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Advanced Drug Delivery Reviews (v.63, #13)

Editorial Board (pp. ii).

Formulating Biomolecules: Mechanistics Insights in Molecular Interactions by Kim Chan Theme Editor; Philippe Rogueda Theme editor (pp. 1051-1052).

Interactions of formulation excipients with proteins in solution and in the dried state by Satoshi Ohtake; Yoshiko Kita; Tsutomu Arakawa (pp. 1053-1073).

A variety of excipients are used to stabilize proteins, suppress protein aggregation, reduce surface adsorption, or to simply provide physiological osmolality. The stabilizers encompass a wide variety of molecules including sugars, salts, polymers, surfactants, and amino acids, in particular arginine. The effects of these excipients on protein stability in solution are mainly caused by their interaction with the protein and the container surface, and most importantly with water. Some excipients stabilize proteins in solution by direct binding, while others use a number of fundamentally different mechanisms that involve indirect interactions. In the dry state, any effects that the excipients confer to proteins through their interactions with water are irrelevant, as water is no longer present. Rather, the excipients stabilize proteins through direct binding and their effects on the physical properties of the dried powder. This review will describe a number of mechanisms by which the excipients interact with proteins in solution and with various interfaces, and their effects on the physical properties of the dried protein structure, and explain how the various interaction forces are related to their observed effects on protein stability.Display Omitted

Keywords: Protein formulation; Excipients; Stability; Attraction pressure; Preferential interaction; Excluded volume; Amorphous glass; Solution; Dry

Molecular level insight into intra-solvent interaction effects on protein stability and aggregation by Diwakar Shukla; Curtiss P. Schneider; Bernhardt L. Trout (pp. 1074-1085).

Protein based therapeutics hold great promise in the treatment of human diseases and disorders and subsequently, they have become the fastest growing sector of new drugs being developed. Proteins are, however, inherently unstable and the degraded form can be quite harmful if administered to a patient. Of the various degradation pathways, aggregation is one of the most common and a cause for great concern. Aggregation suppressing additives have long been used to stabilize proteins, and they still remain the most viable option for combating this problem. Much work has been devoted toward investigating the behavior of commonly used additives and the resulting models give valuable insight toward explaining aggregation suppression. In a few cases, an explanation for unique behavior is lacking or new insight provides an alternate explanation. Additive selection and the development of better performing additives may benefit from a more refined understanding of how commonly used additives inhibit or enhance aggregation. In this review, we focus on recent molecular-level studies into how a select group of commonly used additives interact with proteins and subsequently influence aggregation. The intent of the review is not meant to be comprehensive for each additive but rather to provide new insights into additive–additive interactions, which may be contributing to protein–additive interactions. This is something that is often overlooked but yet essential to understanding the effect of additives on aggregation. The importance of understanding such interactions is clear when one considers that most formulations contain a mixture of cosolutes and that ideal stability might be better achieved through tuning intra-solvent interactions. We give an example of this when we describe how novel aggregation suppressing additives were developed from the knowledge gained from the reviewed studies.Display Omitted

Keywords: Abbreviations; aCgn; α-Chymotrypsinogen; Gdm; guanidinium; SAA; solvent accessible area; TMAO; trimethylamine oxide; VPO; vapor pressure osmometryProtein aggregation; Aggregation suppression; Preferential interactions; Additives; Excipients; Cosolutes; Cosolvents

Protein stabilization by cyclodextrins in the liquid and dried state by Tim Serno; Raimund Geidobler; Gerhard Winter (pp. 1086-1106).

Aggregation is arguably the biggest challenge for the development of stable formulations and robust manufacturing processes of therapeutic proteins. In search of novel excipients inhibiting protein aggregation, cyclodextrins and their derivatives have been under examination for use in parenteral protein products since more than 20years and significant research work has been accomplished highlighting the great potential of cyclodextrins as stabilizers of therapeutic proteins.Oftentimes, the potential of cyclodextrins to inhibit protein aggregation has been attributed to their capability to incorporate hydrophobic residues on aggregation-prone proteins or on their partially unfolded intermediates into the hydrophobic cavity. In addition, also other mechanisms besides or even instead of complex formation play a role in the stabilization mechanism, e.g. non-ionic surfactant-like effects.In this review a comprehensive overview of the available research work on the beneficial use of cyclodextrins and their derivatives in protein formulations, liquid as well as dried, is provided. The mechanisms of stabilization against different kinds of stress conditions, such as thermal or surface-induced, are discussed in detail.Display Omitted

Keywords: Protein; Cyclodextrin; HPβCD; Protein aggregation; Lyophilization; Liquid formulation; Protein stabilization; Non-ionic surfactant; Monoclonal antibody; Protein formulation

Viscosity of concentrated therapeutic protein compositions by Jan Jezek; Martin Rides; Barry Derham; Jonathan Moore; Elenora Cerasoli; Robert Simler; Bernardo Perez-Ramirez (pp. 1107-1117).

