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Current Drug Therapy

Editor-in-Chief

ISSN (Print): 1574-8855
ISSN (Online): 2212-3903

Review Article

Role of Biorelevant Media in the Estimation of In Vitro Lipolysis and Food Impact on Self-emulsifying Drug Delivery Systems

Author(s): Ravinder Verma and Deepak Kaushik*

Volume 16, Issue 1, 2021

Published on: 27 July, 2020

Page: [11 - 21] Pages: 11

DOI: 10.2174/1574885515999200727121540

Price: $65

Abstract

Self-emulsifying drug delivery systems (SEDDS) include self-microemulsifying drug delivery system (SMEDDS) and self-nanoemulsifying drug delivery system (SNEDDS) whose major benefits are reduction of inter/intrasubject variability and food effect that results in a better pharmacological response of the drug. Oral intake of these formulations triggers the digestion process because of pancreatic lipase which emulsifies/digests the lipidic ingredients of the formulation leading to precipitation of the drug. As a tool to foresee in vivo medicament precipitation, in vitro lipolysis models are established. Biorelevant media play an important role to study the effect of in vitro lipolysis and food impact on the bioavailability of SEDDS formulations. It is vital to generate the composition of fluids for both fed and fasting conditions of gastric, small intestine and colon to investigate the impact of in vitro lipolysis and food on drug’s release behavior from the formulation. Fed/Fasted state simulated gastric fluid (Fe/FaSSGF), and Fed/Fasted state simulated gastric fluid (Fe/FaSSIF) (Phosphate buffers) are first-generation. While Fa/FeSSIF-V2 (maleate) are second- generation biorelevant media utilized for these studies. FaSSIF-V3 belongs to the thirdgeneration which differs from other generations in the composition and source of bile salts. With updates in physiological data, it is vital to incorporate changes in dissolution media composition to make it more biorelevant. This review paper mainly emphasized the compositions of biorelevant media of gastric and small intestine for both fed and fasting conditions. Besides, applications of biorelevant media to investigate the effect of in vitro lipolysis and food on SEDDS are discussed with some recent research reports.

Keywords: Biorelevant media, SEDDS, SMEDDS, FeSSIF V-2, in vitro lipolysis, bioavailability.

