The gastrointestinal (GI) tract is one of the most popular and used routes of drug product administration due to the convenience for better patient compliance and reduced costs to the patient compared to other routes. However, its complex nature poses a great challenge for formulation scientists when developing more complex dosage forms such as those combining two or more drugs. Fixed dose combination (FDC) products are two or more single active ingredients combined in a single dosage form. This formulation strategy represents a novel formulation which is as safe and effective compared to every mono-product separately. A complex drug product, to be dosed through a complex route, requires judicious considerations for formulation development. Additionally, it represents a challenge from a regulatory perspective at the time of demonstrating bioequivalence (BE) for generic versions of such drug products. This report gives the reader a summary of a 2-day short course that took place on the third and fourth of November at the Annual Association of Pharmaceutical Scientists (AAPS) meeting in 2018 at Washington, D.C. This manuscript will offer a comprehensive view of the most influential aspects of the GI physiology on the absorption of drugs and current techniques to help understand the fate of orally ingested drug products in the complex environment represented by the GI tract. Through case studies on FDC product development and regulatory issues, this manuscript will provide a great opportunity for readers to explore avenues for successfully developing FDC products and their generic versions.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Janssen P, Vanden Berghe P, Verschueren S, Lehmann A, Depoortere I, Tack J. Review article: the role of gastric motility in the control of food intake. Aliment Pharmacol Ther. 2011;33:880–94.
Deloose E, Janssen P, Depoortere I, Tack J. The migrating motor complex: control mechanisms and its role in health and disease. Nat Rev Gastroenterol Hepatol. 2012;9:271–85.
Vantrappen G, Janssens J, Hellemans J, Ghoos Y. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest. 1977;59:1158–66.
Vantrappen GR, Peeters TL, Janssens J. The secretory component of the interdigestive migrating motor complex in man. Scand J Gastroenterol. 1979;14:663–7.
Camilleri M. Gastrointestinal hormones and regulation of gastric emptying. Curr Opin Endocrinol Diabetes Obes. 2019;26:3–10.
Camilleri M, Malagelada JR, Brown ML, Becker G, Zinsmeister AR. Relation between antral motility and gastric emptying of solids and liquids in humans. American journal of physiology Renal physiology, American journal of physiology Renal physiology [Internet]. 1985 [cited 2017 May 22];249. Available from: https://mayoclinic.pure.elsevier.com/en/publications/relation-between-antral-motility-and-gastric-emptying-of-solids-a.
Farré R, Tack J. Food and symptom generation in functional gastrointestinal disorders: physiological aspects. Am J Gastroenterol. 2013;108:698–706.
Pasricha PJ, Camilleri M, Hasler WL, Parkman HP. White Paper AGA: Gastroparesis: clinical and regulatory insights for clinical trials. Clin Gastroenterol Hepatol. 2017;15:1184–90.
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;14:4281–94.
Paixão P, Bermejo M, Hens B, Tsume Y, Dickens J, Shedden K, et al. Gastric emptying and intestinal appearance of nonabsorbable drugs phenol red and paromomycin in human subjects: a multi-compartment stomach approach. Eur J Pharm Biopharm. 2018;129:162–74.
Oberle RL, Chen TS, Lloyd C, Barnett JL, Owyang C, Meyer J, et al. The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids. Gastroenterology. 1990;99:1275–82.
Mudie DM, Murray K, Hoad CL, Pritchard SE, Garnett MC, Amidon GL, et al. Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state. Mol Pharm. 2014;11:3039–47.
Parker HL, Tucker E, Blackshaw E, Hoad CL, Marciani L, Perkins A, et al. Clinical assessment of gastric emptying and sensory function utilizing gamma scintigraphy: establishment of reference intervals for the liquid and solid components of the Nottingham test meal in healthy subjects. Neurogastroenterol Motil. 2017;29.
Parker H, Hoad CL, Tucker E, Costigan C, Marciani L, Gowland P, et al. Gastric motor and sensory function in health assessed by magnetic resonance imaging: establishment of reference intervals for the Nottingham test meal in healthy subjects. Neurogastroenterol Motil. 2018;30:e13463.
Cassilly D, Kantor S, Knight LC, Maurer AH, Fisher RS, Semler J, et al. Gastric emptying of a non-digestible solid: assessment with simultaneous SmartPill pH and pressure capsule, antroduodenal manometry, gastric emptying scintigraphy. Neurogastroenterol Motil. 2008;20:311–9.
