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In Vitro-In Vivo Predictive Dissolution-Permeation-Absorption Dynamics of Highly Permeable Drug Extended-Release Tablets via Drug Dissolution/Absorption Simulating System and pH Alteration

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Abstract

Each of dissolution and permeation may be a rate-limiting factor in the absorption of oral drug delivery. But the current dissolution test rarely took into consideration of the permeation property. Drug dissolution/absorption simulating system (DDASS) valuably gave an insight into the combination of drug dissolution and permeation processes happening in human gastrointestinal tract. The simulated gastric/intestinal fluid of DDASS was improved in this study to realize the influence of dynamic pH change on the complete oral dosage form. To assess the effectiveness of DDASS, six high-permeability drugs were chosen as model drugs, including theophylline (pKa1 = 3.50, pKa2 = 8.60), diclofenac (pKa = 4.15), isosorbide 5-mononitrate (pKa = 7.00), sinomenine (pKa = 7.98), alfuzosin (pKa = 8.13), and metoprolol (pKa = 9.70). A general elution and permeation relationship of their commercially available extended-release tablets was assessed as well as the relationship between the cumulative permeation and the apparent permeability. The correlations between DDASS elution and USP apparatus 2 (USP2) dissolution and also between DDASS permeation and beagle dog absorption were developed to estimate the predictability of DDASS. As a result, the common elution-dissolution relationship was established regardless of some variance in the characteristic behavior between DDASS and USP2 for drugs dependent on the pH for dissolution. Level A in vitro-in vivo correlation between DDASS permeation and dog absorption was developed for drugs with different pKa. The improved DDASS will be a promising tool to provide a screening method on the predictive dissolution-permeation-absorption dynamics of solid drug dosage forms in the early-phase formulation development.

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Abbreviations

API:

active pharmaceutical ingredient

BCS:

biopharmaceutical classification system

DDASS:

drug dissolution/absorption simulating system

DFS:

diclofenac sodium

GI:

gastrointestinal

ERT:

extended-release tablet

IVIVC:

in vitro-in vivo correlation

ISMN:

isosorbide 5-mononitrate

USP2:

USP apparatus 2

References

  1. Yuen KH. The transit of dosage forms through the small intestine. Int J Pharm. 2010;395:9–16.

    Article  CAS  PubMed  Google Scholar 

  2. Cascone S, Santis FD, Lamberti G, Titomanlio G. The influence of dissolution conditions on the drug ADME phenomena. Eur J Pharm Biopharm. 2011;79:382–91.

    Article  CAS  PubMed  Google Scholar 

  3. Huang W, Lee SL, Lawrence XY. Mechanistic approaches to predicting oral drug absorption. AAPS J. 2009;11:217–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Amidon GL, Lennernäs H, Shah VP, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro, drug product dissolution and in vivo, bioavailability. Pharm Res. 1995;12:413–20.

    Article  CAS  PubMed  Google Scholar 

  5. Hörter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev. 2001;46:75–87.

    Article  PubMed  Google Scholar 

  6. Guerra A, Etienne-Mesmin L, Livrelli V, Denis S, Blanquet-Diot S, Alric M. Relevance and challenges in modeling human gastric and small intestinal digestion. Trends Biotechnol. 2012;30:591–600.

    Article  CAS  PubMed  Google Scholar 

  7. Mcallister M. Dynamic dissolution: a step closer to predictive dissolution testing? Mol Pharm. 2010;7:1374–87.

    Article  CAS  PubMed  Google Scholar 

  8. Vardakou M, Mercuri A, Barker SA, Craig DQM, Faulks RM, Wickham MSJ. 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. 2011;12:620–6.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Puppolo MM, Hughey JR, Dillon T, Storey D, Jansenvarnum S. Biomimetic dissolution: a tool to predict amorphous solid dispersion performance. AAPS PharmSciTech. 2017;18:1–13.

    Article  Google Scholar 

  10. Egan WJ, Lauri G. Prediction of intestinal permeability. Adv Drug Deliver Rev. 2002;54:273–89.

    Article  CAS  Google Scholar 

  11. Ng SF, Rouse JJ, Sanderson FD, Meidan V, Eccleston GM. Validation of a static Franz diffusion cell system for in vitro permeation studies. AAPS PharmSciTech. 2010;11:1432–41.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li ZQ, He X. Physiologically based in vitro models to predict the oral dissolution and absorption of a solid drug delivery system. Curr Drug Metab. 2015;16:777–806.

    Article  CAS  PubMed  Google Scholar 

  13. Ginski MJ, Polli JE. Prediction of dissolution–absorption relationships from a dissolution/Caco-2system. Int J Pharm. 1999;177:117–25.

    Article  CAS  PubMed  Google Scholar 

  14. Ginski MJ, Taneja R, Polli JE. Prediction of dissolution-absorption relationships from a continuous dissolution/Caco-2 system. AAPS PharmSciTech. 1999;1:1–12.