Graphical Abstract
[1]
Wu L, Qiao Y, Wang L, et al. A self-microemulsifying drug delivery system (SMEDDS) for a novel medicative compound against depression: A preparation and bioavailability study in rats. AAPS PharmSciTech 2015; 16(5): 1051-8.
[http://dx.doi.org/10.1208/s12249-014-0280-y] [PMID: 25652729]
[2]
Li X, Yuan Q, Huang Y, Zhou Y, Liu Y. Development of silymarin self-microemulsifying drug delivery system with enhanced oral bioavailability. AAPS PharmSciTech 2010; 11(2): 672-8.
[http://dx.doi.org/10.1208/s12249-010-9432-x] [PMID: 20405254]
[3]
Singh AK, Chaurasiya A, Singh M, Upadhyay SC, Mukherjee R, Khar RK. Exemestane loaded self-microemulsifying drug delivery system (SMEDDS): development and optimization. AAPS PharmSciTech 2008; 9(2): 628-34.
[http://dx.doi.org/10.1208/s12249-008-9080-6] [PMID: 18473177]
[4]
Singh AK, Chaurasiya A, Awasthi A, et al. Oral bioavailability enhancement of exemestane from self-microemulsifying drug delivery system (SMEDDS). AAPS PharmSciTech 2009; 10(3): 906-16.
[http://dx.doi.org/10.1208/s12249-009-9281-7] [PMID: 19609837]
[5]
Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharm Biopharm 2000; 50(1): 179-88.
[http://dx.doi.org/10.1016/S0939-6411(00)00089-8] [PMID: 10840200]
[6]
Spernath A, Aserin A. Microemulsions as carriers for drugs and nutraceuticals. Adv Colloid Interface Sci 2006; 128-130(130): 47-64.
[http://dx.doi.org/10.1016/j.cis.2006.11.016] [PMID: 17229398]
[7]
Patel AR, Vavia PR. Preparation and in vivo evaluation of SMEDDS (self-microemulsifying drug delivery system) containing fenofibrate. AAPS J 2007; 9(3): E344-52.
[http://dx.doi.org/10.1208/aapsj0903041] [PMID: 18170981]
[8]
Cui W, Zhao H, Wang C, et al. Co-encapsulation of docetaxel and cyclosporin A into SNEDDS to promote oral cancer chemotherapy. Drug Deliv 2019; 26(1): 542-50.
[http://dx.doi.org/10.1080/10717544.2019.1616237] [PMID: 31090467]
[9]
Kazi M, Al-Swairi M, Ahmad A, et al. Evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for poorly water-soluble talinolol: preparation, in vitro and in vivo assessment. Front Pharmacol 2019; 10(459): 459.
[http://dx.doi.org/10.3389/fphar.2019.00459] [PMID: 31118895]
[10]
Kim DH, Kim JY, Kim RM, et al. Orlistat-loaded solid SNEDDS for the enhanced solubility, dissolution, and in vivo performance. Int J Nanomedicine 2018; 13(3): 7095-106.
[http://dx.doi.org/10.2147/IJN.S181175] [PMID: 30464461]
[11]
Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res 1998; 15(1): 11-22.
[http://dx.doi.org/10.1023/A:1011984216775] [PMID: 9487541]
[12]
Lipka E, Amidon GL. Setting bioequivalence requirements for drug development based on preclinical data: optimizing oral drug delivery systems. J Control Release 1999; 62(1-2): 41-9.
[http://dx.doi.org/10.1016/S0168-3659(99)00022-X ] [PMID: 10518633]
[13]
Verma R, Kaushik D. In vitro lipolysis as a tool for establishment of IVIVC for lipid based drug delivery systems. Curr Drug Deliv 2019; 16(8): 688-97.
[http://dx.doi.org/10.2174/1567201816666190620115716] [PMID: 31250755]
[14]
Larsen AT, Ohlsson AG, Polentarutti B, et al. Oral bioavailability of cinnarizine in dogs: relation to SNEDDS droplet size, drug solubility and in vitro precipitation. Eur J Pharm Sci 2013; 48(1-2): 339-50.
[http://dx.doi.org/10.1016/j.ejps.2012.11.004] [PMID: 23178440]
[15]
Gahlawat N, Verma R, Kaushik D. Recent developments in self-microemulsifying drug delivery system: An overview. Asian J Pharm 2019; 13(2): 59-72.
[16]
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(3): 413-20.
