The solubility–permeability interplay and oral drug formulation design: Two heads are better than one

Advanced Drug Delivery Reviews

Volumn 101, Issue , 2016, Pages 99-107

  Dahan, Arik ^a   Beig, Avital ^a   Lindley, David ^b   Miller, Jonathan M ^b,c  

^a BEN GURION UNIVERSITY OF THE NEGEV   (Israel)

^b Vertex Pharmaceuticals ^*  (United States)

^c VERTEX PHARMACEUTICALS   (United States)

Author keywords

Biopharmaceutics Classification System (BCS); Drug solubility; Intestinal permeability; Solubility enabling formulations; Solubility permeability tradeoff

Indexed keywords

DRUG DELIVERY; MEDICINE;

APPARENT PERMEABILITIES; CLASSIFICATION SYSTEM; DRUG SOLUBILITY; INTELLIGENT DESIGNS; INTESTINAL PERMEABILITIES; MATHEMATICAL EQUATIONS; MEMBRANE PERMEABILITY; PARTITION COEFFICIENT;

SOLUBILITY;

ANTIBIOTIC AGENT; CYCLODEXTRIN; RIFAXIMIN; DRUG;

CONTROLLED STUDY; DRUG ABSORPTION; DRUG DESIGN; DRUG EXPOSURE; DRUG FORMULATION; DRUG MECHANISM; DRUG PENETRATION; DRUG SOLUBILITY; HYDROPHILICITY; HYDROPHOBICITY; LIPOPHILICITY; MEMBRANE PERMEABILITY; PARTITION COEFFICIENT; PHARMACEUTICS; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; REVIEW; ANIMAL; CELL MEMBRANE PERMEABILITY; CHEMISTRY; HUMAN; INTESTINE ABSORPTION; ORAL DRUG ADMINISTRATION; SOLUBILITY;

ADMINISTRATION, ORAL; ANIMALS; BIOPHARMACEUTICS; CELL MEMBRANE PERMEABILITY; DRUG COMPOUNDING; DRUG DESIGN; HUMANS; INTESTINAL ABSORPTION; PHARMACEUTICAL PREPARATIONS; SOLUBILITY;

EID: 84966698443     PISSN: 0169409X     EISSN: 18728294     Source Type: Journal    
DOI: 10.1016/j.addr.2016.04.018     Document Type: Review

References (87)

