Details
| Original language | English |
|---|---|
| Pages (from-to) | 529-543 |
| Number of pages | 15 |
| Journal | Drug Delivery and Translational Research |
| Volume | 7 |
| Issue number | 4 |
| Publication status | Published - 20 Apr 2017 |
Abstract
Development of highly concentrated formulations of protein and peptide drugs is a major challenge due to increased susceptibility to aggregation and precipitation. Numerous drug delivery systems including implantable and wearable controlled-release devices require thermally stable formulations with high concentrations due to limited device sizes and long-term use. Herein we report a highly concentrated insulin gel formulation (up to 80 mg/mL, corresponding to 2200 IU/mL), stabilized with a non-ionic amphiphilic triblock copolymer (i.e., Pluronic F-127 (PF-127)). Chemical and physical stability of insulin was found to be improved with increasing polymer concentration, as evidenced by reduced insulin fibrillation, formation of degradation products, and preserved secondary structure as measured by HPLC and circular dichroism spectroscopy, respectively. This formulation exhibits excellent insulin stability for up to 30 days in vitro under conditions of continuous shear at 37 °C, attributable to the amphiphilic properties of the copolymer and increased formulation viscosity. The mechanism of stabilizing insulin structure by PF-127 was investigated by coarse-grained molecular dynamics (CG-MD), all-atom MD, and molecular docking simulations. The computation results revealed that PF-127 could reduce fibrillation of insulin by stabilizing the secondary structure of unfolded insulin and forming hydrophobic interaction with native insulin. The gel formulations contained in microfabricated membrane-reservoir devices released insulin at a constant rate dependent on both membrane porosity and copolymer concentration. Subcutaneous implantation of the gel formulation-containing devices into diabetic rats resulted in normal blood glucose levels for the duration of drug release. These findings suggest that the thermally stable gel formulations are suitable for long-term and implantable drug delivery applications.
Keywords
- Coarse-grained molecular dynamics, Diabetes, Effect of amphiphilic triblock copolymer, Highly concentrated insulin formulation, Implantable drug delivery device, Long-term thermal stability, Molecular docking
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmaceutical Science
Sustainable Development Goals
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In: Drug Delivery and Translational Research, Vol. 7, No. 4, 20.04.2017, p. 529-543.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Enhancing thermal stability of a highly concentrated insulin formulation with Pluronic F-127 for long-term use in microfabricated implantable devices
AU - Li, Jason
AU - Chu, Michael K.
AU - Lu, Brian
AU - Mirzaie, Sako
AU - Chen, Kuan
AU - Gordijo, Claudia R.
AU - Plettenburg, Oliver
AU - Giacca, Adria
AU - Wu, Xiao Yu
N1 - Funding information: This work was supported partially by the Ontario Research Fund-Research Excellence (ORF-RE) Nanomaterials grant (No. RE03-058) in partnership with Sanofi Aventis and the Equipment Grants from the Natural Sciences and Engineering Research Council (NSERC) of Canada to X.Y. Wu. The NSERC CGS scholarship to J. Li and OGS Scholarship and Ben Cohen top-up awards to both J. Li and M. Chu are also acknowledged. S. Mirzaie is supported by an Islamic Azad University, Sanandaj Branch, scholarship.
PY - 2017/4/20
Y1 - 2017/4/20
N2 - Development of highly concentrated formulations of protein and peptide drugs is a major challenge due to increased susceptibility to aggregation and precipitation. Numerous drug delivery systems including implantable and wearable controlled-release devices require thermally stable formulations with high concentrations due to limited device sizes and long-term use. Herein we report a highly concentrated insulin gel formulation (up to 80 mg/mL, corresponding to 2200 IU/mL), stabilized with a non-ionic amphiphilic triblock copolymer (i.e., Pluronic F-127 (PF-127)). Chemical and physical stability of insulin was found to be improved with increasing polymer concentration, as evidenced by reduced insulin fibrillation, formation of degradation products, and preserved secondary structure as measured by HPLC and circular dichroism spectroscopy, respectively. This formulation exhibits excellent insulin stability for up to 30 days in vitro under conditions of continuous shear at 37 °C, attributable to the amphiphilic properties of the copolymer and increased formulation viscosity. The mechanism of stabilizing insulin structure by PF-127 was investigated by coarse-grained molecular dynamics (CG-MD), all-atom MD, and molecular docking simulations. The computation results revealed that PF-127 could reduce fibrillation of insulin by stabilizing the secondary structure of unfolded insulin and forming hydrophobic interaction with native insulin. The gel formulations contained in microfabricated membrane-reservoir devices released insulin at a constant rate dependent on both membrane porosity and copolymer concentration. Subcutaneous implantation of the gel formulation-containing devices into diabetic rats resulted in normal blood glucose levels for the duration of drug release. These findings suggest that the thermally stable gel formulations are suitable for long-term and implantable drug delivery applications.
AB - Development of highly concentrated formulations of protein and peptide drugs is a major challenge due to increased susceptibility to aggregation and precipitation. Numerous drug delivery systems including implantable and wearable controlled-release devices require thermally stable formulations with high concentrations due to limited device sizes and long-term use. Herein we report a highly concentrated insulin gel formulation (up to 80 mg/mL, corresponding to 2200 IU/mL), stabilized with a non-ionic amphiphilic triblock copolymer (i.e., Pluronic F-127 (PF-127)). Chemical and physical stability of insulin was found to be improved with increasing polymer concentration, as evidenced by reduced insulin fibrillation, formation of degradation products, and preserved secondary structure as measured by HPLC and circular dichroism spectroscopy, respectively. This formulation exhibits excellent insulin stability for up to 30 days in vitro under conditions of continuous shear at 37 °C, attributable to the amphiphilic properties of the copolymer and increased formulation viscosity. The mechanism of stabilizing insulin structure by PF-127 was investigated by coarse-grained molecular dynamics (CG-MD), all-atom MD, and molecular docking simulations. The computation results revealed that PF-127 could reduce fibrillation of insulin by stabilizing the secondary structure of unfolded insulin and forming hydrophobic interaction with native insulin. The gel formulations contained in microfabricated membrane-reservoir devices released insulin at a constant rate dependent on both membrane porosity and copolymer concentration. Subcutaneous implantation of the gel formulation-containing devices into diabetic rats resulted in normal blood glucose levels for the duration of drug release. These findings suggest that the thermally stable gel formulations are suitable for long-term and implantable drug delivery applications.
KW - Coarse-grained molecular dynamics
KW - Diabetes
KW - Effect of amphiphilic triblock copolymer
KW - Highly concentrated insulin formulation
KW - Implantable drug delivery device
KW - Long-term thermal stability
KW - Molecular docking
UR - http://www.scopus.com/inward/record.url?scp=85025460986&partnerID=8YFLogxK
U2 - 10.1007/s13346-017-0381-8
DO - 10.1007/s13346-017-0381-8
M3 - Article
C2 - 28429276
AN - SCOPUS:85025460986
VL - 7
SP - 529
EP - 543
JO - Drug Delivery and Translational Research
JF - Drug Delivery and Translational Research
SN - 2190-393X
IS - 4
ER -