The use of monoclonal antibodies as therapeutic agents has been increasing steadily over the last decade for the treatment of various conditions. There is often a need to deliver a large dose of the protein, so there is a trend toward developing commercially viable liquid formulations of highly concentrated antibodies. Such concentrated solutions are associated with a number of challenges, including optimization of production processes, plus chemical and physical stability of the final product where solution viscosity becomes a critical quality attribute. Assessment of the rheological characteristics of concentrated compositions is essential as are development strategies to reduce the viscosity. This review covers the state-of-the-art rheology measurement techniques, focusing particularly on concentrated protein solutions. Current understanding of the mechanisms leading to high viscosity and control by formulation parameters is discussed.

Keywords: Rheology; Formulation; Antibody; Shear; Surfactant

Protein–excipient interactions: Mechanisms and biophysical characterization applied to protein formulation development by Tim J. Kamerzell; Reza Esfandiary; Sangeeta B. Joshi; C. Russell Middaugh; David B. Volkin (pp. 1118-1159).

The purpose of this review is to demonstrate the critical importance of understanding protein–excipient interactions as a key step in the rational design of formulations to stabilize and deliver protein-based therapeutic drugs and vaccines. Biophysical methods used to examine various molecular interactions between solutes and protein molecules are discussed with an emphasis on applications to pharmaceutical excipients in terms of their effects on protein stability. Key mechanisms of protein–excipient interactions such as electrostatic and cation–pi interactions, preferential hydration, dispersive forces, and hydrogen bonding are presented in the context of different physical states of the formulation such as frozen liquids, solutions, gels, freeze-dried solids and interfacial phenomenon. An overview of the different classes of pharmaceutical excipients used to formulate and stabilize protein therapeutic drugs is also presented along with the rationale for use in different dosage forms including practical pharmaceutical considerations. The utility of high throughput analytical methodologies to examine protein–excipient interactions is presented in terms of expanding formulation design space and accelerating experimental timelines.Display Omitted

Keywords: Protein; Excipient; Interaction; High throughput screening; Biophysical; Formulation; Stability

Molecular origins of surfactant-mediated stabilization of protein drugs by Hyo Jin Lee; Arnold McAuley; Karl F. Schilke; Joseph McGuire (pp. 1160-1171).

Loss of activity through aggregation and surface-induced denaturation is a significant problem in the production, formulation and administration of therapeutic proteins. Surfactants are commonly used in upstream and downstream processing and drug formulation. However, the effectiveness of a surfactant strongly depends on its mechanism(s) of action and properties of the protein and interfaces. Surfactants can modulate adsorption loss and aggregation by coating interfaces and/or participating in protein-surfactant associations. Minimizing protein loss from colloidal and interfacial interaction requires a fundamental understanding of the molecular factors underlying surfactant effectiveness and mechanism. These concepts provide direction for improvements in the manufacture and finishing of therapeutic proteins. We summarize the roles of surfactants, proteins, and surfactant-protein complexes in modulating interfacial behavior and aggregation. These events depend on surfactant properties that may be quantified using a thermodynamic model, to provide physical/chemical direction for surfactant selection or design, and to effectively reduce aggregation and adsorption loss.Display Omitted

Keywords: Adsorption; Aggregation; Formulation; Protein; Stabilization; Surfactant

Microgels and microcapsules in peptide and protein drug delivery by Helena Bysell; Mansson Ronja Månsson; Per Hansson; Martin Malmsten (pp. 1172-1185).

The present review focuses on the interaction of microgels and microcapsules with biological macromolecules, particularly peptides and proteins, as well as drug delivery applications of such systems. Results from recent studies on factors affecting peptide/protein binding to, and release from, microgels and related systems are discussed, including effects of network properties, as well as protein aggregation, peptide length, hydrophobicity and charge (distributions), secondary structure, and cyclization. Effects of ambient conditions (pH, ionic strength, temperature, etc.) are also discussed, all with focus on factors of importance for the performance of microgel and microcapsule delivery systems for biomacromolecular drugs.Microgels and microcapsules offer opportunities for peptide and protein delivery. Loading and release of such drugs (gray in figure) depend sensitively on a number of parameters, including microcapsule shell (left) or microgel network (right) properties, but also on ambient conditions, as well as peptide/protein characteristics, including size, charge (distribution), hydrophobicity (distribution), self-assembly properties, and secondary structure.Display Omitted

Keywords: Biomacromolecules; DNA; Drug delivery; Microgel; Microcapsule; Peptide; Protein; siRNA

Multiple aspects of the interaction of biomacromolecules with inorganic surfaces by Ivana Fenoglio; Bice Fubini; Elena M. Ghibaudi; Francesco Turci (pp. 1186-1209).

