Self-Assembled, Dilution-Responsive Hydrogels for Enhanced Thermal Stability of Insulin Biopharmaceuticals.

Catherine M Meis,Anton A A Smith,Abigail K Grosskopf,Erika E Salzman,Caitlin L Maikawa,Joseph L Mann,Eric A Appel

doi:10.1021/acsbiomaterials.0c01306

Catherine M Meis, Anton A A Smith + Show 5 more

Open Access

https://doi.org/10.1021/acsbiomaterials.0c01306

Copy DOI

Abstract

Biotherapeutics currently dominate the landscape of new drugs because of their exceptional potency and selectivity. Yet, the intricate molecular structures that give rise to these beneficial qualities also render them unstable in formulation. Hydrogels have shown potential as stabilizing excipients for biotherapeutic drugs, providing protection against harsh thermal conditions experienced during distribution and storage. In this work, we report the utilization of a cellulose-based supramolecular hydrogel formed from polymer–nanoparticle (PNP) interactions to encapsulate and stabilize insulin, an important biotherapeutic used widely to treat diabetes. Encapsulation of insulin in these hydrogels prevents insulin aggregation and maintains insulin bioactivity through stressed aging conditions of elevated temperature and continuous agitation for over 28 days. Further, insulin can be easily recovered by dilution of these hydrogels for administration at the point of care. This supramolecular hydrogel system shows promise as a stabilizing excipient to reduce the cold chain dependence of insulin and other biotherapeutics.

Highlights

Biotherapeutics have grown to be a dominant portion of the pharmaceutical market over the past two decades
We investigate the thermal stability of insulin encapsulated in these hydrogels with stressed aging experiments under relevant simulated environmental conditions to demonstrate the possibility for cold chain independence (Figure 1b)
We show that these supramolecular hydrogels are promising for use as thermal stabilization agents in insulin formulations, and potentially other parenteral biotherapeutic formulations as well

Summary

Introduction

Biotherapeutics have grown to be a dominant portion of the pharmaceutical market over the past two decades. There are many approaches to improving the stability of biotherapeutic formulations, but typical strategies include modifying the drug molecule itself, altering its physical state, or formulating with excipients often in combination such as salts, amino acids, polymers, and surfactants.[9,10] One prevalent method is to use protein engineering to design biotherapeutic analogues.[10] While this has been successful, it carries the risk of altered drug potency or immunogenicity.[3] Another commonly used stabilization technique is lyophilization, or freeze-drying, of the drug into a dry powder prior to shipping and long-term storage.[11,12] lyophilization is not ideal for many drug products because the drastic changes in temperature, pressure, and hydration state during processing can result in activity loss. The drug delivery field has made considerable advances in the formulation of biotherapeutics in soft materials to modulate drug pharmacokinetics; this body of knowledge and materials could be leveraged to advance materials for biostability as well.[2,3,14−19]

Methods

Results

Conclusion