ABSTRACT
Surfactants such as Poloxamer 188 (PX188) play an important role in controlling particle formation in biotherapeutic formulations due to interfacial stresses. This study demonstrates for the first time that hydrophobicity of PX188 is a potential critical material attribute (CMA) as far as control of visible particle (VP) formation is concerned. We have found that within PX188 lots satisfying pharmacopeial specifications, there is variability in material attributes such as hydrophobicity, as determined from their reversed-phase high-performance liquid chromatography profiles. However, it currently remains unknown how such variability in hydrophobicity of PX188 affects surfactant function and VP formation. Here, we compared the effect of seven PX188 lots in two monoclonal antibody drug product formulations under various stress conditions. Notably, proteinaceous VP formation was reduced while using a PX188 lot with higher hydrophobicity. Our findings emphasize the importance of monitoring lot-to-lot variability of PX188 and provide insight into potential CMA for improving and controlling material attributes of PX188 for use in liquid biotherapeutic formulations.
Subject(s)
Antibodies, Monoclonal , Poloxamer , Antibodies, Monoclonal/chemistry , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Surface-Active Agents/chemistryABSTRACT
Poloxamer 188 (P188) is formulated in proteinaceous therapeutics as an alternative surfactant to polysorbate because of its good chemical stability and surfactant properties, which enable interfacial protection, preventing visible and sub-visible particle formation. However, due to the nature of polymer heterogeneity and limited analytical approaches to resolve the superimposed components of P188, the impact of its quality variance on protein stability is still not well understood. In this study, we developed an analytical method to evaluate the components of P188 as a function of the length of polypropylene oxide (PPO), by maintaining polyethylene oxide (PEO) at the critical point of adsorption (CPA) to eliminate its chromatographic interference. The effectiveness of the separation was confirmed by nuclear magnetic resonance (NMR) spectroscopy and mass spectroscopy (MS) of the individual fractions corresponding to each peak. Additionally, a design of experiments (DoE) and method qualification were carried out to identify and optimize the key operation parameters, including column temperature and evaporative light scattering detector (ELSD) settings that need to be strictly controlled for reliable analytical results. In conclusion, this method is sensitive and reliable to compare the quality variance of commercial P188 and is suitable for routine quality control purposes. The application of this method could help in further understanding the Critical Material Attributes (CMA) that may affect the quality attributes of proteins in formulations.
Subject(s)
Chromatography, Liquid/methods , Poloxamer/chemistry , Surface-Active Agents/chemistry , Adsorption , Magnetic Resonance Spectroscopy , Mass Spectrometry , Poloxamer/isolation & purification , Polyethylene Glycols/chemistry , Polymers/chemistry , Propylene Glycols/chemistry , Proteins/therapeutic use , Surface-Active Agents/isolation & purificationABSTRACT
Polymersome vesicles and wormlike filomicelles self-assembled with amphiphilic, degradable block copolymers have recently shown promise in application to cancer therapy. In the case of filomicelles, dense, hydrophilic brushes of poly(ethylene glycol) on these nanoparticles combine with flexibility to nonspecifically delay clearance by phagocytes in vivo, which has motivated the development of "self" peptides that inhibit nanoparticle clearance through specific interactions. Delayed clearance, as well as robustness of polymer assemblies, opens the dosage window for delivery of increased drug loads in the polymer assemblies and increased tumor accumulation of drug(s). Antibody-targeting and combination therapies, such as with radiotherapy, are emerging in preclinical animal models of cancer. Such efforts are expected to combine with further advances in polymer composition, structure, and protein/peptide functionalization to further enhance transport through the circulation and permeation into disease sites.
Subject(s)
Micelles , Nanoparticles/chemistry , Neoplasms/therapy , Paclitaxel/administration & dosage , Peptides/chemistry , Polymers/chemistry , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/chemistry , Drug Delivery Systems/methods , Humans , Nanoparticles/administration & dosage , Neoplasms/pathology , Paclitaxel/chemistry , Tumor Burden/drug effectsABSTRACT
Nanoparticles that are made by self-assembly into non-spherical shapes are promising as drug delivery vehicles. This review focuses on flexible and fragmentable filamentous micelles referred to as filomicelles made of degradable block copolymer amphiphiles. They are inspired by filoviruses and also by tubular proplatelets that break up into smaller platelets in blood flow. The synthesis and assembly of the constituent block copolymers are described together with ligand targeting and fragmentation as well as drug release in therapeutic applications to model tumors and most recently brain tumors.
Subject(s)
Oligonucleotides/metabolism , Tetrahydrofolate Dehydrogenase/metabolism , Animals , Base Sequence , Biocatalysis , Mice , NADP/metabolism , Nucleic Acid Hybridization , Oligonucleotides/chemistry , Oligonucleotides/genetics , Protein Engineering , Protein Subunits/chemistry , Protein Subunits/metabolism , Tetrahydrofolate Dehydrogenase/chemistry , Tetrahydrofolate Dehydrogenase/geneticsABSTRACT
A novel modular strategy towards the assembly of DNA-based catalysts containing a covalently anchored metal complex is presented.