Diaz Tartera HO, Webb D-L, Al-Saffar AK, Halim MA, Lindberg G, Sangfelt P, et al. Validation of SmartPill® wireless motility capsule for gastrointestinal transit time: intra-subject variability, software accuracy and comparison with video capsule endoscopy. Neurogastroenterol Motil. 2017;29:1–9.
Heissam K, Abrehart N, Hoad CL, Wright J, Menys A, Murray K, et al. Measuring fasted state gastric motility before and after a standard BA/BE 8 oz drink of water: validation of new MRI imaging protocols against concomitant perfused manometry in healthy participants. Annual AAPS Meeting. Washington, DC, November 4-7 2018.
Hoad C, Clarke C, Marciani L, Graves MJ, Corsetti M. Will MRI of gastrointestinal function parallel the clinical success of cine cardiac MRI? BJR. 2018;92:20180433.
Schiller C, Fröhlich C-P, Giessmann T, Siegmund W, Mönnikes H, Hosten N, et al. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2005;22:971–9.
Hens B, Bolger MB. Application of a dynamic fluid and pH model to simulate intraluminal and systemic concentrations of a weak base in GastroPlus™. J Pharm Sci. 2019;108:305–15.
Riethorst D, Mols R, Duchateau G, Tack J, Brouwers J, Augustijns P. Characterization of human duodenal fluids in fasted and fed state conditions. J Pharm Sci. 2016;105:673–81.
Koenigsknecht MJ, Baker JR, Wen B, Frances A, Zhang H, Yu A, et al. In vivo dissolution and systemic absorption of immediate release ibuprofen in human gastrointestinal tract under fed and fasted conditions. Mol Pharm. 2017;14:4295–304.
Dahlgren D, Roos C, Lundqvist A, Abrahamsson B, Tannergren C, Hellström PM, et al. Regional intestinal permeability of three model drugs in human. Mol Pharm. 2016;13:3013–21.
Lennernäs H. Human intestinal permeability. J Pharm Sci. 1998;87:403–10.
Dahlgren D, Roos C, Sjögren E, Lennernäs H. Direct in vivo human intestinal permeability (Peff ) determined with different clinical perfusion and intubation methods. J Pharm Sci. 2015;104:2702–26.
Wuyts B, Riethorst D, Brouwers J, Tack J, Annaert P, Augustijns P. Evaluation of fasted and fed state simulated and human intestinal fluids as solvent system in the Ussing chambers model to explore food effects on intestinal permeability. Int J Pharm. 2015;478:736–44.
Corsetti M, Costa M, Bassotti G, Bharucha AE, Borrelli O, Dinning PG. First “translational” consensus on terminology and definition of colonic motility as studied in humans and animals by means of manometric and non-manometric techniques. Nat Rev. in press.
Mark EB, Poulsen JL, Haase A-M, Espersen M, Gregersen T, Schlageter V, et al. Ambulatory assessment of colonic motility using the electromagnetic capsule tracking system. Neurogastroenterology & Motility. 2019;31:e13451.
Wilkinson-Smith VC, Major G, Ashleigh L, Murray K, Hoad CL, Marciani L, et al. Insights into the different effects of Food on intestinal secretion using magnetic resonance imaging. JPEN J Parenter Enteral Nutr. 2018;42:1342–8.
Costa M, Wiklendt L, Keightley L, Brookes SJH, Dinning PG, Spencer NJ. New insights into neurogenic cyclic motor activity in the isolated guinea-pig colon. Neurogastroenterol Motil. 2017;29:1–13.
Amidon GL, Lennernäs H, 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.
Wei H, Dalton C, Di Maso M, Kanfer I, Löbenberg R. Physicochemical characterization of five glyburide powders: a BCS based approach to predict oral absorption. Eur J Pharm Biopharm. 2008;69:1046–56.
Wei H, Löbenberg R. Biorelevant dissolution media as a predictive tool for glyburide a class II drug. Eur J Pharm Sci. 2006;29:45–52.
Okumu A, DiMaso M, Löbenberg R. Dynamic dissolution testing to establish in vitro/in vivo correlations for montelukast sodium, a poorly soluble drug. Pharm Res. 2008;25:2778–85.
Almukainzi M, Jamali F, Aghazadeh-Habashi A, Löbenberg R. Disease specific modeling: simulation of the pharmacokinetics of meloxicam and ibuprofen in disease state vs. healthy conditions. Eur J Pharm Biopharm. 2016;100:77–84.