1. [1] Lennernas, H., Human intestinal permeability. J. Pharm. Sci. 87 (1998), 403–410.
2. [2] Yu, L.X., Lipka, E., Crison, J.R., Amidon, G.L., Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. Adv. Drug Deliv. Rev. 19 (1996), 359–376.
3. [3] Dahan, A., Miller, J., Amidon, G., Prediction of solubility and permeability class membership: provisional BCS classification of the world's top oral drugs. AAPS J. 11 (2009), 740–746.
4. [4] Amidon, G.L., Lennernas, H., Shah, V.P., Crison, J.R., A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res., 12, 1995, 413.
5. [5] Lobenberg, R., Amidon, G.L., Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur. J. Pharm. Biopharm. 50 (2000), 3–12.
6. [6] Martinez, M.N., Amidon, G.L., A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J. Clin. Pharmacol. 42 (2002), 620–643.
7. [7] Dahan, A., Lennernäs, H., Amidon, G.L., The fraction dose absorbed, in humans, and high jejunal human permeability relationship. Mol. Pharm. 9 (2012), 1847–1851.
8. [8] Dahan, A., Wolk, O., Kim, Y.H., Ramachandran, C., Crippen, G.M., Takagi, T., Bermejo, M., Amidon, G.L., Purely in silico BCS classification: science based quality standards for the world's drugs. Mol. Pharm. 10 (2013), 4378–4390.
9. [9] Ku, M.S., Use of the biopharmaceutical classification system in early drug development. AAPS J. 10 (2008), 208–212.
10. [10] Lennernäs, H., Abrahamsson, B., The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension. J. Pharm. Pharmacol. 57 (2005), 273–285.
11. [11] Wolk, O., Agbaria, R., Dahan, A., Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development. Drug Des. Devel. Ther. 8 (2014), 1563–1575.
12. [12] 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 129 (2008), 1–10.
13. [13] Faller, B., Ertl, P., Computational approaches to determine drug solubility. Adv. Drug Deliv. Rev. 59 (2007), 533–545.
14. [14] Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46 (2001), 3–26.
15. [15] Singh, A., Worku, Z.A., Van den Mooter, G., Oral formulation strategies to improve solubility of poorly water-soluble drugs. Expert Opin. Drug Deliv. 8 (2011), 1361–1378.
16. [16] Dahan, A., Miller, J.M., Hoffman, A., Amidon, G.E., Amidon, G.L., The solubility–permeability interplay in using cyclodextrins as pharmaceutical solubilizers: mechanistic modeling and application to progesterone. J. Pharm. Sci. 99 (2010), 2739–2749.
17. [17] Miller, J.M., Beig, A., Carr, R.A., Spence, J.K., Dahan, A., A win–win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability. Mol. Pharm. 9 (2012), 2009–2016.
18. [18] Miller, J.M., Beig, A., Carr, R.A., Webster, G.K., Dahan, A., The solubility–permeability interplay when using cosolvents for solubilization: Revising the way we use solubility-enabling formulations. Mol. Pharm. 9 (2012), 581–590.
19. [19] Miller, J.M., Beig, A., Krieg, B.J., Carr, R.A., Borchardt, T.B., Amidon, G.E., Amidon, G.L., Dahan, A., The solubility–permeability Interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation. Mol. Pharm. 8 (2011), 1848–1856.
20. [20] Grant, D., Higuchi, T., Activities of solutes, selection of standard state, and Henry's law constants. Weissberger, A., (eds.) Solubility Behavior of Organic Compounds, 1990, John Wiley & Sons, New York, 89–133.
21. [21] Amidon, G.E., Higuchi, W.I., Ho, N.F.H., Theoretical and experimental studies of transport of micelle-solubilized solutes. J. Pharm. Sci. 71 (1982), 77–84.
22. [22] Loftsson, T., Brewster, M.E., Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J. Pharm. Sci. 85 (1996), 1017–1025.
23. [23] Higuchi, T., Physical chemical analysis of percutaneous absorption process from creams and ointments. J. Soc. Cosmet. Chem. 11 (1960), 85–97.
24. [24] Higuchi, T., Prodrug, molecular structure and percutaneous delivery. Roche, E., (eds.) Design of Biopharm Properties Through Prodrugs and Analogs, 1977, American Pharmaceutical Association Academy of Pharmaceutical Sciences, Washington D.C., 409–421.
25. [25] Brewster, M.E., Loftsson, T., Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev. 59 (2007), 645–666.
26. [26] Davis, M.E., Brewster, M.E., Cyclodextrin-based pharmaceutics: past, present and future. Nat. Rev. Drug Discov., 3, 2004, 1023.