[http://dx.doi.org/10.1023/A:1016212804288] [PMID: 7617530]
[17]
Marques M. Dissolution media simulating fasted and fed states. Dissolut Technol 2004; 11(2): 16.
[http://dx.doi.org/10.14227/DT110204P16]
[18]
Karuppiah V, Kannappan N, Manavalan R. In-vitro and simulated in-vivo dissolution of dipyridamole extended release capsules. Eur J Pharm Biopharm 2012; 13(1): 68-72.
[19]
Galia E, Nicolaides E, Hörter D, Löbenberg R, Reppas C, Dressman JB. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res 1998; 15(5): 698-705.
[http://dx.doi.org/10.1023/A:1011910801212] [PMID: 9619777]
[20]
Klein S. The use of biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J 2010; 12(3): 397-406.
[http://dx.doi.org/10.1208/s12248-010-9203-3] [PMID: 20458565]
[21]
Bhagat NB, Yadav AV, Mali SS, et al. A review on development of biorelevant dissolution medium. J Drug Deliv Ther 2014; 4(2): 140-8.
[http://dx.doi.org/10.22270/jddt.v4i2.800]
[22]
Wang Q, Fotaki N, Mao Y. Biorelevant dissolution: Methodology and application in drug development. Dissolut Technol 2009; 16(3): 6-12.
[http://dx.doi.org/10.14227/DT160309P6]
[23]
Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res 2008; 25(7): 1663-76.
[http://dx.doi.org/10.1007/s11095-008-9569-4] [PMID: 18404251]
[24]
Juenemann D, Bohets H, Ozdemir M, et al. Online monitoring of dissolution tests using dedicated potentiometric sensors in biorelevant media. Eur J Pharm Biopharm 2011; 78(1): 158-65.
[http://dx.doi.org/10.1016/j.ejpb.2010.12.014] [PMID: 21168489]
[25]
Yasir M, Asif M. Ammeduzafar, Chauhan I, Singh A. In vitro-in vivo correlation: a review. Drug Invent Today 2010; 2(6): 282-6.
[26]
Yadav A, Kalaskar S, Patil V. In vitro-in vivo correlation: A ground discussion. Ind J Pharm Edu Res 2007; 41(4): 306-18.
[27]
Ghosh A, Choudhury G. In vitro-in vivo correlation (IVIVC): A review. J Pharm Res 2009; 2(8): 1255-60.
[28]
Souliman S, Blanquet S, Beyssac E, Cardot JM. A level A in vitro/in vivo correlation in fasted and fed states using different methods: applied to solid immediate release oral dosage form. Eur J Pharm Sci 2006; 27(1): 72-9.
[http://dx.doi.org/10.1016/j.ejps.2005.08.006] [PMID: 16169713]
[29]
Luner PE, VanDer Kamp D. Wetting characteristics of media emulating gastric fluids. Int J Pharm 2001; 212(1): 81-91.
[http://dx.doi.org/10.1016/S0378-5173(00)00602-5 ] [PMID: 11165823]
[30]
Vertzoni M, Pastelli E, Psachoulias D, Kalantzi L, Reppas C. Estimation of intragastric solubility of drugs: in what medium? Pharm Res 2007; 24(5): 909-17.
[http://dx.doi.org/10.1007/s11095-006-9209-9] [PMID: 17372688]
[31]
Fotaki N, Vertzoni M. Biorelevant dissolution methods and their applications in in vitro- in vivo correlations for oral formulations. Open Drug Deliv J 2010; 4: 2-13.
[http://dx.doi.org/10.2174/1874126601004020002]
[32]
Jantratid E, Jennifer D. Biorelevant dissolution media simulating the proximal human gastrointestinal tract: An update. Dissolut Technol 2009; 1: 21-5.
[http://dx.doi.org/10.14227/DT160309P21]
[33]
Klein S, Butler J, Hempenstall JM, Reppas C, Dressman JB. Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts. J Pharm Pharmacol 2004; 56(5): 605-10.
[http://dx.doi.org/10.1211/0022357023367] [PMID: 15142337]
[34]
Greenwood D. Small intestinal pH and buffer capacity: implications for dissolution of ionizable compounds 1994.
[35]
Redinger RN, Small DM. Bile composition, bile salt metabolism and gallstones. Arch Intern Med 1972; 130(4): 618-30.
[http://dx.doi.org/10.1001/archinte.1972.03650040142013 ] [PMID: 4629238]
[36]