Al-Gousous J, Amidon GL, Langguth P. Toward biopredictive dissolution for enteric coated dosage forms. Mol Pharm. 2016;13:1927–36.
Levy G, Hollister LE. FAILURE OF U.S.P. Disintegration test to assess physiologic availability of enteric coated tablets. N Y State J Med. 1964;64:3002–5.
Karkossa F, Klein S. Individualized in vitro and in silico methods for predicting in vivo performance of enteric-coated tablets containing a narrow therapeutic index drug. European Journal of Pharmaceutics and Biopharmaceutics. 2019;135:13–24.
Shi Y, Gao P, Gong Y, Ping H. Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption. Mol Pharm. 2010;7:1458–65.
Xu H, Vela S, Shi Y, Marroum P, Gao P. In vitro characterization of ritonavir drug products and correlation to human in vivo performance. Mol Pharm. 2017;14:3801–14.
Bolger MB, Macwan JS, Sarfraz M, Almukainzi M, Löbenberg R. The irrelevance of in vitro dissolution in setting product specifications for drugs like dextromethorphan that are subject to lysosomal trapping. J Pharm Sci. 2019;108:268–78.
Tsume Y, Mudie DM, Langguth P, Amidon GE, Amidon GL. The biopharmaceutics classification system: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC. Eur J Pharm Sci. 2014;57:152–63.
Butler JM, Dressman JB. The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci. 2010;99:4940–54.
Rosenberger J, Butler J, Dressman J. A refined developability classification system. J Pharm Sci. 2018;107:2020–32.
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.
Psachoulias D, Vertzoni M, Butler J, Busby D, Symillides M, Dressman J, et al. An in vitro methodology for forecasting luminal concentrations and precipitation of highly permeable lipophilic weak bases in the fasted upper small intestine. Pharm Res. 2012;29:3486–98.
Takeuchi S, Tsume Y, Amidon GE, Amidon GL. Evaluation of a three compartment in vitro gastrointestinal simulator dissolution apparatus to predict in vivo dissolution. J Pharm Sci. 2014;103:3416–22.
Klein S, Buchanan NL, Buchanan CM. Miniaturized transfer models to predict the precipitation of poorly soluble weak bases upon entry into the small intestine. AAPS PharmSciTech. 2012;13:1230–5.
Takano R, Kataoka M, Yamashita S. Integrating drug permeability with dissolution profile to develop IVIVC. Biopharm Drug Dispos. 2012;33:354–65.
Mudie DM, Amidon GL, Amidon GE. Physiological parameters for oral delivery and in vitro testing. Mol Pharm. 2010;7:1388–405.
Sjögren E, Abrahamsson B, Augustijns P, Becker D, Bolger MB, Brewster M, et al. In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects. Eur J Pharm Sci. 2014;57:99–151.
Rege BD, Yu LX, Hussain AS, Polli JE. Effect of common excipients on Caco-2 transport of low-permeability drugs. J Pharm Sci. 2001;90:1776–86.
Rege BD, Kao JPY, Polli JE. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci. 2002;16:237–46.
Bermejo MV, Pérez-Varona AT, Segura-Bono MJ, Martín-Villodre A, Plá-Delfina JM, Garrigues TM. Compared effects of synthetic and natural bile acid surfactants on xenobiotic absorption I. Studies with polysorbate and taurocholate in rat colon. Int J Pharm. 1991;69:221–31.
Carmona-Ibáñez G, del Bermejo-Sanz MV, Rius-Alarcó F, Martin-Villodre A. Experimental studies on the influence of surfactants on intestinal absorption of drugs cefadroxil as model drug and sodium taurocholate as natural model surfactant: studies in rat colon and in rat duodenum. Arzneimittelforschung. 1999;49:44–50.
Brouwers J, Mols R, Annaert P, Augustijns P. Validation of a differential in situ perfusion method with mesenteric blood sampling in rats for intestinal drug interaction profiling. Biopharm Drug Dispos. 2010;31:278–85.
Mols R, Brouwers J, Schinkel AH, Annaert P, Augustijns P. Intestinal perfusion with mesenteric blood sampling in wild-type and knockout mice: evaluation of a novel tool in biopharmaceutical drug profiling. Drug Metab Dispos. 2009;37:1334–7.