    Google Scholar 

  15. Kataoka M, Masaoka Y, Yamazaki Y, Sakane T, Sezaki H, Yamashita S. In vitro system to evaluate oral absorption of poorly water-soluble drugs: simultaneous analysis on dissolution and permeation of drugs. Pharm Res. 2003;20:1674–80.

    Article  CAS  PubMed  Google Scholar 

  16. Kataoka M, Masaoka Y, Sakuma S, Yamashita S. Effect of food intake on the oral absorption of poorly water-soluble drugs: in vitro assessment of drug dissolution and permeation assay system. J Pharm Sci. 2006;95:2051–61.

    Article  CAS  PubMed  Google Scholar 

  17. Gao Z. Development of a continuous dissolution/absorption system—a technical note. AAPS PharmSciTech. 2012;13:1287–92.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Anderson KE, Yun KT. Simulated biological dissolution and absorption system [P]. WO, 1999, WO 1999028437 A1.

  19. Motz SA, Klimundova J, Schaefer UF, Balbach S, Eichinger T, Solich P, et al. Automated measurement of permeation and dissolution of propranolol HCl tablets using sequential injection analysis. Anal Chim Acta. 2007;581:174–80.

    Article  CAS  PubMed  Google Scholar 

  20. Motz SA, Schaefer UF, Balbach S, Eichinger T, Lehr CM. Permeability assessment for solid oral drug formulations based on Caco-2 monolayer in combination with a flow through dissolution cell. Eur J Pharm Biopharm. 2007;66:286–95.

    Article  CAS  PubMed  Google Scholar 

  21. Kobayashi M, Sada N, Sugawara M, Iseki K, Miyazaki K. Development of a new system for prediction of drug absorption that takes into account drug dissolution and pH change in the gastro-intestinal tract. Int J Pharm. 2001;221:87–94.

    Article  CAS  PubMed  Google Scholar 

  22. He X, Sugawara M, Kobayashi M, Takekuma Y, Miyazaki K. An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs. Int J Pharm. 2003;263:35–44.

    Article  CAS  PubMed  Google Scholar 

  23. He X, Kadomura S, Takekuma Y, Sugawara M, Miyazaki K. A new system for the prediction of drug absorption using a pH-controlled Caco-2 model: evaluation of pH-dependent soluble drug absorption and pH-related changes in absorption. J Pharm Sci. 2004;93:71–7.

    Article  CAS  PubMed  Google Scholar 

  24. He X, Sugawara M, Takekuma Y, Miyazaki K. Absorption of ester prodrugs in Caco-2 and rat intestine models. Antimicrob Agents Chemother. 2004;48:2604–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li ZQ, He X, Gao XM, Xu YY, Wang YF, Gu H, et al. Study on dissolution and absorption of four dosage forms of isosorbide mononitrate: level A in vitro-in vivo correlation. Eur J Pharm Biopharm. 2011;79:364–71.

    Article  CAS  PubMed  Google Scholar 

  26. Liu W, He X, Li Z, Gao X, Ma Y, Xun M, et al. Development of a bionic system for the simultaneous prediction of the release/absorption characteristics of enteric-coated formulations. Pharm Res. 2012;30:596–605.

    Article  PubMed  Google Scholar 

  27. Davies NM, Anderson KE. Clinical pharmacokinetics of diclofenac. Clin Pharmacokinet. 1997;33:184–213.

    Article  CAS  PubMed  Google Scholar 

  28. Manca ML, Zaru M, Ennas G, Valenti D, Sinico C, Loy G, et al. Diclofenac-β-cyclodextrin binary systems: physicochemical characterization and in vitro dissolution and diffusion studies. AAPS PharmSciTech. 2005;6:E464–72.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chuasuwan B, Binjesoh V, Polli JE, Zhang H, Amidon GL, Shah VP, et al. Biowaiver monographs for immediate release solid oral dosage forms: diclofenac sodium and diclofenac potassium. J Pharm Sci. 2009;98:1206–19.

    Article  CAS  PubMed  Google Scholar 

  30. Ogilvie RI. Clinical pharmacokinetics of theophylline. Clin Pharmacokinet. 1978;3:267–93.

    Article  CAS  PubMed  Google Scholar 

  31. Adeyeye CM, Rowley J, Madu D, Javadi M, Sabnis SS. Evaluation of crystallinity and drug release stability of directly compressed theophylline hydrophilic matrix tablets stored under varied moisture conditions. Int J Pharm. 1995;116:65–75.

    Article  Google Scholar 

  32. Sriamornsak P, Sungthongjeeh S. Modification of theophylline release with alginate gel formed in hard capsules. AAPS PharmSciTech. 2007;8(3):E1–8.

    Article  PubMed Central  Google Scholar 

  33. Regårdh CG, Johnsson G. Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet. 1980;5:557–69.

    Article  PubMed  Google Scholar 

  34. Eddington N, Marroum P, Uppoor R, Hussain A, Augsburger L. Development and internal validation of an in vitro-in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation. Pharm Res. 1998;15:466–73.

