The importance of interfaces in protein drug delivery – why is protein adsorption of interest in pharmaceutical formulations?

Pinholt, Charlotte; Hartvig, Rune Andersen; Medlicott, Natalie J.; Jørgensen, Lene

doi:10.1517/17425247.2011.577062

Cited by 110 publications

(75 citation statements)

References 181 publications

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“…3 Briefly, they include covalent changes such as oxidation and deamination, and physical changes arising from protein-protein interactions and surface adsorption-desorption. 4,5 The latter is encountered by mAbs exposed to air/liquid, solid/liquid and silicone oil/liquid interfaces as present during filling (pumping) and storage in primary packaging, such as glass vials with rubber stoppers and plastic/glass prefilled syringes. 6,7 Aggregation leading to particulate formation may be accelerated during manufacturing processes, in particular, fill-finish activities wherein the mAb is exposed to interfacial stresses.…”

Section: Introductionmentioning

confidence: 99%

Antibody adsorption on the surface of water studied by neutron reflection

Smith

Holman

et al. 2017

mAbs

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Surface and interfacial adsorption of antibody molecules could cause structural unfolding and desorbed molecules could trigger solution aggregation, resulting in the compromise of physical stability. Although antibody adsorption is important and its relevance to many mechanistic processes has been proposed, few techniques can offer direct structural information about antibody adsorption under different conditions. The main aim of this study was to demonstrate the power of neutron reflection to unravel the amount and structural conformation of the adsorbed antibody layers at the air/water interface with and without surfactant, using a monoclonal antibody 'COE-3 0 as the model. By selecting isotopic contrasts from different ratios of H 2 O and D 2 O, the adsorbed amount, thickness and extent of the immersion of the antibody layer could be determined unambiguously. Upon mixing with the commonly-used non-ionic surfactant Polysorbate 80 (Tween 80), the surfactant in the mixed layer could be distinguished from antibody by using both hydrogenated and deuterated surfactants. Neutron reflection measurements from the co-adsorbed layers in null reflecting water revealed that, although the surfactant started to remove antibody from the surface at 1/100 critical micelle concentration (CMC) of the surfactant, complete removal was not achieved until above 1/10 CMC. The neutron study also revealed that antibody molecules retained their globular structure when either adsorbed by themselves or co-adsorbed with the surfactant under the conditions studied.

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Section: Introductionmentioning

confidence: 99%

Antibody adsorption on the surface of water studied by neutron reflection

Smith

Holman

et al. 2017

mAbs

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“…2 For this reason, in-use stability studies must be conducted prior to administration of drug in a clinical setting to assess the stability of the diluted product, the compatibility of the product or dosing solution to clinically-relevant materials of construction, and the recovery and quality of active compound when prepared using the intended method for dose preparation and administration. [13][14][15][16][17] Otelixizumab drug product was formulated at a concentration of 0.2 mg/mL in a histidine-based buffer.…”

Section: Discussionmentioning

confidence: 99%

“…[34][35][36][37] The excipients used to prevent or reduce adsorption are either more surfaceactive than the protein, thus preferentially adsorbing at interfaces, or act as competitive inhibitors of adsorption. 2 For example, the conventional surfactants used in protein formulations are typically small non-ionic surfactants that either occupy the interface by direct competition with the protein, form surfactant-protein complexes that are less surface-interactive and thus remain in solution, or a combination of both. 38 Non-ionic surfactants from the polysorbate class, such as PS80 (also known as Tween Ò 80), are common excipients used in formulations of therapeutic proteins.…”

Section: Discussionmentioning

confidence: 99%

“…route, several factors such as protein properties, formulation composition, concentration of the active pharmaceutical ingredient, choice of diluent, product contact surfaces, and infusion time and rate must be considered. 1,2 The final critical factors assessed are environmental effects (e.g., area lighting and temperatures). The contact surface is of particular interest because proteins tend to adsorb at interfaces due to their amphiphilic nature.…”

Section: Introductionmentioning

confidence: 99%

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Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Morar-Mitrica

Puri

Sassi

et al. 2015

mAbs

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The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.

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“…Preservative excipients may also be required for multidose products (42)(43)(44). Compatibility with primary containers/closures must be evaluated, as the amphiphilic nature of peptides render them prone to adsorption to surfaces including glass, rubber, and plastic, resulting in loss of material during processing and storage (45)(46)(47)(48)(49)(50). Formulation and manufacturing processes should be evaluated to minimize loss via adsorption, and appropriate containers must be used for peptide storage and delivery.…”

Section: Processing Stabilitymentioning

confidence: 99%

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

Bak

Leung

Barrett

et al. 2014

AAPS J

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Abstract. Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential to alleviate many severe disease states. Despite their therapeutic potential, peptides frequently pose drug delivery challenges to scientists. This review introduces the physicochemical, biophysical, biopharmaceutical, and formulation developability aspects of peptides pertinent to the drug discovery-to-development interface. It introduces the relevance of these properties with respect to the delivery modalities available for peptide pharmaceuticals, with the parenteral route being the most prevalent route of administration. This review also presents characterization strategies for oral delivery of peptides with the aim of illuminating developability issues with the drug candidate. A brief overview of other routes of administration, including inhaled, transdermal, and intranasal routes, is provided as these routes are generally preferred by patients over injectables. Finally, this review presents formulation techniques to mitigate some of the developability obstacles associated with peptide delivery. The authors emphasize opportunities for the thoughtful application of pharmaceutical science to the development of peptide drugs and to the general advancement of this promising class of pharmaceuticals.

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The importance of interfaces in protein drug delivery – why is protein adsorption of interest in pharmaceutical formulations?

Abstract: Protein adsorption is widely studied; however, a more unified approach is still needed, especially on the adsorption of pharmaceutically relevant proteins, modified proteins and surfaces.

Cited by 110 publications

References 181 publications

Antibody adsorption on the surface of water studied by neutron reflection

Antibody adsorption on the surface of water studied by neutron reflection

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

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