Abstract
Protein therapeutics have a major role in medicine in that they are used to treat diverse pathologies. Their three-dimensional structures not only offer higher specificity and lower toxicity than small organic compounds but also make them less stable, limiting their in vivo half-life. Protein analogues obtained by recombinant DNA technology or by chemical modification and/or the use of drug delivery vehicles has been adopted to improve or modulate the in vivo pharmacological activity of proteins. Nevertheless, strategies to improve the shelf-life of protein pharmaceuticals have been less explored, which has challenged the preservation of their activity. Herein, we present a methodology that simultaneously increases the stability of proteins and modulates the release profile, and implement it with human insulin as a proof of concept. Two novel thermally stable insulin composite crystal formulations intended for the therapeutic treatment of diabetes are reported. These composite crystals have been obtained by crystallizing insulin in agarose and fluorenylmethoxycarbonyl-dialanine (Fmoc-AA) hydrogels. This process affords composite crystals, in which hydrogel fibers are occluded. The insulin in both crystalline formulations remains unaltered at 50 °C for 7 days. Differential scanning calorimetry, high-performance liquid chromatography, mass spectrometry, and in vivo studies have shown that insulin does not degrade after the heat treatment. The nature of the hydrogel modifies the physicochemical properties of the crystals. Crystals grown in Fmoc-AA hydrogel are more stable and have a slower dissolution rate than crystals grown in agarose. This methodology paves the way for the development of more stable protein pharmaceuticals overcoming some of the existing limitations.
Highlights
Thanks to the advance of the recombinant DNA technology, the number of therapeutic proteins that are used for the treatment of different diseases has increased enormously in recent years, revolutionizing the pharmaceutical industry.[1]
Injectable hydrogels have attracted a great interest due to the capacity of in vivo administration by noninvasive injection methods.[9,10]. Most of these hydrogel systems have exclusively focused on controlling the release rate of the protein and less attention has been paid to developing hydrogels that can improve the stability of the protein, this is the center of active research.[11,12]
We have proven that owing to its inherent nature, the hydrogel is able to modify certain characteristics of the crystals, such as quality, polymorphism, etc.[16−22] we show that the hydrogel can modify the in vitro and in vivo release profiles of insulin crystals and, at the same time, enhance the stability of the protein in its crystal form
Summary
Thanks to the advance of the recombinant DNA technology, the number of therapeutic proteins that are used for the treatment of different diseases has increased enormously in recent years, revolutionizing the pharmaceutical industry.[1]. Are biocompatible and biodegradable and, can be used for in vivo applications and can be prepared under mild conditions, preserving the protein stability.[6] Hydrogels have been intensively studied as protein carriers that can modulate the protein release profile based on the chemical nature of the hydrogel, concentration, and type and degree of crosslinking.[7,8] In particular, injectable hydrogels have attracted a great interest due to the capacity of in vivo administration by noninvasive injection methods.[9,10] most of these hydrogel systems have exclusively focused on controlling the release rate of the protein and less attention has been paid to developing hydrogels that can improve the stability of the protein, this is the center of active research.[11,12] The preservation of a protein’s native structure is one of the main issues for many hydrogel formulations that limits their application in clinics.[6] Besides, proteins in crystalline form can show some advantages when intended for therapeutic uses, such as ease of handling, higher concentration doses per volume than their soluble format, varied dissolution rates, and even improved stability.[13,14] In this respect, we have developed a strategy to create novel protein delivery formulations that can simultaneously improve protein stability and modify the release profile. Short-peptide supramolecular hydrogels[23,24] are able to stabilize insulin crystals to a higher degree, slowing down their release, compared to agarose crystals and the crystal control grown without hydrogel
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