File(s) under embargo

140

days

6

hours

until file(s) become available

Development of Co-solvent Freeze-Drying Method for the Encapsulation of Waterinsoluble Thiostrepton in Sterically Stabilized Micelles

journal contribution
posted on 24.05.2019 by Karina Esparza, Hayat Onyuksel
The purpose of this work was to develop a practical and scalable method to encapsulate the hydrophobic antibiotic thiostrepton (TST) in sterically stabilized micelles (SSM). Using the conventional method of thin-film hydration, we encapsulated up to 5 drug molecules per SSM (diameter ~16nm). However, since this method is not suitable for large-scale production – a limiting factor for clinical translation – we applied the co-solvent freeze drying method using tertbutanol (TBA): water co-solvent system. We found that the presence of phosphate buffered saline (PBS) salts in the lyophilized cake accelerated the reconstitution time and allowed efficient drug encapsulation without the formation of larger drug particles. In addition, TBA proportion of 50% (v/v) was sufficient to maintain both phospholipid and drug in solution prior to the freeze-drying. The increase of drug and phospholipid concentrations in the formulation extended the reconstitution time and led to drug precipitation. Therefore, to increase the strength of the formulation, we prepared lyophilized cakes with lower phospholipid content (5mM) and reconstituted them in one-third of the fill volume. In conclusion, we found optimum conditions to prepare TST-SSM using the co-solvent freeze-drying method. This scalable the freeze-drying. The increase of drug and phospholipid concentrations in the formulation extended the reconstitution time and led to drug precipitation. Therefore, to increase the strength of the formulation, we prepared lyophilized cakes with lower phospholipid content (5mM) and reconstituted them in one-third of the fill volume. In conclusion, we found optimum conditions to prepare TST-SSM using the co-solvent freeze-drying method. This scalable production method can facilitate the further clinical development and industrial production of TST-SSM nanomedicine.

Funding

This work was supported by the TUBITAK Science Award given to Dr. Hayat Onyuksel. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06RR15482 from the National Center for Research Resources, NIH.

History

Publisher Statement

NOTICE: This is the author’s version of a work that was accepted for publication in International Journal of Pharmaceutics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in International Journal of Pharmaceutics, [Vol 556, (2019)] DOI:10.1016/j.ijpharm.2018.12.001

Citation

Esparza, K., & Onyuksel, H. (2019). Development of co-solvent freeze-drying method for the encapsulation of water-insoluble thiostrepton in sterically stabilized micelles. International Journal of Pharmaceutics, 556, 21-29. doi:10.1016/j.ijpharm.2018.12.001

Publisher

Elsevier

Language

en

issn

0378-5173

Issue date

10/02/2019

Exports

Categories

Exports