    Article  CAS  PubMed  Google Scholar 

  35. Quan L, Fassihi R. Zero-order delivery of a highly soluble, low dose drug alfuzosin hydrochloride via gastro-retentive system. Int J Pharm. 2008;348:27–34.

    Article  Google Scholar 

  36. Nicholas ME, Karunakar R, Pavan KK, Raghunadha GC. Development and evaluation of extended release matrix tablets of Alfuzosin HCl and its comparison with marketed product. J Pharm Res. 2011;4:1436–7.

    CAS  Google Scholar 

  37. Li X, Li X, Zhou Y, Liu Y, Guo M, Zhu Q, et al. Development of patch and spray formulations for enhancing topical delivery of sinomenine hydrochloride. J Pharm Sci. 2009;99:1790–9.

    Article  Google Scholar 

  38. Zhao XX, Peng C, Zhang H, Qin LP. Sinomenium acutum: a review of chemistry, pharmacology, pharmacokinetics, and clinical use. Pharm Biol. 2012;50(8):1053–61.

    Article  PubMed  Google Scholar 

  39. Lemmer B, Scheidel B, Blume H, Becker HJ. Clinical chronopharmacology of oral sustained-release isosorbide-5-mononitrate in healthy subjects. Eur J Clin Pharmacol. 1991;40:71–5.

    Article  CAS  PubMed  Google Scholar 

  40. Gunasekara NS, Noble S. Isosorbide 5-mononitrate: a review of a sustained- release formulation (Imdur) in stable angina pectoris. Drugs. 1999;57:261–77.

    Article  CAS  PubMed  Google Scholar 

  41. Baldini F, Bechi P, Bracci S, Cosi F, Pucciani F. In vivo optical-fibre pH sensor for gastro-oesophageal measurements. Sensor Actuat B-Chem. 1995;29:164–8.

    Article  CAS  Google Scholar 

  42. He X, Sugawara M, Zhu XB, Kadomura S, Takekuma Y, Liu CX. Application of an in vitro dissolution and absorption system to evaluate oral absorption of ketoprofen and two preparations of ketoprofen. Asian J Pharmacodynamic Pharmacokinet. 2009;9:203–10.

    Google Scholar 

  43. Watanabe E, Takahashi M, Hayashi M. A possibility to predict the absorbability of poorly water-soluble drugs in humans based on rat intestinal permeability assessed by an in vitro chamber method. Eur J Pharm Biopharm. 2004;58:659–65.

    Article  CAS  PubMed  Google Scholar 

  44. Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man-factor myth. Pharm Res. 1997;14:763–6.

    Article  CAS  PubMed  Google Scholar 

  45. Kostewicz ES, Abrahamsson B, Brewster M, Brouwers J, Butler J, Carlert S, et al. In vitro models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci. 2014;57:342–66.

    Article  CAS  PubMed  Google Scholar 

  46. Mudie DM, Amidon GL, Amidon GE. Physiological parameters for oral delivery and in vitro testing. Mol Pharm. 2010;7:1388–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang Y, Manda P, Pavurala N, Khan MA, Krishnaiah YS. Development and validation of in vitro-in vivo correlation (IVIVC) for estradiol transdermal drug delivery systems. J Control Release. 2015;210:58–66.

    Article  CAS  PubMed  Google Scholar 

  48. Zakerimilani P, Valizadeh H, Tajerzadeh H, Azarmi Y, Islambolchilara Z, Barzegara S, et al. Predicting human intestinal permeability using single-pass intestinal perfusion in rat. J Pharmacy Pharm Sci. 2007;10:368–79.

    CAS  Google Scholar 

  49. Dunne A, O'Hara T, Devane J. Level A in vivo-in vitro correlation: nonlinear models and statistical methodology. J Pharm Sci. 1997;86:1245–9.

    Article  CAS  PubMed  Google Scholar 

  50. Polli JE, Crison JR, Amidon GL. Novel approach to the analysis of in vitro-in vivo relationships. J Pharm Sci. 1996;85:753–60.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by the grants from Key Support Projects of Tianjin Science and Technology (No. 16YFZCSY00440), Natural Science Foundation of China (No. 81303141), Integrative Chinese Medicine Research Project of Tianjin Municipal Commission Health and Family Planning (No. 2017144), and Program for Changjiang Scholars and Innovative Research Team in University (No. IRT_14R41).

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Correspondence to Xin He.

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The study was performed in accordance with the Principles of Laboratory Animal Care (NIH No. 8523) and was approved by the Ethical Review Committee of Tianjin University of Traditional Chinese Medicine.

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The authors declare that they have no conflict of interest.

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Li, Zq., Tian, S., Gu, H. et al. In Vitro-In Vivo Predictive Dissolution-Permeation-Absorption Dynamics of Highly Permeable Drug Extended-Release Tablets via Drug Dissolution/Absorption Simulating System and pH Alteration. AAPS PharmSciTech 19, 1882–1893 (2018). https://doi.org/10.1208/s12249-018-0996-1

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