS  PubMed  Google Scholar 

  41. Yao HM, Hsu A, Gupta S, Modi N. Clinical pharmacokinetics of IPX066: evaluation of dose proportionality and effect of food in healthy volunteers. Clin Neuropharmacol. 2016;39:10–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fleming AB, Carlson DR, Varanasi RK, Grima M, Mayock SP, Saim S, et al. Evaluation of an extended-release, abuse-deterrent, microsphere-in-capsule analgesic for the management of patients with chronic pain with dysphagia. Pain Practice. 2016;16:334–44.

    Article  PubMed  Google Scholar 

  43. Wendling T, Ogungbenro K, Pigeolet E, Dumitras S, Woessner R, Aarons L. Model-based evaluation of the impact of formulation and food intake on the complex oral absorption of mavoglurant in healthy subjects. Pharm Res. 2015;32:1764–78.

    Article  CAS  PubMed  Google Scholar 

  44. 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;98:1568–76.

    Article  CAS  PubMed  Google Scholar 

  45. Jantratid E, De Maio V, Ronda E, Mattavelli V, Vertzoni M, Dressman JB. Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form. Eu J Pharm Sci. 2009;37:434–41.

    Article  CAS  Google Scholar 

  46. Palaparthy R, Banfield C, Alvarez P, Yan L, Smith B, Johnson J, et al. Relative bioavailability, food effect, and safety of the single-dose pharmacokinetics of omecamtiv mecarbil following administration of different modified-release formulations in healthy subjects. Int J Clin Pharmacol Ther. 2016;54:217–27.

    Article  CAS  PubMed  Google Scholar 

  47. Derendorf H, Ruebsamen K, Clarke L, Schaeffler A, Kirwan JR. Pharmacokinetics of modified release prednisone. J Clin Pharmacol. 2013;53:326–33.

    Article  CAS  PubMed  Google Scholar 

  48. Burnside BA, Chang RK, Guo X. Sustained release pharmaceutical dosage forms with minimized pH dependent dissolution profiles, U.S. Patent 6,287,599 (2001) and 6,811,794 (2004).

  49. Burnside BA, Guo X, Fiske K, Couch RA, Chang RK., Treacy DJ, McGuiness CM, Rudnic EM. Oral pulsed drug delivery system, U.S. Patents RE41, 148 (2010) and RE42, 096, (2011).

  50. Baraldo M. The influence of circadiam rhythms on the kinetics of drugs in humans. Expert Opin Drug Metab Toxicol. 2008;4:175–92.

    Article  CAS  PubMed  Google Scholar 

  51. Roberts D, Easter D, O'Bryan-Tear G. Epilim Chrono: a multidose, cross over comparison of two formulations of valproate in healthy volunteers. Biopharm Drug Dispo. 1996;17:175–80.

    Article  CAS  Google Scholar 

  52. Jacobs MH, Senior RM, Kessler G. Clinical experience with theophylline. Relationships between dosage, serum concentrations and toxicity. J Am Med. 1976;235:1983–6.

    CAS  Google Scholar 

  53. Patel N, Cook A, Greenhalgh E, Rech MA, Rusinak J, Heinrich L. Overview of extended release tacrolimus in solid organ transplantation. World J Transplant. 2016;24:144–54.

    Article  Google Scholar 

  54. AAPS Workshop / meeting. Pharmaceutical quality assessment—a science and risk-based CMC approach in the 21st century. North Bethesda, MD, USA; 2005.

  55. AAPS Workshop / Meeting. Utilization of process modeling and advanced process control in QbD based drug development and manufacturing. Baltimore, MD, USA; 2009.

  56. GPhA/FDA Meeting. Quality-by-design workshop for ANDAs. North Bethesda, MD, USA; 2011.

  57. Lionberger R, Lee S, Raw A, Yu L. Quality by design: concepts for ANDAs. AAPS J. 2008;10:268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yu L. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25:781–91.

    Article  CAS  PubMed  Google Scholar 

  59. Raw A, Lionberger R, Yu L. Pharmaceutical equivalence by design for generic drugs: modified-release products. Pharm Res. 2011;28:1445–53.

    Article  CAS  PubMed  Google Scholar 

  60. Yu LX. Pharmaceutical quality by design: product and process development, understanding and control. Pharm Res. 2008;25:781–91.

    Article  CAS  PubMed  Google Scholar 

  61. Huang J, Kaul G, Cai C, Chatlapalli R, Hernandez-Abad P. Quality by design case study: an integrated multivariate approach to drug product and process development. Int J Pharm. 2009;382:23–32.

    Article  CAS  PubMed  Google Scholar 

  62. Wu H, Tawakkul M, White M, Khan M. Quality-by-design (QbD): an integrated multivariate approach for the component quantification in powder blends. Int J Pharm. 2009;372:39–46.

    Article  CAS  PubMed  Google Scholar 

  63. Wu H, White M, Khan M. Quality-by-design (QbD): an integrated process analytical technology (PAT) approach for a dynamic pharmaceutical co-precipitation process characterization and process design space development. Int J Pharm. 2011;405:63–78.

    Article  CAS  PubMed  Google Scholar 

  64. Chang R, Raw A, Lionberger R, Yu L. Development of topical dermatologic products. Part II: quality by design for topical dermatologic products. AAPS J. 2013;15:45–52.

    Google Scholar 

  65. www.fda.gov/ Quality by design for ANDAs: an example for modified release dosage forms, http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm286595.pdf, 2011.

  66. www.fda.gov/ Quality by design for ANDAs: an example for immediate-release dosage forms, http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm304305.pdf, 2012.

  67. www.accessdata.fda.gov/scripts/cder/dissolution/

  68. Guidance for industry bioavailability and bioequivalence studies submitted in NDAs or INDs—general considerations DRAFT GUIDANCE. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm389370.pdf

  69. Guidance for industry bioavailability and bioequivalence studies for orally administered drug products—general considerations, http://www.gmp.compliance.org/guidemgr/files/UCM154838.pdf

  70. Lin Z, Zhou D, Hoag S, Qiu Y. Influence of drug properties and formulation on in vitro drug release and biowaiver regulation of oral extended release dosage forms. AAPS J. 2016;18:333–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Office of Life Cycle Products, Office of Pharmaceutical Quality, Center of Drug Evaluation and Research, US Food and Drug Administrations, Silver Spring, Maryland, USA

    Rong-Kun Chang

  2. Drug Product Science & Technology, Bristol-Myers Squibb Co., P.O. Box Bldg. 105/Room 2474, One Squibb Drive, New Brunswick, New Jersey, 08903, USA

    Neil Mathias & Munir A. Hussain

Authors
  1. Rong-Kun Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil Mathias
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Munir A. Hussain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Munir A. Hussain.

Additional information

Guest Editors: Duxin Sun and Simon Zhou

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chang, RK., Mathias, N. & Hussain, M.A. Biopharmaceutical Evaluation and CMC Aspects of Oral Modified Release Formulations. AAPS J 19, 1348–1358 (2017). https://doi.org/10.1208/s12248-017-0112-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-017-0112-6

KEY WORDS

Search

Navigation