Klein S, Reppas C, Dressman JB. In vitro methods to predict food effectsInternational bioequivalence standards: a new era. Ann Arbor: TSRL Inc. 2006.
[37]
Klein S, Stippler E, Wunderlich M, Dressman J. Development of dissolution tests on the basis of gastrointestinal physiology 2005.
[38]
Vertzoni M, Dressman J, Butler J, Hempenstall J, Reppas C. Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds. Eur J Pharm Biopharm 2005; 60(3): 413-7.
[http://dx.doi.org/10.1016/j.ejpb.2005.03.002] [PMID: 15893920]
[39]
Fuchs A, Dressman JB. Composition and physicochemical properties of fasted-state human duodenal and jejunal fluid: a critical evaluation of the available data. J Pharm Sci 2014; 103(11): 3398-411.
[http://dx.doi.org/10.1002/jps.24183] [PMID: 25277073]
[40]
Galia E. Physiologically based dissolution tests Doctoral thesis 1999.
[41]
Chen L, Li X, Pang Y, Li L, Zhang X, Yu L. Resistant starch as a carrier for oral colon-targeting drug matrix system. J Mater Sci Mater Med 2007; 18(11): 2199-203.
[http://dx.doi.org/10.1007/s10856-007-3009-6] [PMID: 17665124]
[42]
Chen LR, Wesley JA, Bhattachar S, Ruiz B, Bahash K, Babu SR. Dissolution behavior of a poorly water soluble compound in the presence of Tween 80. Pharm Res 2003; 20(5): 797-801.
[http://dx.doi.org/10.1023/A:1023493821302] [PMID: 12751636]
[43]
Marciani L, Cox EF, Hoad CL, et al. Postprandial changes in small bowel water content in healthy subjects and patients with irritable bowel syndrome. Gastroenterology 2010; 138(2): 469-477 477.e1..
[http://dx.doi.org/10.1053/j.gastro.2009.10.055] [PMID: 19909743]
[44]
Dressman JB, Reppas C. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. Eur J Pharm Sci 2000; 11(Suppl. 2): S73-80.
[http://dx.doi.org/10.1016/S0928-0987(00)00181-0 ] [PMID: 11033429]
[45]
Shono Y, Jantratid E, Janssen N, et al. Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling. Eur J Pharm Biopharm 2009; 73(1): 107-14.
[http://dx.doi.org/10.1016/j.ejpb.2009.05.009] [PMID: 19465123]
[46]
Mohsin K, Long MA, Pouton CW. Design of lipid-based formulations for oral administration of poorly water-soluble drugs: precipitation of drug after dispersion of formulations in aqueous solution. J Pharm Sci 2009; 98(10): 3582-95.
[http://dx.doi.org/10.1002/jps.21659] [PMID: 19130605]
[47]
Reymond JP, Sucker H, Vonderscher J. In vivo model for ciclosporin intestinal absorption in lipid vehicles. Pharm Res 1988; 5(10): 677-9.
[http://dx.doi.org/10.1023/A:1015939307478] [PMID: 3244623]
[48]
Wickham M, Garrood M, Leney J, Wilson PDG, Fillery-Travis A. Modification of a phospholipid stabilized emulsion interface by bile salt: effect on pancreatic lipase activity. J Lipid Res 1998; 39(3): 623-32.
[PMID: 9548594]
[49]
Patton JS, Carey MC. Inhibition of human pancreatic lipase-colipase activity by mixed bile salt-phospholipid micelles. Am J Physiol 1981; 241(4): G328-36.
[PMID: 7315970]
[50]
Dahan A, Hoffman A. Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: correlation with in vivo data and the relationship to intra-enterocyte processes in rats. Pharm Res 2006; 23(9): 2165-74.
[http://dx.doi.org/10.1007/s11095-006-9054-x] [PMID: 16902814]
[51]
Li Y, McClements DJ. New mathematical model for interpreting pH-stat digestion profiles: impact of lipid droplet characteristics on in vitro digestibility. J Agric Food Chem 2010; 58(13): 8085-92.
[http://dx.doi.org/10.1021/jf101325m] [PMID: 20557040]
[52]
Zangenberg NH, Müllertz A, Kristensen HG, Hovgaard L. A dynamic in vitro lipolysis model. I. Controlling the rate of lipolysis by continuous addition of calcium. Eur J Pharm Sci 2001; 14(2): 115-22.
