Polymer-Based Sustained-Release Dosage Forms for Protein Drugs, Challenges, and Recent Advances

Abstract

Abstract. While the concept of using polymer-based sustained-release delivery systems to maintain therapeutic concentration of protein drugs for extended periods of time has been well accepted for decades, there has not been a single product in this category successfully commercialized to date despite clinical and market demands. To achieve successful systems, technical difficulties ranging from protein denaturing during formulation process and the course of prolonged in vivo release, burst release, and incomplete release, to low encapsulation efficiency and formulation complexity have to be simultaneously resolved. Based on this updated understanding, formulation strategies attempting to address these aspects comprehensively were reported in recent years. This review article (with 134 citations) aims to summarize recent studies addressing the issues above, especially those targeting practical industrial solutions. Formulation strategies representative of three areas, microsphere technology using degradable hydrophobic polymers, microspheres made of water soluble polymers, and hydrophilic in vivo gelling systems will be selected and introduced. To better understand the observations and conclusions from different studies for different systems and proteins, physicochemical basis of the technical challenges and the pros and cons of the corresponding formulation methods will be discussed.

Growth Factor-Loaded Microparticles for Tissue Engineering: The Discrepancies of In Vitro Characterization Assays

“…2,3 However, the development of controlled release formulations for proteins faces many challenges due to the relatively large and complex architecture of most proteins, which incorporate hydrophilic and hydrophobic domains with numerous reactive groups. 4,5 The unfolding of polypeptide chains can expose hydrophobic groups, which can interact with other molecules (aggregation) and with hydrophobic matrices (nonspecific adsorption) (Fig. 1, top).…”

“…1 When encapsulating in biodegradable polymeric particles, dry encapsulation has become a preferred option compared with aqueous incorporation, which requires a water-in-oil (w/o) emulsion, a potent cause of protein denaturation 9 due to the w/o interfacial tension causing protein molecules to unfold. 4 By using dry encapsulation, such as in spray-drying or with solid emulsions, the bioactivity of proteins can be improved or maintained. 10,11 Stabilizers can also be used to protect proteins, 12 by increasing the energy barrier between the native and denatured states of protein molecules, for example.…”

“…10,11 Stabilizers can also be used to protect proteins, 12 by increasing the energy barrier between the native and denatured states of protein molecules, for example. 4 Size reduction of protein aggregates (or micronization) with poly(ethylene glycol) (PEG) upon colyophilization 13 can also effectively lead to a more favorable state of the protein, 5,14,15 as seen for nerve growth factor (GF) 16 and albumin, 14 and may also reduce protein adsorption to the polymer matrix. 5,7 Alternatively, the use of saccharides is another approach to protect proteins 4,6,17 by stabilizing proteins through preferential hydration of the native form during lyophilization.…”

“…4 Size reduction of protein aggregates (or micronization) with poly(ethylene glycol) (PEG) upon colyophilization 13 can also effectively lead to a more favorable state of the protein, 5,14,15 as seen for nerve growth factor (GF) 16 and albumin, 14 and may also reduce protein adsorption to the polymer matrix. 5,7 Alternatively, the use of saccharides is another approach to protect proteins 4,6,17 by stabilizing proteins through preferential hydration of the native form during lyophilization. 1,6 Sugars were already shown to protect several types of GFs 18 and proteins.…”

“…In terms of reducing denaturation, electrospraying holds great potential considering the limited exposure to organic solvents and the possibility to use dry encapsulation. 22 Although sugars blended into the polymer matrix have been widely used for improving protein bioactivity in traditional encapsulation techniques, 4,5,[14][15][16]26 to our knowledge, no studies have investigated their use in electrospraying and hence this possibility represented an avenue of interest.…”