Spray-dried indomethacin-loaded polymeric micelles for the improvement of intestinal drug release and permeability

Current study aimed to develop a spray-dried powder containing indomethacin (IND)-loaded polymeric micelles which can be administered perorally as a dissolved powder to enhance the drug release and permeability of the active substance. The resulting low dense spray-dried spherical particles have decreased particle size (7.21 µm) in monodisperse distribution. The polymeric micelles had a nano size range (130 nm) also in monodisperse size distribution. These nanoparticulate properties and the high encapsulation efficiency (> 80%) lead to the improvement of gastrointestinal drug release in fasted and fed state conditions.

Highlights

The spray-dried intermediate product showed proper flowability and characteristics.

Indomethacin-loaded polymeric micelle showed increased drug release.

Ex vivo studies confirmed high gastrointestinal flux and permeability.

The intermediate product is colloidally stable.

Following second order and Higuchi kinetics, a rapid drug release was experienced exceeding the initial IND suspension. In vitro cell line studies on Caco-2 human colorectal adenocarcinoma cells showed that the formulation does not increase the toxicity of initial IND, therefore can be considered safe for oral application. Ex vivo semiquantitative and quantitative studies were performed on porcine small intestine where increased flux and permeability values of IND were achieved. The physical stability of the solid formulation was sufficient through a 6-month intermediate study caused by the hydrogen-bond formation between IND and the micelle-forming co-polymer.

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Material

The micelle-forming agent Soluplus® (SP, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) was provided from BASF GmbH (Hanover, Germany). Indomethacin (IND), D-trehalose-dihydrate (D-Tre), Tween 80, phosphate buffer saline (PBS) powder, sodium acetate and acetic acid were purchased from Merck Ltd. (Budapest, Hungary). Analytical grade solvents methanol, acetonitrile and cholesterol (CHO), L-α phosphatidylcholine (PC) were also obtained from Merck Ltd. Powders for the biorelevant gastric and intestinal fluids were purchased from Biorelevant.com Ltd. (London, United Kingdom). Distilled water was purified for the experiments using the Millipore Milli-Q® Gradient Water Purification System (Merck Ltd., Budapest, Hungary).

Bence Sipos, Ildikó Csóka, Rita Ambrus, Zsuzsanna Schelz, István Zupkó, György Tibor Balogh, Gábor Katona,
Spray-dried indomethacin-loaded polymeric micelles for the improvement of intestinal drug release and permeability,
European Journal of Pharmaceutical Sciences,
Volume 174, 2022, 106200, ISSN 0928-0987,
https://doi.org/10.1016/j.ejps.2022.106200.