Development of a New Ex Vivo Lipolysis-Absorption Model for Nanoemulsions

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2019 Apr 17

PMID 30987303

Citations 1

Authors

Lu Xiao

Ying Liu

Tao Yi

Affiliations

Soon will be listed here.

Abstract

The use of lipid-based formulations (LBFs) in improving the absorption of poorly water-soluble drugs has now well established. Because the in vivo evaluation of LBFs is labor-intensive, in vitro or ex vivo approaches could provide advantages. In this study, a new ex vivo lipolysis-absorption model (LAM) composed of an intestinal digestion system and an intestinal tissue system was developed to evaluate and predict the in vivo absorption performances of LBFs. Model factors, including the pH of the system and concentrations of d-glucose and pancreatic lipase, were investigated and optimized by a Box-Behnken design. To evaluate this new model, a lipid formulation of indomethacin, which was chosen based on preliminary studies of pseudo-ternary phase diagrams, emulsion droplets, and solubility, was further investigated by an in vivo pharmacokinetic study of rats, the everted gut sac model, and the LAM, respectively. The absorption percentages obtained from the LAM were much more similar to the data of rats in vivo than those from the everted gut sac model, showing a preferable in vitro-in vivo correlation ( = 0.9772). Compared with the conventional in vitro and in vivo methods, the LAM, which allowed precise insights into the in vivo absorption characteristics without much time or a complicated process, could be a better tool for assessing LBFs of poorly water-soluble drugs.

Citing Articles

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Huang Y, Yu Q, Chen Z, Wu W, Zhu Q, Lu Y Acta Pharm Sin B. 2021; 11(8):2469-2487.

PMID: 34522595 PMC: 8424225. DOI: 10.1016/j.apsb.2021.03.025.

References

Kim H, Yoon K, Hahn M, Park E, Chi S . Preparation and in vitro evaluation of self-microemulsifying drug delivery systems containing idebenone. Drug Dev Ind Pharm. 2000; 26(5):523-9. DOI: 10.1081/ddc-100101263. View

Sek L, Porter C, Charman W . Characterisation and quantification of medium chain and long chain triglycerides and their in vitro digestion products, by HPTLC coupled with in situ densitometric analysis. J Pharm Biomed Anal. 2001; 25(3-4):651-61. DOI: 10.1016/s0731-7085(00)00528-8. View

Wasan K . Formulation and physiological and biopharmaceutical issues in the development of oral lipid-based drug delivery systems. Drug Dev Ind Pharm. 2001; 27(4):267-76. DOI: 10.1081/ddc-100103726. View

Zangenberg N, Mullertz A, Kristensen H, 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. DOI: 10.1016/s0928-0987(01)00169-5. View

Sek L, Porter C, Kaukonen A, Charman W . 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. DOI: 10.1211/0022357021771896. View

Wiedmann T, Kamel L . Examination of the solubilization of drugs by bile salt micelles. J Pharm Sci. 2002; 91(8):1743-64. DOI: 10.1002/jps.10158. View

Kossena G, Boyd B, Porter C, Charman W . Separation and characterization of the colloidal phases produced on digestion of common formulation lipids and assessment of their impact on the apparent solubility of selected poorly water-soluble drugs. J Pharm Sci. 2003; 92(3):634-48. DOI: 10.1002/jps.10329. View

Kossena G, Charman W, Boyd B, Dunstan D, Porter C . Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems: a phase diagram approach. J Pharm Sci. 2004; 93(2):332-48. DOI: 10.1002/jps.10554. View

Kaukonen A, Boyd B, Porter C, Charman W . Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res. 2004; 21(2):245-53. DOI: 10.1023/b:pham.0000016282.77887.1f. View

10.

Kaukonen A, Boyd B, Charman W, Porter C . 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. DOI: 10.1023/b:pham.0000016283.87709.a9. View

11.

Porter C, Kaukonen A, Taillardat-Bertschinger A, Boyd B, OConnor J, Edwards G . 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. DOI: 10.1002/jps.20039. View

12.

van Tilbeurgh H, Sarda L, Verger R, Cambillau C . Structure of the pancreatic lipase-procolipase complex. Nature. 1992; 359(6391):159-62. DOI: 10.1038/359159a0. View

13.

Porter C, Kaukonen A, Boyd B, Edwards G, Charman W . Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation. Pharm Res. 2004; 21(8):1405-12. DOI: 10.1023/b:pham.0000036914.22132.cc. View

14.

Kossena G, Charman W, Boyd B, Porter C . Influence of the intermediate digestion phases of common formulation lipids on the absorption of a poorly water-soluble drug. J Pharm Sci. 2004; 94(3):481-92. DOI: 10.1002/jps.20260. View

15.

Hofmann A, MYSELS K . Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions. J Lipid Res. 1992; 33(5):617-26. View

16.

Al Zaabi M, Dehghanzadeh G, Norris R, Charles B . A rapid and sensitive microscale HPLC method for the determination of indomethacin in plasma of premature neonates with patent ductus arteriousus. J Chromatogr B Analyt Technol Biomed Life Sci. 2005; 830(2):364-7. DOI: 10.1016/j.jchromb.2005.11.025. View

17.

Pouton C . Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006; 29(3-4):278-87. DOI: 10.1016/j.ejps.2006.04.016. View

18.

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. DOI: 10.1007/s11095-006-9054-x. View

19.

Brogard M, Troedsson E, Thuresson K, Ljusberg-Wahren H . A new standardized lipolysis approach for characterization of emulsions and dispersions. J Colloid Interface Sci. 2007; 308(2):500-7. DOI: 10.1016/j.jcis.2006.12.015. View

20.

Cirri M, Mura P, Mora P . Liquid spray formulations of xibornol by using self-microemulsifying drug delivery systems. Int J Pharm. 2007; 340(1-2):84-91. DOI: 10.1016/j.ijpharm.2007.03.021. View