The understanding of the mechanisms involved in the interaction of biological systems with inorganic materials is of interest in both fundamental and applied disciplines. The adsorption of proteins modulates the formation of biofilms onto surfaces, a process important in infections associated to medical implants, in dental caries, in environmental technologies. The interaction with biomacromolecules is crucial to determine the beneficial/adverse response of cells to foreign inorganic materials as implants, engineered or accidentally produced inorganic nanoparticles. A detailed knowledge of the surface/biological fluids interface processes is needed for the design of new biocompatible materials. Researchers involved in the different disciplines face up with similar difficulties in describing and predicting phenomena occurring at the interface between solid phases and biological fluids. This review represents an attempt to integrate the knowledge from different research areas by focussing on the search for determinants driving the interaction of inorganic surfaces with biological matter.Display Omitted

Keywords: Abbreviations; AFM; atomic force microscopy; ANS; 1-anilino-8-naphthalenesulfonate; BSA; bovine serum albumin; CNT; carbon nanotubes; DC; circular dichroism; DSC; differential scanning calorimetry; ESR; electron spin resonance; FTIR; Fourier transform infrared spectroscopy; HEL; hen egg lysozyme; IEP; isoelectric point; MWCNT; multi-walled carbon nanotubes; NMR; nuclear magnetic resonance; PZC; point of zero-charge; ROS; reactive oxygen species; SDS; sodium dodecyl sulfate; SDSL; site-directed spin-labeling; SEM; scanning electron microscopy; SERS; surface-enhanced Raman scattering; SWCNT; single-walled carbon nanotubes; TEM; transmission electron microscopy; TIRFM; total internal reflection fluorescence microscopy; Trp; tryptophan; UV; ultravioletProtein corona; DNA; Oxidative damage; Free radicals; Silica; Titania; Gold nanoparticles; Carbon nanotubes; Conformation; Adsorption

Using drug-excipient interactions for siRNA delivery by Katharina Bruno (pp. 1210-1226).

SiRNA is the trigger of RNA interference, a mechanism discovered in the late 1990s. To release the therapeutic potential of this versatile but large and fragile molecule, excipients are used which either interact by electrostatic interaction, passively encapsulate siRNA or are covalently attached to enable specific and safe delivery of the drug substance. Controlling the delicate balance between protective complexation and release of siRNA at the right point and time is done by understanding excipients–siRNA interactions. These can be lipids, polymers such as PEI, PLGA, Chitosans, Cyclodextrins, as well as aptamers and peptides. This review describes the mechanisms of interaction of the most commonly used siRNA delivery vehicles, and looks at the results of their clinical and preclinical studies.

Keywords: Abbreviations; AFM; atomic force microscopy; ApoB; Apolipoprotein B; AMD; age related macular degeneration; Bp; base-pairs; bPEI; branched PEI; CDP; Cyclodextrin-containing polymers; CPP; cell penetrating peptide; D5W; 5% (w/v) glucose in water; DD; deacetylation degree; DLS; Dynamic light scattering; ds; double-stranded; IL; Interleukin; ITC; Isothermal titration calorimetry; i.v.; intravenous; mRNA; messenger RNA; MW; molecular weight; N/P ratio; Nitrogen to Phosphor ratio; PAMAM; poly(amidoamine); PEG; polyethylene glycol; PEI; Polyethyleneimine; R8; octaarginine; RES; reticuloendothelial system; RISC; RNA-induced silencing complex; RNAi; RNA interference; SAXS; Small angle X-ray scattering; shRNA; small hairpin RNA; siRNA; small interfering RNA; STR-R8; stearyl octaarginine; t½; half-life; TEM; transmission electron microscopy; TLR; Toll-like receptor; TNF-α; Tumor necrosis factor-α; VEGF; Vascular Endothelial Growth FactorSmall interfering RNA; siRNA; RNAi; Formulation; Delivery; Clinic

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Advanced Drug Delivery Reviews (v.63, #13)