27. [27] Rajewski, R.A., Stella, V.J., Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. J. Pharm. Sci. 85 (1996), 1142–1169.
28. [28] Loftsson, T., Brewster, M.E., Masson, M., Role of cyclodextrins in improving oral drug delivery. Am. J. Drug Deliv., 2, 2004, 261.
29. [29] Rao, V.M., Stella, V.J., When can cyclodextrins be considered for solubilization purposes?. J. Pharm. Sci. 92 (2003), 927–932.
30. [30] Carrier, R.L., Miller, L.A., Ahmed, I., The utility of cyclodextrins for enhancing oral bioavailability. J. Control. Release, 123, 2007, 78.
31. [31] Loftsson, T., Jarho, P., Másson, M., Järvinen, T., Cyclodextrins in drug delivery. Expert Opin. Drug Deliv. 2 (2005), 335–351.
32. [32] Cern, A., Nativ-Roth, E., Goldblum, A., Barenholz, Y., Effect of solubilizing agents on mupirocin loading into and release from PEGylated nanoliposomes. J. Pharm. Sci. 103 (2014), 2131–2138.
33. [33] Gamsiz, E., Miller, L., Thombre, A., Ahmed, I., Carrier, R.L., Modeling the influence of cyclodextrins on oral absorption of low-solubility drugs: I. model development. Biotechnol. Bioeng. 105 (2010), 409–420.
34. [34] Gamsiz, E., Thombre, A., Ahmed, I., Carrier, R.L., Drug salts and solubilization: modeling the influence of cyclodextrins on oral absorption. Ann. Biomed. Eng. 39 (2011), 455–468.
35. [35] Gamsiz, E.D., Miller, L., Thombre, A.G., Ahmed, I., Carrier, R.L., Modeling the influence of cyclodextrins on oral absorption of low solubility drugs: II. Experimental validation. Biotechnol. Bioeng. 105 (2010), 421–430.
36. [36] Beig, A., Agbaria, R., Dahan, A., Oral delivery of lipophilic drugs: the tradeoff between solubility increase and permeability decrease when using cyclodextrin-based formulations. PLoS One, 8, 2013, e68237.
37. [37] Beig, A., Agbaria, R., Dahan, A., The use of captisol (SBE7-β-CD) in oral solubility-enabling formulations: comparison to HPβCD and the solubility–permeability interplay. Eur. J. Pharm. Sci. 77 (2015), 73–78.
38. [38] Beig, A., Miller, J.M., Dahan, A., The interaction of nifedipine with selected cyclodextrins and the subsequent solubility–permeability trade-off. Eur. J. Pharm. Biopharm. 85 (2013), 1293–1299.
39. [39] Brewster, M.E., Noppe, M., Peeters, J., Loftsson, T., Effect of the unstirred water layer on permeability enhancement by hydrophilic cyclodextrins. Int. J. Pharm. 342 (2007), 250–253.
40. [40] Miller, J.M., Dahan, A., Predicting the solubility–permeability interplay when using cyclodextrins in solubility-enabling formulations: Model validation. Int. J. Pharm. 430 (2012), 388–391.
41. [41] Grass, G.M., Sinko, P.J., Physiologically-based pharmacokinetic simulation modelling. Adv. Drug Deliv. Rev. 54 (2002), 433–451.
42. [42] van de Waterbeemd, H., Gifford, E., ADMET in silico modelling: towards prediction paradise?. Nat. Rev. Drug Discov. 2 (2003), 192–204.
43. [43] Yu, L.X., Amidon, G.L., A compartmental absorption and transit model for estimating oral drug absorption. Int. J. Pharm. 186 (1999), 119–125.
44. [44] Bermejo, M.V., Pérez-Varona, A.T., Segura-Bono, M.J., Martín-Villodre, A., Plá-Delfina, J.M., Garrigues, T.M., Compared effects of synthetic and natural bile acid surfactants on xenobiotic absorption I. Studies with polysorbate and taurocholate in rat colon. Int. J. Pharm. 69 (1991), 221–231.
45. [45] Frank, K.J., Westedt, U., Rosenblatt, K.M., Hölig, P., Rosenberg, J., Mägerlein, M., Brandl, M., Fricker, G., Impact of FaSSIF on the solubility and dissolution-/permeation rate of a poorly water-soluble compound. Eur. J. Pharm. Sci. 47 (2012), 16–20.
46. [46] Garrigues, T.M., Segura-Bono, M.J., Bermejo, M.V., Merino, V., Plá-Delfina, J.M., Compared effects of synthetic and natural bile acid surfactant on xenobiotic absorption. II. Studies with sodium glycocholate to confirm a hypothesis. Int. J. Pharm. 101 (1994), 209–217.
47. [47] Holmstock, N., Bruyn, T.D., Bevernage, J., Annaert, P., Mols, R., Tack, J., Augustijns, P., Exploring food effects on indinavir absorption with human intestinal fluids in the mouse intestine. Eur. J. Pharm. Sci. 49 (2013), 27–32.