[http://dx.doi.org/10.1016/S0928-0987(01)00169-5 ] [PMID: 11500257]
[53]
Cuiné JF, McEvoy CL, Charman WN, et al. Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs. J Pharm Sci 2008; 97(2): 995-1012.
[http://dx.doi.org/10.1002/jps.21246] [PMID: 18064698]
[54]
Ali H, Nazzal M, Zaghloul AA, Nazzal S. Comparison between lipolysis and compendial dissolution as alternative techniques for the in vitro characterization of α-tocopherol self-emulsified drug delivery systems (SEDDS). Int J Pharm 2008; 352(1-2): 104-14.
[http://dx.doi.org/10.1016/j.ijpharm.2007.10.023] [PMID: 18065173]
[55]
Han SF, Yao TT, Zhang XX, et al. Lipid-based formulations to enhance oral bioavailability of the poorly water-soluble drug anethol trithione: effects of lipid composition and formulation. Int J Pharm 2009; 379(1): 18-24.
[http://dx.doi.org/10.1016/j.ijpharm.2009.06.001] [PMID: 19508887]
[56]
Verma R, Mittal V, Kaushik D. Quality based design approach for improving oral bioavailability of valsartan loaded SMEDDS and study of impact of lipolysis on the drug diffusion. Drug Deliv Lett 2018; 8(2): 130-9.
[http://dx.doi.org/10.2174/2210303108666180313141956]
[57]
Thomas N, Richter K, Pedersen TB, Holm R, Müllertz A, Rades T. In vitro lipolysis data does not adequately predict the in vivo performance of lipid-based drug delivery systems containing fenofibrate. AAPS J 2014; 16(3): 539-49.
[http://dx.doi.org/10.1208/s12248-014-9589-4] [PMID: 24687210]
[58]
Zangenberg NH, Müllertz A, Kristensen HG, Hovgaard L. A dynamic in vitro lipolysis model. II: Evaluation of the model. Eur J Pharm Sci 2001; 14(3): 237-44.
[http://dx.doi.org/10.1016/S0928-0987(01)00182-8 ] [PMID: 11576829]
[59]
Christensen JO, Schultz K, Mollgaard B, Kristensen HG, Mullertz A. Solubilisation of poorly water-soluble drugs during in vitro lipolysis of medium- and long-chain triacylglycerols. Eur J Pharm Sci 2004; 23(3): 287-96.
[http://dx.doi.org/10.1016/j.ejps.2004.08.003] [PMID: 15489130]
[60]
Porter CJH, Kaukonen AM, Taillardat-Bertschinger A, et al. Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine. J Pharm Sci 2004; 93(5): 1110-21.
[http://dx.doi.org/10.1002/jps.20039] [PMID: 15067688]
[61]
Kaukonen AM, Boyd BJ, Porter CJH, Charman WN. Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res 2004; 21(2): 245-53.
[http://dx.doi.org/10.1023/B:PHAM.0000016282.77887.1f] [PMID: 15032305]
[62]
Kaukonen AM, Boyd BJ, Charman WN, Porter CJ. Drug solubilization behavior during in vitro digestion of suspension formulations of poorly water-soluble drugs in triglyceride lipids. Pharm Res 2004; 21(2): 254-60.
[http://dx.doi.org/10.1023/B:PHAM.0000016283.87709.a9 ] [PMID: 15032306]
[63]
Sek L, Porter CJ, Kaukonen AM, Charman WN. Evaluation of the in-vitro digestion profiles of long and medium chain glycerides and the phase behaviour of their lipolytic products. J Pharm Pharmacol 2002; 54(1): 29-41.
[http://dx.doi.org/10.1211/0022357021771896] [PMID: 11833493]
[64]
Dahan A, Hoffman A. Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs. J Control Release 2008; 129(1): 1-10.
[http://dx.doi.org/10.1016/j.jconrel.2008.03.021] [PMID: 18499294]
[65]
Charman WN, Porter CJ, Mithani S, Dressman JB. Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci 1997; 86(3): 269-82.
[http://dx.doi.org/10.1021/js960085v] [PMID: 9050793]
[66]
Fatouros DG, Bergenstahl B, Mullertz A. Morphological observations on a lipid-based drug delivery system during in vitro digestion. Eur J Pharm Sci 2007; 31(2): 85-94.
