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Effect of hydrophilic additives on the dissolution and pharmacokinetic properties of itraconazole-enteric polymer hot-melt extruded amorphous solid dispersions.
Drug Dev Ind Pharm. 2016; 42(3):429-45.DD

Abstract

Hot-melt extrusion technology has been widely reported for producing amorphous solid dispersions of poorly water-soluble compounds. A number of studies revealed that enteric polymers containing ionizable groups are able to improve the physical stability and maintain drug supersaturation, thereby enhancing oral bioavailability. However, our previous studies found that itraconazole (ITZ)-enteric polymer amorphous solid dispersions are hydrophobic and poorly wettable. Moreover, drug release in an acidic environment (i.e. stomach) is very limited, indicating a narrow absorption window. In the present study, we investigated the effect of hydrophilic additives on the in vitro and in vivo performance of ITZ-enteric polymer amorphous solid dispersions. Incorporating Vitamin E TPGS into ITZ-HPMCAS amorphous solid dispersions significantly improved drug release in the acidic media. Surprisingly, a low concentration of Vitamin E TPGS also enhanced the degree of drug supersaturation in neutral pH media, which is unique as compared with other tested hydrophilic additives. This effect is not due to the solubilization of the surfactant. We further formulated the amorphous solid dispersions into tablet dosage forms and evaluated their performance in a bio-relevant dissolution media. Our optimized formulations exhibited drastically enhanced dissolution profiles as compared with the commercial ITZ product and ITZ amorphous solid dispersion without hydrophilic additive. In vivo study showed that Vitamin E TPGS induced rapid drug absorption after oral administration. Moreover, the elimination half-life of ITZ was prolonged due to the enzyme inhibition effect of Vitamin E TPGS.

Authors+Show Affiliations

a Division of Pharmaceutics , College of Pharmacy, The University of Texas at Austin , Austin , TX , USA and.a Division of Pharmaceutics , College of Pharmacy, The University of Texas at Austin , Austin , TX , USA and. b Department of Pharmacology , Shandong University School of Medicine , Shandong , China.a Division of Pharmaceutics , College of Pharmacy, The University of Texas at Austin , Austin , TX , USA and.a Division of Pharmaceutics , College of Pharmacy, The University of Texas at Austin , Austin , TX , USA and.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26355819

Citation

Lang, Bo, et al. "Effect of Hydrophilic Additives On the Dissolution and Pharmacokinetic Properties of Itraconazole-enteric Polymer Hot-melt Extruded Amorphous Solid Dispersions." Drug Development and Industrial Pharmacy, vol. 42, no. 3, 2016, pp. 429-45.
Lang B, Liu S, McGinity JW, et al. Effect of hydrophilic additives on the dissolution and pharmacokinetic properties of itraconazole-enteric polymer hot-melt extruded amorphous solid dispersions. Drug Dev Ind Pharm. 2016;42(3):429-45.
Lang, B., Liu, S., McGinity, J. W., & Williams, R. O. (2016). Effect of hydrophilic additives on the dissolution and pharmacokinetic properties of itraconazole-enteric polymer hot-melt extruded amorphous solid dispersions. Drug Development and Industrial Pharmacy, 42(3), 429-45. https://doi.org/10.3109/03639045.2015.1075031
Lang B, et al. Effect of Hydrophilic Additives On the Dissolution and Pharmacokinetic Properties of Itraconazole-enteric Polymer Hot-melt Extruded Amorphous Solid Dispersions. Drug Dev Ind Pharm. 2016;42(3):429-45. PubMed PMID: 26355819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of hydrophilic additives on the dissolution and pharmacokinetic properties of itraconazole-enteric polymer hot-melt extruded amorphous solid dispersions. AU - Lang,Bo, AU - Liu,Sha, AU - McGinity,James W, AU - Williams,Robert O,3rd Y1 - 2015/09/10/ PY - 2015/9/11/entrez PY - 2015/9/12/pubmed PY - 2016/12/30/medline KW - Glass transition temperature KW - TPGS KW - miscibility KW - supersaturation KW - tablet SP - 429 EP - 45 JF - Drug development and industrial pharmacy JO - Drug Dev Ind Pharm VL - 42 IS - 3 N2 - Hot-melt extrusion technology has been widely reported for producing amorphous solid dispersions of poorly water-soluble compounds. A number of studies revealed that enteric polymers containing ionizable groups are able to improve the physical stability and maintain drug supersaturation, thereby enhancing oral bioavailability. However, our previous studies found that itraconazole (ITZ)-enteric polymer amorphous solid dispersions are hydrophobic and poorly wettable. Moreover, drug release in an acidic environment (i.e. stomach) is very limited, indicating a narrow absorption window. In the present study, we investigated the effect of hydrophilic additives on the in vitro and in vivo performance of ITZ-enteric polymer amorphous solid dispersions. Incorporating Vitamin E TPGS into ITZ-HPMCAS amorphous solid dispersions significantly improved drug release in the acidic media. Surprisingly, a low concentration of Vitamin E TPGS also enhanced the degree of drug supersaturation in neutral pH media, which is unique as compared with other tested hydrophilic additives. This effect is not due to the solubilization of the surfactant. We further formulated the amorphous solid dispersions into tablet dosage forms and evaluated their performance in a bio-relevant dissolution media. Our optimized formulations exhibited drastically enhanced dissolution profiles as compared with the commercial ITZ product and ITZ amorphous solid dispersion without hydrophilic additive. In vivo study showed that Vitamin E TPGS induced rapid drug absorption after oral administration. Moreover, the elimination half-life of ITZ was prolonged due to the enzyme inhibition effect of Vitamin E TPGS. SN - 1520-5762 UR - https://www.unboundmedicine.com/medline/citation/26355819/Effect_of_hydrophilic_additives_on_the_dissolution_and_pharmacokinetic_properties_of_itraconazole_enteric_polymer_hot_melt_extruded_amorphous_solid_dispersions_ L2 - https://www.tandfonline.com/doi/full/10.3109/03639045.2015.1075031 DB - PRIME DP - Unbound Medicine ER -