48. [48] Katneni, K., Charman, S.A., Porter, C.J.H., Permeability assessment of poorly water-soluble compounds under solubilizing conditions: the reciprocal permeability approach. J. Pharm. Sci. 95 (2006), 2170–2185.
49. [49] Katneni, K., Charman, S.A., Porter, C.J.H., Impact of cremophor-EL and polysorbate-80 on digoxin permeability across rat jejunum: delineation of thermodynamic and transporter related events using the reciprocal permeability approach. J. Pharm. Sci. 96 (2007), 280–293.
50. [50] Katneni, K., Charman, S.A., Porter, C.J.H., Use of plasma proteins as solubilizing agents in in vitro permeability experiments: correction for unbound drug concentration using the reciprocal permeability approach. J. Pharm. Sci. 97 (2008), 209–224.
51. [51] Mudra, D.R., Borchardt, R.T., Absorption barriers in the rat intestinal mucosa. 3: Effects of polyethoxylated solubilizing agents on drug permeation and metabolism. J. Pharm. Sci. 99 (2010), 1016–1027.
52. [52] Mudra, D.R., Borchardt, R.T., Absorption barriers in the rat intestinal mucosa: 1. application of an in situ perfusion model to simultaneously assess drug permeation and metabolism. J. Pharm. Sci. 99 (2010), 982–998.
53. [53] Mudra, D.R., Jin, J.Y., Borchardt, R.T., Absorption barriers in the rat intestinal mucosa: 2. application of physiologically based mathematical models to quantify mechanisms of drug permeation and metabolism. J. Pharm. Sci. 99 (2010), 999–1015.
54. [54] Nerurkar, M.M., Ho, N.F.H., Burton, P.S., Vidmar, T.J., Borchardt, R.T., Mechanistic roles of neutral surfactants on concurrent polarized and passive membrane transport of a model peptide in Caco-2 cells. J. Pharm. Sci. 86 (1997), 813–821.
55. [55] Poelma, F.G.J., Breäs, R., Tukker, J.J., Intestinal absorption of drugs. III. the influence of taurocholate on the disappearance kinetics of hydrophilic and lipophilic drugs from the small intestine of the rat. Pharm. Res. 7 (1990), 392–397.
56. [56] Poelma, F.G.J., Breäs, R., Tukker, J.J., Crommelin, D.J.A., Intestinal absorption of drugs. The influence of mixed micelles on on the disappearance kinetics of drugs from the small Intestine of the rat. J. Pharm. Pharmacol. 43 (1991), 317–324.
57. [57] Segura-Bono, M.J., Garrigues, T.M., Merino, V., Bermejo, M.V., Compared effects of synthetic and natural bile acid surfactants on xenobiotic absorption. III. studies with mixed micelles. Int. J. Pharm. 107 (1994), 159–166.
58. [58] Yano, K., Masaoka, Y., Kataoka, M., Sakuma, S., Yamashita, S., Mechanisms of membrane transport of poorly soluble drugs: role of micelles in oral absorption processes. J. Pharm. Sci. 99 (2010), 1336–1345.
59. [59] Buyukozturk, F., Benneyan, J.C., Carrier, R.L., Impact of emulsion-based drug delivery systems on intestinal permeability and drug release kinetics. J. Control. Release 142 (2010), 22–30.
60. [60] 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. 67 (2007), 96–105.
61. [61] Dahan, A., Miller, J., The solubility–permeability interplay and its implications in formulation design and development for poorly soluble drugs. AAPS J. 14 (2012), 244–251.
62. [62] Hens, B., Brouwers, J., Corsetti, M., Augustijns, P., Gastrointestinal behavior of nano- and microsized fenofibrate: in vivo evaluation in man and in vitro simulation by assessment of the permeation potential. Eur. J. Pharm. Sci. 77 (2015), 40–47.
63. [63] Buckley, S.T., Fischer, S.M., Fricker, G., Brandl, M., In vitro models to evaluate the permeability of poorly soluble drug entities: challenges and perspectives. Eur. J. Pharm. Sci. 45 (2012), 235–250.
64. [64] Buckley, S.T., Frank, K.J., Fricker, G., Brandl, M., Biopharmaceutical classification of poorly soluble drugs with respect to “enabling formulations”. Eur. J. Pharm. Sci. 50 (2013), 8–16.
65. [65] Fischer, S.M., Parmentier, J., Buckley, S.T., Reimold, I., Brandl, M., Fricker, G., Oral bioavailability of ketoprofen in suspension and solution formulations in rats: the influence of poloxamer 188. J. Pharm. Pharmacol. 64 (2012), 1631–1637.
66. [66] Yalkowsky, S.H., Rubino, J.T., Solubilization by cosolvents I: organic solutes in propylene glycol–water mixtures. J. Pharm. Sci. 74 (1985), 416–421.
