Abstract
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.
Similar content being viewed by others
References
Press AG, Hauptmann IA, Hauptmann L, Fuchs B, Fuchs M, Ewe K, et al. Gastrointestinal pH profiles in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 1998;12(7):673–8. https://doi.org/10.1046/j.1365-2036.1998.00358.x.
Fallingborg J, Pedersen P, Jacobsen BA. Small intestinal transit time and intraluminal pH in ileocecal resected patients with Crohn's disease. Dig Dis Sci. 1998;43(4):702–5. https://doi.org/10.1023/a:1018893409596.
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.
Sasaki Y, Hada R, Nakajima H, Fukuda S, Munakata A. Improved localizing method of radiopill in measurement of entire gastrointestinal pH profiles: colonic luminal pH in normal subjects and patients with Crohn's disease. Am J Gastroenterol. 1997;92(1):114–8.
Iida H, Endo H, Sekino Y, Sakai E, Uchiyama T, Hosono K, et al. A new non-invasive modality for recording sequential images and the pH of the small bowel. Hepato-Gastroenterology. 2012;59(114):413–4. https://doi.org/10.5754/hge11394.
Koziolek M, Grimm M, Becker D, Iordanov V, Zou H, Shimizu J, et al. Investigation of pH and temperature profiles in the GI tract of fasted human subjects using the Intellicap® system. J Pharm Sci. 2015;104(9):2855–63. https://doi.org/10.1002/jps.24274.
Pišlar M, Brelih H, Mrhar A, Bogataj M. Analysis of small intestinal transit and colon arrival times of non-disintegrating tablets administered in the fasted state. Eur J Pharm Sci. 2015;75:131–41. https://doi.org/10.1016/j.ejps.2015.03.001.
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.
Fadda HM, Sousa T, Carlsson AS, Abrahamsson B, Williams JG, Kumar D, et al. Drug solubility in luminal fluids from different regions of the small and large intestine of humans. Mol Pharm. 2010;7(5):1527–32. https://doi.org/10.1021/mp100198q.
Persson EM, Gustafsson AS, Carlsson AS, Nilsson RG, Knutson L, Forsell P, et al. The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids. Pharm Res. 2005;22(12):2141–51. https://doi.org/10.1007/s11095-005-8192-x.
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.
de la Cruz Moreno MP, Oth M, Deferme S, Lammert F, Tack J, Dressman J, et al. Characterization of fasted-state human intestinal fluids collected from duodenum and jejunum. J Pharm Pharmacol. 2006;58(8):1079–89. https://doi.org/10.1211/jpp.58.8.0009.
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.
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.
Chiarini A, Tartarini A, Fini A. pH-Solubility relationship and partition coefficients for some anti-inflammatory arylaliphatic acids. Arc Pharm. 1984;317(3):268–73. https://doi.org/10.1002/ardp.19843170314.
Adeyeye CM, Li P-K. Diclofenac sodium. In: Florey K, editor. Analytical profiles of drug substances. New Jersey: Academic Press; 1990. p. 123–44.
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.
Mitchell M, Muftakhidnov B, Winchen T. Engauge Digitizer Software http://markummitchell.github.io/engauge-digitizer. Accessed 22 Jan 2018.
Bogataj M, Cof G, Mrhar A. Development of a glass-bead device for dissolution testing. Dissolut Technol. 2015;22(3):18–24. https://doi.org/10.14227/DT220315P18.
McIlvaine TC. A buffer solution for colorimetric comparison. J Biol Chem. 1921;49(1):183–6.
Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut. 1988;29(8):1035–41.
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.
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.
Ph.Eur. European pharmacopoeia. 9th ed. Strasbourg: EDQM Council of Europe; 2017.
USP. The United States Pharmacopeia-National Formulary (USP40-NF35). Rockville: United States Pharmacopeial Convention 2017.
Klein S, Stein J, Dressman J. Site-specific delivery of anti-inflammatory drugs in the gastrointestinal tract: an in-vitro release model. J Pharm Pharmacol. 2005;57(6):709–19. https://doi.org/10.1211/0022357056172.
Goyanes A, Hatton GB, Merchant HA, Basit AW. Gastrointestinal release behaviour of modified-release drug products: dynamic dissolution testing of mesalazine formulations. Int J Pharm. 2015;484(1–2):103–8. https://doi.org/10.1016/j.ijpharm.2015.02.051.
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.
Al-Gousous J, Tsume Y, Fu M, Salem II, Langguth P. Unpredictable performance of pH-dependent coatings accentuates the need for improved predictive in vitro test systems. Mol Pharm. 2017;14(12):4209–19. https://doi.org/10.1021/acs.molpharmaceut.6b00877.
Karkossa F, Klein S. A biopredictive in vitro comparison of oral locally acting mesalazine formulations by a novel dissolution model for assessing intraluminal drug release in individual subjects. J Pharm Sci. 2018;107:1680–9. https://doi.org/10.1016/j.xphs.2018.02.016.
Russell TL, Berardi RR, Barnett JL, Dermentzoglou LC, Jarvenpaa KM, Schmaltz SP, et al. Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women. Pharm Res. 1993;10(2):187–96. https://doi.org/10.1023/a:1018970323716.
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.
Guhmann M, Thommes M, Gerber F, Pöllinger N, Klein S, Breitkreutz J, et al. Design of biorelevant test setups for the prediction of diclofenac in vivo features after oral administration. Pharm Res. 2013;30(6):1483–501. https://doi.org/10.1007/s11095-013-0974-y.
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.
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.
Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986;27(8):886–92. https://doi.org/10.1136/gut.27.8.886.
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.
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.
Chuasuwan B, Binjesoh V, Polli JE, Zhang H, Amidon GL, Junginger HE, et al. Biowaiver monographs for immediate release solid oral dosage forms: diclofenac sodium and diclofenac potassium. J Pharm Sci. 2009;98(4):1206–19. https://doi.org/10.1002/jps.21525.
Gleiter CH, Antonin KH, Bieck P, Godbillon J, Schönleber W, Malchow H. Colonoscopy in the investigation of drug absorption in healthy volunteers. Gastrointest Endosc. 1985;31(2):71–3. https://doi.org/10.1016/S0016-5107(85)71996-7.
Funding
This study was financially supported by the Slovenian Research Agency (research core funding No. P1-0189).
Author information
Authors and Affiliations
Corresponding author
Additional information
Guest Editor: Sandra Klein
Rights and permissions
About this article
Cite this article
Felicijan, T., Pišlar, M., Vene, K. et al. The Influence of Simulated Fasted Gastrointestinal pH Profiles on Diclofenac Sodium Dissolution in a Glass-Bead Flow-Through System. AAPS PharmSciTech 19, 2875–2884 (2018). https://doi.org/10.1208/s12249-018-1140-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12249-018-1140-y