Guillaume P, Provost D, Lacroix P. Gastrointestinal models: intestinal transit, gastric emptying, and ulcerogenic activity in the rat. Curr Protoc Pharmacol. 2008;Chapter 5:Unit5.3.
Goineau S, Guillaume P, Castagné V. Comparison of the effects of clonidine, loperamide and metoclopramide in two models of gastric emptying in the rat. Fundam Clin Pharmacol. 2015;29:86–94.
Pestel S, Martin H-J, Maier G-M, Guth B. Effect of commonly used vehicles on gastrointestinal, renal, and liver function in rats. J Pharmacol Toxicol Methods. 2006;54:200–14.
Gundogdu E, Mangas-Sanjuan V, Gonzalez-Alvarez I, Bermejo M, Karasulu E. In vitro-in situ permeability and dissolution of fexofenadine with kinetic modeling in the presence of sodium dodecyl sulfate. Eur J Drug Metab Pharmacokinet. 2012;37:65–75.
Gundogdu E, Alvarez IG, Karasulu E. Improvement of effect of water-in-oil microemulsion as an oral delivery system for fexofenadine: in vitro and in vivo studies. Int J Nanomedicine. 2011;6:1631–40.
Colón-Useche S, González-Álvarez I, Mangas-Sanjuan V, González-Álvarez M, Pastoriza P, Molina-Martínez I, et al. Investigating the discriminatory power of BCS-biowaiver in vitro methodology to detect bioavailability differences between immediate release products containing a class I drug. Mol Pharm. 2015;12:3167–74.
World Health Organization. WHO Expert Committee on Specifications for Pharmaceutical Preparations. World Health Organ Tech Rep Ser. 2005;929:1–142 backcover.
US Food & Drug Administration. Guidance for industry on fixed dose combinations, co-packaged drug products, and single-entity versions of previously approved antiretrovirals for the treatment of HIV; availability [Internet]. Federal Register. 2006 [cited 2019 Jan 15]. Available from: https://www.federalregister.gov/documents/2006/10/18/E6-17324/guidance-for-industry-on-fixed-dose-combinations-co-packaged-drug-products-and-single-entity.
European Medicines Agency. Guideline on clinical development of fixed combination medicinal products. 2017;12. Last accessed on March 6, 2019.
When to Submit an ANDA vs. a 505(b)(2) Application: FDA Discusses in Draft Guidance [Internet]. [cited 2019 Jan 15]. Available from: https://www.raps.org/regulatory-focus™/news-articles/2017/10/when-to-submit-an-anda-vs-a-505(b)(2)-application-fda-discusses-in-draft-guidance.
Podolsky SH, Greene JA. Combination drugs--hype, harm, and hope. N Engl J Med. 2011;365:488–91.
Kohlrausch A. Bilayer tablet of telmisartan and simvastatin [Internet]. 2006 [cited 2019 Jan 15]. Available from: https://patents.google.com/patent/US20060078615A1/en.
Mitra A, Wu Y. Challenges and opportunities in achieving bioequivalence for fixed-dose combination products. AAPS J. 2012;14:646–55.
Food & Drug Administration. Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system guidance for industry [Internet]. 2015 [cited 2017 Jan 17]. Available from: http://www.fda.gov/downloads/Drugs/Guidances/ucm070246.pdf.
European Medicines Agency. Guideline on the investigation of bioequivalence [Internet]. 2010. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf.
Canada H, Canada H. Guidance document: biopharmaceutics classification system based biowaiver [Internet]. aem. 2014 [cited 2019 Jan 15]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/biopharmaceutics-classification-system-based-biowaiver.html.
US Food & Drug Administration. In vitro metabolism- and transporter-mediated drug-drug interaction studies, and clinical drug interaction studies-study design, data analysis, and clinical implications; draft guidances for industry; availability [Internet]. Federal Register. 2017 [cited 2019 Jan 15]. Available from: https://www.federalregister.gov/documents/2017/10/25/2017-23102/in-vitro-metabolism%2D%2Dand-transporter-mediated-drug-drug-interaction-studies-and-clinical-drug.
European Medicines Agency. European Medicines Agency updates guideline on drug interactions [Internet]. 2012 [cited 2019 Jan 15]. Available from: https://www.ema.europa.eu/en/news/european-medicines-agency-updates-guideline-drug-interactions.
Dobson PD, Kell DB. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Discov. 2008;7:205–20.
