The Influence of Simulated Fasted Gastrointestinal pH Profiles on Diclofenac Sodium Dissolution in a Glass-Bead Flow-Through System
- 111 Downloads
High inter- and intra-individual variability in the pH of fluids in the human gastrointestinal (GI) tract has been described in the literature. The aim of this study was to assess the influence of physiological variability in fasted pH profiles of media along the GI tract on diclofenac sodium (DF-Na) dissolution from matrix tablets. Four individual in vivo fasted pH profiles were selected from the literature that differed in pH values and transit times from the stomach to the proximal colon. Using a glass-bead device flow-through dissolution system, these pH profiles were simulated in vitro using a specific media sequence and considering simulated intestinal buffer capacities corresponding to in vivo literature data. Dissolution experiments were then performed in the same system with media sequence following individual pH profiles. In dissolution experiments, where influences of simulated gastric emptying time (GET), gastric pH value, small intestinal transit time, and colonic pH were studied; high influence of gastric pH value and GET on DF-Na dissolution was observed. The effect of variability in pH profiles in the range of individual in vivo data on DF-Na dissolution was also clearly observed in experiments, where dissolution studies were performed following three simulated in vivo individual pH profiles. The differences in DF-Na release between three individual pH profiles were substantial; they also reflected in simulated plasma concentration profiles and can be attributed to pH dependent diclofenac solubility.
KEY WORDSgastrointestinal pH profiles simulation dissolution diclofenac sodium glass-bead flow-through dissolution system
This study was financially supported by the Slovenian Research Agency (research core funding No. P1-0189).
- 3.Ibekwe VC, Fadda HM, McConnell EL, Khela MK, Evans DF, Basit AW. Interplay between intestinal pH, transit time and feed status on the in vivo performance of pH responsive ileo-colonic release systems. Pharm Res. 2008;25(8):1828–35. https://doi.org/10.1007/s11095-008-9580-9.CrossRefPubMedGoogle Scholar
- 8.Kalantzi L, Goumas K, Kalioras V, Abrahamsson B, Dressman JB, Reppas C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharm Res. 2006;23(1):165–76. https://doi.org/10.1007/s11095-005-8476-1.CrossRefPubMedGoogle Scholar
- 11.Reppas C, Karatza E, Goumas C, Markopoulos C, Vertzoni M. Characterization of contents of distal ileum and cecum to which drugs/drug products are exposed during bioavailability/bioequivalence studies in healthy adults. Pharm Res. 2015;32(10):3338–49. https://doi.org/10.1007/s11095-015-1710-6.CrossRefPubMedGoogle Scholar
- 13.Diakidou A, Vertzoni M, Goumas K, Söderlind E, Abrahamsson B, Dressman J, et al. Characterization of the contents of ascending colon to which drugs are exposed after oral administration to healthy adults. Pharm Res. 2009;26(9):2141–51. https://doi.org/10.1007/s11095-009-9927-x.CrossRefPubMedGoogle Scholar
- 14.Hens B, Tsume Y, Bermejo M, Paixao P, Koenigsknecht MJ, Baker JR, et al. Low buffer capacity and alternating motility along the human gastrointestinal tract: implications for in vivo dissolution and absorption of ionizable drugs. Mol Pharm. 2017;14(12):4281–94. https://doi.org/10.1021/acs.molpharmaceut.7b00426.CrossRefPubMedGoogle Scholar
- 16.Adeyeye CM, Li P-K. Diclofenac sodium. In: Florey K, editor. Analytical profiles of drug substances. New Jersey: Academic Press; 1990. p. 123–44.Google Scholar
- 17.Van Den Abeele J, Schilderink R, Schneider F, Mols R, Minekus M, Weitschies W, et al. Gastrointestinal and systemic disposition of diclofenac under fasted and fed state conditions supporting the evaluation of in vitro predictive tools. Mol Pharm. 2017;14(12):4220–32. https://doi.org/10.1021/acs.molpharmaceut.7b00253.CrossRefGoogle Scholar
- 18.Mitchell M, Muftakhidnov B, Winchen T. Engauge Digitizer Software http://markummitchell.github.io/engauge-digitizer. Accessed 22 Jan 2018.