67. [67] Yalkowsky, S.H., Valvani, S.C., Amidon, G.L., Solubility of nonelectrolytes in polar solvents IV: nonpolar drugs in mixed solvents. J. Pharm. Sci. 65 (1976), 1488–1494.
68. [68] Riad, L.E., Sawchuk, R.J., Effect of polyethylene glycol 400 on the intestinal permeability of carbamazepine in the rabbit. Pharm. Res. 8 (1991), 491–497.
69. [69] Beig, A., Miller, J.M., Dahan, A., Accounting for the solubility–permeability interplay in oral formulation development for poor water solubility drugs: the effect of PEG-400 on carbamazepine absorption. Eur. J. Pharm. Biopharm., 81, 2012.
70. [70] Baird, J.A., Taylor, L.S., Evaluation of amorphous solid dispersion properties using thermal analysis techniques. Adv. Drug Deliv. Rev. 64 (2012), 396–421.
71. [71] Gardner, C.R., Walsh, C.T., Almarsson, O., Drugs as materials: valuing physical form in drug discovery. Nat. Rev. Drug Discov. 3 (2004), 926–934.
72. [72] Hancock, B.C., Parks, M., What is the true solubility advantage for amorphous pharmaceuticals?. Pharm. Res. 17 (2000), 397–404.
73. [73] Hancock, B.C., Zografi, G., Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 86 (1997), 1–12.
74. [74] Dahan, A., Beig, A., Ioffe-Dahan, V., Agbaria, R., Miller, J., The twofold advantage of the amorphous form as an oral drug delivery practice for lipophilic compounds: increased apparent solubility and drug flux through the intestinal membrane. AAPS J. 15 (2013), 347–353.
75. [75] Beig, A., Miller, J.M., Lindley, D., Carr, R.A., Zocharski, P., Agbaria, R., Dahan, A., Head-to-head comparison of different solubility-enabling formulations of etoposide and their consequent solubility–permeability Interplay. J. Pharm. Sci. 104 (2015), 2941–2947.
76. [76] Ilevbare, G.A., Taylor, L.S., Liquid–liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: implications for solubility enhancing formulations. Cryst. Growth Des. 13 (2013), 1497–1509.
77. [77] Raina, S.A., Zhang, G.G.Z., Alonzo, D.E., Wu, J., Zhu, D., Catron, N.D., Gao, Y., Taylor, L.S., Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs. J. Pharm. Sci. 103 (2014), 2736–2748.
78. [78] Raina, S.A., Zhang, G.G.Z., Alonzo, D.E., Wu, J., Zhu, D., Catron, N.D., Gao, Y., Taylor, L.S., Impact of solubilizing additives on supersaturation and membrane transport of drugs. Pharm. Res. 32 (2015), 3350–3364.
79. [79] Thomas, N., Richter, K., Pedersen, T., 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. 16 (2014), 539–549.
80. [80] Yeap, Y.Y., Trevaskis, N.L., Porter, C.J.H., The potential for drug supersaturation during intestinal processing of lipid-based formulations may be enhanced for basic drugs. Mol. Pharm. 10 (2013), 2601–2615.
81. [81] Yeap, Y.Y., Trevaskis, N.L., Quach, T., Tso, P., Charman, W.N., Porter, C.J.H., Intestinal bile secretion promotes drug absorption from lipid colloidal phases via induction of supersaturation. Mol. Pharm. 10 (2013), 1874–1889.
82. [82] Custodio, J.M., Wu, C.-Y., Benet, L.Z., Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv. Drug Deliv. Rev. 60 (2008), 717–733.
83. [83] Estudante, M., Morais, J.G., Soveral, G., Benet, L.Z., Intestinal drug transporters: an overview. Adv. Drug Deliv. Rev. 65 (2013), 1340–1356.
84. [84] Giacomini, K.M., Huang, S.M., Tweedie, D.J., Benet, L.Z., Brouwer, K.L., Chu, X., Dahlin, A., Evers, R., Fischer, V., Hillgren, K.M., Hoffmaster, K.A., Ishikawa, T., Keppler, D., Kim, R.B., Lee, C.A., Niemi, M., Polli, J.W., Sugiyama, Y., Swaan, P.W., Ware, J.A., Wright, S.H., Yee, S.W., Zamek-Gliszczynski, M.J., Zhang, L., Membrane transporters in drug development. Nat. Rev. Drug Discov. 9 (2010), 215–236.
85. [85] Benet, L.Z., Broccatelli, F., Oprea, T.I., BDDCS applied to over 900 drugs. AAPS J. 13 (2011), 519–547.
86. [86] Pham-The, H., Garrigues, T., Bermejo, M., González-Álvarez, I., Monteagudo, M.C., Cabrera-Pérez, M.Á., Provisional classification and in silico study of biopharmaceutical system based on caco-2 cell permeability and dose number. Mol. Pharm. 10 (2013), 2445–2461.
87. [87] Inc, S.P., Substrate evaluation in the presence of specific P-glycoprotein inhibitors and repetition of inhibitor evaluation. XT58-Salix-02, 2009.