Dahlgren D, Roos C, Lundqvist A, Tannergren C, Langguth P, Sjöblom M, et al. Preclinical effect of absorption modifying excipients on rat intestinal transport of model compounds and the mucosal barrier marker 51Cr-EDTA. Mol Pharm. 2017;14:4243–51.
Engel A, Oswald S, Siegmund W, Keiser M. Pharmaceutical excipients influence the function of human uptake transporting proteins. Mol Pharm. 2012;9:2577–81.
Otter M, Oswald S, Siegmund W, Keiser M. Effects of frequently used pharmaceutical excipients on the organic cation transporters 1-3 and peptide transporters 1/2 stably expressed in MDCKII cells. Eur J Pharm Biopharm. 2017;112:187–95.
Cardot J-M, Garcia-Arieta A, Paixao P, Tasevska I, Davit B. Implementing the additional strength biowaiver for generics: EMA recommended approaches and challenges for a US-FDA submission. Eur J Pharm Sci. 2018;111:399–408.
Maltais F, Hamilton A, Voß F, Maleki-Yazdi MR. Dose determination for a fixed-dose drug combination: a phase II randomized controlled trial for tiotropium/olodaterol versus tiotropium in patients with COPD. Adv Ther. 2019;36:962–8.
Silver DE. Clinical experience with the novel levodopa formulation entacapone + levodopa + carbidopa (Stalevo). Expert Rev Neurother. 2004;4:589–99.
Dey S, Chattopadhyay S, Mazumder B. Formulation and Evaluation of fixed-dose combination of bilayer gastroretentive matrix tablet containing atorvastatin as fast-release and atenolol as sustained-release. Biomed Res Int [Internet]. 2014 [cited 2019 Apr 25];2014. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909979/.
Riekes MK, Engelen A, Appeltans B, Rombaut P, Stulzer HK, Van den Mooter G. New perspectives for fixed dose combinations of poorly water-soluble compounds: a case study with ezetimibe and lovastatin. Pharm Res. 2016;33:1259–75.
Oh J-H, Lee JE, Kim YJ, Oh T-O, Han S, Jeon EK, et al. Designing of the fixed-dose gastroretentive bilayer tablet for sustained release of metformin and immediate release of atorvastatin. Drug Dev Ind Pharm. 2016;42:340–9.
Sleight P, Pouleur H, Zannad F. Benefits, challenges, and registerability of the polypill. Eur Heart J. 2006;27:1651–6.
Guia para Registro de Novas Associações em Dose Fixa - Busca - Anvisa [Internet]. [cited 2019 Jan 15]. Available from: http://portal.anvisa.gov.br/resultado-de-busca?p_p_id=101&p_p_lifecycle=0&p_p_state=maximized&p_p_mode=view&p_p_col_id=column-1&p_p_col_count=1&_101_struts_action=%2Fasset_publisher%2Fview_content&_101_assetEntryId=352621&_101_type=document.
Gautam Y, Bjerrum OJ, Schmiegelow M. The wider use of fixed-dose combinations emphasizes the need for a global approach to regulatory guideline development. Drug Inf J. 2015;49:197–204.
Desai D, Wang J, Wen H, Li X, Timmins P. Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms. Pharm Dev Technol. 2013;18:1265–76.
Desai D, Rinaldi F, Kothari S, Paruchuri S, Li D, Lai M, et al. Effect of hydroxypropyl cellulose (HPC) on dissolution rate of hydrochlorothiazide tablets. Int J Pharm. 2006;308:40–5.
Narang AS, Rao VM, Desai DS. Effect of antioxidants and silicates on peroxides in povidone. J Pharm Sci. 2012;101:127–39.
US Food & Drug Administration. Guidance, compliance, & regulatory information [Internet]. [cited 2019 Mar 5]. Available from: https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/default.htm.
The authors received financial support from the Flemish Research Council (FWO – applicant number: 12R2119N).
This report represents the scientific views of the authors and not necessarily that of the regulatory authorities presented in this manuscript (U.S. Food and Drug Administration and ANAMED).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Hens, B., Corsetti, M., Bermejo, M. et al. “Development of Fixed Dose Combination Products” Workshop Report: Considerations of Gastrointestinal Physiology and Overall Development Strategy. AAPS J 21, 75 (2019). https://doi.org/10.1208/s12248-019-0346-6
- fixed dose combination drug products
- formulation prediction
- in vivo predictions
- gastrointestinal physiology