- 20.McIlvaine TC. A buffer solution for colorimetric comparison. J Biol Chem. 1921;49(1):183–6.Google Scholar
- 22.Lötsch J, Kettenmann B, Renner B, Drover D, Brune K, Geisslinger G, et al. Population pharmacokinetics of fast release oral diclofenac in healthy volunteers: relation to pharmacodynamics in an experimental pain model. Pharm Res. 2000;17(1):77–84. https://doi.org/10.1023/a:1007574710140.CrossRefPubMedGoogle Scholar
- 23.Nagelj Kovačič N, Pišlar M, Ilić I, Mrhar A, Bogataj M. Influence of the physiological variability of fasted gastric pH and tablet retention time on the variability of in vitro dissolution and simulated plasma profiles. Int J Pharm. 2014;473(1–2):552–9. https://doi.org/10.1016/j.ijpharm.2014.07.031.CrossRefGoogle Scholar
- 24.Ph.Eur. European pharmacopoeia. 9th ed. Strasbourg: EDQM Council of Europe; 2017.Google Scholar
- 25.USP. The United States Pharmacopeia-National Formulary (USP40-NF35). Rockville: United States Pharmacopeial Convention 2017.Google Scholar
- 28.Wulff R, Rappen GM, Koziolek M, Garbacz G, Leopold CS. Controlled release of acidic drugs in compendial and physiological hydrogen carbonate buffer from polymer blend-coated oral solid dosage forms. Eur J Pharm Sci. 2015;77:246–53. https://doi.org/10.1016/j.ejps.2015.06.015.CrossRefPubMedGoogle Scholar
- 32.Ovesen L, Bendtsen F, Tage-Jensen U, Pedersen NT, Gram BR, Rune SJ. Intraluminal pH in the stomach, duodenum, and proximal jejunum in normal subjects and patients with exocrine pancreatic insufficiency. Gastroenterology. 1986;90(4):958–62. https://doi.org/10.1016/0016-5085(86)90873-5.CrossRefPubMedGoogle Scholar
- 34.Bartolomei M, Bertocchi P, Antoniella E, Rodomonte A. Physico-chemical characterisation and intrinsic dissolution studies of a new hydrate form of diclofenac sodium: comparison with anhydrous form. J Pharm Biomed Anal. 2006;40(5):1105–13. https://doi.org/10.1016/j.jpba.2005.09.009.CrossRefPubMedGoogle Scholar
- 35.Bartolomei M, Rodomonte A, Antoniella E, Minelli G, Bertocchi P. Hydrate modifications of the non-steroidal anti-inflammatory drug diclofenac sodium: solid-state characterisation of a trihydrate form. J Pharm Biomed Anal. 2007;45(3):443–9. https://doi.org/10.1016/j.jpba.2007.07.002.CrossRefPubMedGoogle Scholar
- 37.Fischer M, Siva S, Wo JM, Fadda HM. Assessment of small intestinal transit times in ulcerative colitis and Crohn's disease patients with different disease activity using video capsule endoscopy. AAPS PharmSciTech. 2017;18(2):404–9. https://doi.org/10.1208/s12249-016-0521-3.CrossRefPubMedGoogle Scholar
- 38.Fallingborg J, Christensen LA, Ingeman-Nielsen M, Jacobsen BA, Abildgaard K, Rasmussen HH. pH-Profile and regional transit times of the normal gut measured by a radiotelemetry device. Aliment Pharmacol Ther. 1989;3(6):605–13. https://doi.org/10.1111/j.1365-2036.1989.tb00254.x.CrossRefPubMedGoogle Scholar