Formulation, Characterization, and Stability of Protein Drugs: Case Histories

Pearlman, Rodney; Wang, Y. John

doi:10.1007/b112935

Cited by 6 publications

(7 citation statements)

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“…The presence of two exposed thiol groups on the FGF-2 surface promotes the formation of disulphide-linked multimers, and this propensity to form disulphide bonds drives FGF-2 to form aggregates. Interestingly, aggregation in the presence of glucosaminoglycans appeared to preserve the native FGF-2 conformation while the absence of glucosaminoglycans led to a denatured conformation similar to those induced by heat or chaotrope exposure [42].…”

Section: Fgf-2 Structure and Stabilitymentioning

confidence: 95%

“…Hydrophobic residues line the core of the barrel while a large number of charged residues are present on the protein surface. A cluster of positively charged residues to one side is thought to constitute the heparin binding region of the protein [42]. The receptor binding domain is also in this vicinity but is distinct from the heparin binding region [41].…”

Section: Fgf-2 Structure and Stabilitymentioning

confidence: 99%

“…The receptor binding domain is also in this vicinity but is distinct from the heparin binding region [41]. The latent instability of FGF-2 has been attributed to the significant amount of structural energy associated with the heparin binding site; binding with heparin or similar glucosaminoglycans at a ratio as low as 0.3:1 w/w (heparin:FGF-2) has been shown to stabilise the FGF-2 against trypsin-, heat-, acid-and protease-mediated inactivation [42][43][44]. In vivo, the interactions of FGF-2 with other endogenous molecules (e.g., heparin sulphate proteoglycan, heparin, fibrinogen/fibrin), presented in soluble form or bound to cell membrane, are known to control its receptor interactions, stability and concentration in an extracellular microenvironment [45].…”

Section: Fgf-2 Structure and Stabilitymentioning

confidence: 99%

“…Clinical applications of FGF-2, e.g., administration to a wound or further formulation into a tissue engineering construct, require the lyophilised powder to be reconstituted into solutions, e.g., by the addition of water. It is this solubilized FGF-2 that is highly vulnerable to aggregation and precipitation, resulting in rapid loss of biological function [42]. The presence of two exposed thiol groups on the FGF-2 surface promotes the formation of disulphide-linked multimers, and this propensity to form disulphide bonds drives FGF-2 to form aggregates.…”

Section: Fgf-2 Structure and Stabilitymentioning

confidence: 99%

“…Common strategies include the complexation of FGF-2 with its endogenous stabiliser, heparin, or heparin-like polymers, or polycations [51][52][53]. Ionic interactions between FGF-2 and the additives reduce the structural energy at the heparin-binding site, stabilise the FGF-2 native conformation and prolong its bioactivity in aqueous media [42][43][44]. Successful examples are given in Table 1, many of which demonstrated prolonged bioactivity of FGF-2 following the addition of excipients when compared with solutions of free FGF-2.…”

Section: Modulating Ionic Interactions In Solutionsmentioning

confidence: 99%

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Fibroblast Growth Factor 2—A Review of Stabilisation Approaches for Clinical Applications

et al. 2020

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Basic fibroblast growth factor (FGF)-2 has been shown to regulate many cellular functions including cell proliferation, migration, and differentiation, as well as angiogenesis in a variety of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve. These multiple functions make FGF-2 an attractive component for wound healing and tissue engineering constructs; however, the stability of FGF-2 is widely accepted to be a major concern for the development of useful medicinal products. Many approaches have been reported in the literature for preserving the biological activity of FGF-2 in aqueous solutions. Most of these efforts were directed at sustaining FGF-2 activity for cell culture research, with a smaller number of studies seeking to develop sustained release formulations of FGF-2 for tissue engineering applications. The stabilisation approaches may be classified into the broad classes of ionic interaction modification with excipients, chemical modification, and physical adsorption and encapsulation with carrier materials. This review discusses the underlying causes of FGF-2 instability and provides an overview of the approaches reported in the literature for stabilising FGF-2 that may be relevant for clinical applications. Although efforts have been made to stabilise FGF-2 for both in vitro and in vivo applications with varying degrees of success, the lack of comprehensive published stability data for the final FGF-2 products represents a substantial gap in the current knowledge, which has to be addressed before viable products for wider tissue engineering applications can be developed to meet regulatory authorisation.

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Section: Fgf-2 Structure and Stabilitymentioning

confidence: 95%

Section: Fgf-2 Structure and Stabilitymentioning

confidence: 99%

Section: Fgf-2 Structure and Stabilitymentioning

confidence: 99%

Section: Fgf-2 Structure and Stabilitymentioning

confidence: 99%

Section: Modulating Ionic Interactions In Solutionsmentioning

confidence: 99%

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Fibroblast Growth Factor 2—A Review of Stabilisation Approaches for Clinical Applications

et al. 2020

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StarPEG‐Heparin Hydrogels to Protect and Sustainably Deliver IL‐4

Schirmer

Atallah

Werner

et al. 2016

Adv Healthcare Materials

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A major limitation for the therapeutic applications of cytokines is their short half-life time. Glycosaminoglycans (GAGs), known to complex and stabilize cytokines in vivo, are therefore used to form 3D-biohybrid polymer networks capable of aiding the effective administration of Interleukin-4, a key regulator of the inflammatory response. Mimicking the in vivo situation of a protease-rich inflammatory milieu, star-shaped poly(ethylene glycol) (starPEG)-heparin hydrogels and starPEG reference hydrogels without heparin are loaded with Interleukin-4 and subsequently exposed to trypsin as a model protease. Heparin-containing hydrogels retain significantly higher amounts of the Interleukin-4 protein thus exhibiting a significantly higher specific activity than the heparin-free controls. StarPEG-heparin hydrogels are furthermore shown to enable a sustained delivery of the cytokine for time periods of more than two weeks. Primary murine macrophages adopt a wound healing supporting (M2) phenotype when conditioned with Interleukin-4 releasing starPEG-heparin hydrogels. The reported results suggest that GAG-based hydrogels offer valuable options for the effective administration of cytokines in protease-rich proinflammatory milieus such as chronic wounds of diabetic patients.

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Chemical and Physicochemical Solutions to Formulation Problems

Wermuth¹

2003

The Practice of Medicinal Chemistry

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Formulation, Characterization, and Stability of Protein Drugs: Case Histories

Cited by 6 publications

References 0 publications

Fibroblast Growth Factor 2—A Review of Stabilisation Approaches for Clinical Applications

Fibroblast Growth Factor 2—A Review of Stabilisation Approaches for Clinical Applications

StarPEG‐Heparin Hydrogels to Protect and Sustainably Deliver IL‐4

Chemical and Physicochemical Solutions to Formulation Problems

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