TY - JOUR

T1 - Hyperthermia-Induced In Situ Drug Amorphization by Superparamagnetic Nanoparticles in Oral Dosage Forms

AU - Ansari, Shaquib Rahman

AU - Hempel, Nele Johanna

AU - Asad, Shno

AU - Svedlindh, Peter

AU - Bergström, Christel A.S.

AU - Löbmann, Korbinian

AU - Teleki, Alexandra

N1 - Funding Information: The authors express gratitude to Dr. Georgios Sotiriou for assistance with FSP, Dr. Reinier Oropesa-Nunez for help with the magnetometry measurements, and Dr. Caroline Alvebratt for help with the μDISS profiler. The authors acknowledge the BioVis core facility/electron microscopy node at the Department of Immunology, Genetics and Pathology, Uppsala University, for assistance with TEM analysis. The authors gratefully acknowledge funding from NordForsk (Nordic University Hub project no. 85352; Nordic POP) and the Independent Research Fund Denmark (grant no. DFF-7026-00052B). The Science for Life Laboratory is gratefully acknowledged for financial support. This project has also received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 101002582).

PY - 2022

Y1 - 2022

N2 - Superparamagnetic iron oxide nanoparticles (SPIONs) generate heat upon exposure to an alternating magnetic field (AMF), which has been studied for hyperthermia treatment and triggered drug release. This study introduces a novel application of magnetic hyperthermia to induce amorphization of a poorly aqueous soluble drug, celecoxib, in situ in tablets for oral administration. Poor aqueous solubility of many drug candidates is a major hurdle in oral drug development. A novel approach to overcome this challenge is in situ amorphization of crystalline drugs. This method facilitates amorphization by molecular dispersion of the drug in a polymeric network inside a tablet, circumventing the physical instability encountered during the manufacturing and storage of conventional amorphous solid dispersions. However, the current shortcomings of this approach include low drug loading, toxicity of excipients, and drug degradation. Here, doped SPIONs produced by flame spray pyrolysis are compacted with polyvinylpyrrolidone and celecoxib and exposed to an AMF in solid state. A design of experiments approach was used to investigate the effects of SPION composition (Zn0.5Fe2.5O4 and Mn0.5Fe2.5O4), doped SPION content (10-20 wt %), drug load (30-50 wt %), and duration of AMF (3-15 min) on the degree of drug amorphization. The degree of amorphization is strongly linked to the maximum tablet temperature achieved during the AMF exposure (r = 0.96), which depends on the SPION composition and content in the tablets. Complete amorphization is achieved with 20 wt % Mn0.5Fe2.5O4 and 30 wt % celecoxib in the tablets that reached the maximum temperature of 165.2 °C after 15 min of AMF exposure. Furthermore, manganese ferrite exhibits no toxicity in human intestinal Caco-2 cell lines. The resulting maximum solubility of in situ amorphized celecoxib is 5 times higher than that of crystalline celecoxib in biorelevant intestinal fluid. This demonstrates the promising capability of SPIONs as enabling excipients to magnetically induce amorphization in situ in oral dosage forms.

AB - Superparamagnetic iron oxide nanoparticles (SPIONs) generate heat upon exposure to an alternating magnetic field (AMF), which has been studied for hyperthermia treatment and triggered drug release. This study introduces a novel application of magnetic hyperthermia to induce amorphization of a poorly aqueous soluble drug, celecoxib, in situ in tablets for oral administration. Poor aqueous solubility of many drug candidates is a major hurdle in oral drug development. A novel approach to overcome this challenge is in situ amorphization of crystalline drugs. This method facilitates amorphization by molecular dispersion of the drug in a polymeric network inside a tablet, circumventing the physical instability encountered during the manufacturing and storage of conventional amorphous solid dispersions. However, the current shortcomings of this approach include low drug loading, toxicity of excipients, and drug degradation. Here, doped SPIONs produced by flame spray pyrolysis are compacted with polyvinylpyrrolidone and celecoxib and exposed to an AMF in solid state. A design of experiments approach was used to investigate the effects of SPION composition (Zn0.5Fe2.5O4 and Mn0.5Fe2.5O4), doped SPION content (10-20 wt %), drug load (30-50 wt %), and duration of AMF (3-15 min) on the degree of drug amorphization. The degree of amorphization is strongly linked to the maximum tablet temperature achieved during the AMF exposure (r = 0.96), which depends on the SPION composition and content in the tablets. Complete amorphization is achieved with 20 wt % Mn0.5Fe2.5O4 and 30 wt % celecoxib in the tablets that reached the maximum temperature of 165.2 °C after 15 min of AMF exposure. Furthermore, manganese ferrite exhibits no toxicity in human intestinal Caco-2 cell lines. The resulting maximum solubility of in situ amorphized celecoxib is 5 times higher than that of crystalline celecoxib in biorelevant intestinal fluid. This demonstrates the promising capability of SPIONs as enabling excipients to magnetically induce amorphization in situ in oral dosage forms.

KW - amorphous solid dispersions

KW - in situ drug amorphization

KW - magnetic hyperthermia

KW - oral drug delivery

KW - superparamagnetic nanoparticles

U2 - 10.1021/acsami.2c03556

DO - 10.1021/acsami.2c03556

M3 - Journal article

C2 - 35452221

AN - SCOPUS:85129516193

VL - 14

SP - 21978

EP - 21988

JO - ACS applied materials & interfaces

JF - ACS applied materials & interfaces

SN - 1944-8244

IS - 19

ER -