[http://dx.doi.org/10.1016/j.ejps.2007.02.009] [PMID: 17418543]
[67]
Dahan A, Hoffman A. The effect of different lipid based formulations on the oral absorption of lipophilic drugs: the ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats. Eur J Pharm Biopharm 2007; 67(1): 96-105.
[http://dx.doi.org/10.1016/j.ejpb.2007.01.017] [PMID: 17329087]
[68]
Chakraborty S, Shukla D, Mishra B, Singh S. Lipid--an emerging platform for oral delivery of drugs with poor bioavailability. Eur J Pharm Biopharm 2009; 73(1): 1-15.
[http://dx.doi.org/10.1016/j.ejpb.2009.06.001] [PMID: 19505572]
[69]
Xiao L, Yi T, Liu Y, Zhou H. The in vitro lipolysis of lipid-based drug delivery systems: a newly identified relationship between drug release and liquid crystalline phase. BioMed Res Int 2016; 20162364317
[http://dx.doi.org/10.1155/2016/2364317]] [PMID: 27294110]
[70]
Dening TJ, Joyce P, Prestidge CA. Improving correlations between drug solubilization and in vitro lipolysis by monitoring the phase partitioning of lipolytic species for lipid-based formulations. J Pharm Sci 2019; 108(1): 295-304.
[http://dx.doi.org/10.1016/j.xphs.2018.09.016] [PMID: 30257194]
[71]
Kazi M, Badran MM, Alanazi FK. Role of alternative lipid excipients in the design of self-nanoemulsifying formulations for Fenofibrate: Characterization, in vitro dispersion, digestion and ex vivo guts permeation studies. Front Pharmacol 2018; 8: 1-20.
[72]
Michaelsen MH, Wasan KM, Sivak O, Müllertz A, Rades T. The effect of digestion and drug load on halofantrine absorption from self-nanoemulsifying drug delivery System (SNEDDS). AAPS J 2016; 18(1): 180-6.
[http://dx.doi.org/10.1208/s12248-015-9832-7] [PMID: 26486790]
[73]
Memvanga PB, Coco R, Préat V. An oral malaria therapy: curcumin-loaded lipid-based drug delivery systems combined with β-arteether. J Control Release 2013; 172(3): 904-13.
[http://dx.doi.org/10.1016/j.jconrel.2013.09.001] [PMID: 24021359]
[74]
Mohsin K. Design of lipid-based formulations for oral administration of poorly water-soluble drug fenofibrate: Effects of digestion. AAPS PharmSciTech 2012; 13(2): 637-46.
[http://dx.doi.org/10.1208/s12249-012-9787-2] [PMID: 22547370]
[75]
Boyd BJ, Salim M, Clulow AJ, Ramirez G, Pham AC, Hawley A. The impact of digestion is essential to the understanding of milk as a drug delivery system for poorly water soluble drugs. J Control Release 2018; 292(1): 13-7.
[http://dx.doi.org/10.1016/j.jconrel.2018.10.027] [PMID: 30359667]
[76]
Zgair A, Wong JCM, Lee JB, et al. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines. Am J Transl Res 2016; 8(8): 3448-59.
[PMID: 27648135]
[77]
Zhang J, Lv Y, Zhao S, et al. Effect of lipolysis on drug release from self-microemulsifying drug delivery systems (SMEDDS) with different core/shell drug location. AAPS PharmSciTech 2014; 15(3): 731-40.
[http://dx.doi.org/10.1208/s12249-014-0096-9] [PMID: 24554238]
[78]
Thomas N, Holm R, Garmer M, Karlsson JJ, Müllertz A, Rades T. Supersaturated self-nanoemulsifying drug delivery systems (Super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug simvastatin in dogs. AAPS J 2013; 15(1): 219-27.
[http://dx.doi.org/10.1208/s12248-012-9433-7] [PMID: 23180162]
[79]
Larsen AT, Ogbonna A, Abu-Rmaileh R, Abrahamsson B, Østergaard J, Müllertz A. SNEDDS containing poorly water soluble cinnarizine; development and in vitro characterization of dispersion, digestion and solubilization. Pharmaceutics 2012; 4(4): 641-65.
[http://dx.doi.org/10.3390/pharmaceutics4040641] [PMID: 24300374]

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