Biology subjects

Mann, J. L.

Publications and source records attributed to Mann, J. L..

5 recordsLinked to original sources

bioRxiv2022

Formulation excipients and their role in insulin stability and association state in formulation

While excipients are often overlooked as the "inactive" ingredients in pharmaceutical formulations, they often play a critical role in protein stability and absorption kinetics. Recent work has identified an ultrafast absorbing insulin formulation that is the result of excipient modifications. Specifically, the insulin monomer can be isolated by replacing zinc and the phenolic preservative metacresol with phenoxyethanol as an antimicrobial agent and an amphiphilic acrylamide copolymer excipient for stability. A greater understanding is needed of the interplay between excipients, insulin association state, and stability in order to optimize this formulation. Here, we formulated insulin with different preservatives and stabilizing excipient concentrations using both insulin lispro and regular human insulin and assessed the insulin association states using analytical ultracentrifugation as well as formulation stability. We determined that phenoxyethanol is required to eliminate hexamers and promote a high monomer content even in a zinc-free lispro formulation. There is also a concentration dependent relationship between the concentration of polyacrylamide-based copolymer excipient and insulin stability, where a concentration greater than 0.1 g/mL copolymer is required for a mostly monomeric zinc-free lispro formulation to achieve stability exceeding that of Humalog in a stressed aging assay. Further, we determined that under the formulation conditions tested zinc-free regular human insulin remains primarily hexameric and is not at this time a promising candidate for rapid-acting formulations.

bioengineering↗

bioRxiv2022

Stable High-Concentration Monoclonal Antibody Formulations Enabled by an Amphiphilic Copolymer Excipient

Monoclonal antibodies are a staple in modern pharmacotherapy. Unfortunately, these biopharmaceuticals are limited by their tendency to aggregate in formulation, resulting in poor stability and often requiring low concentration drug formulations. Moreover, existing excipients designed to stabilize these formulations are often limited by their toxicity and tendency to form particles such as micelles. Here, we demonstrate the ability of a simple "drop-in", amphiphilic copolymer excipient to enhance the stability of high concentration formulations of clinically-relevant monoclonal antibodies without altering their pharmacokinetics or injectability. Through interfacial rheology and surface tension measurements, we demonstrate that the copolymer excipient competitively adsorbs to formulation interfaces. Further, through determination of monomeric composition and retained bioactivity through stressed aging, we show that this excipient confers a significant stability benefit to high concentration antibody formulations. Finally, we demonstrate that the excipient behaves as an inactive ingredient, having no significant impact on the pharmacokinetic profile of a clinically relevant antibody in mice. This amphiphilic copolymer excipient demonstrates promise as a simple formulation additive to create stable, high concentration antibody formulations, thereby enabling improved treatment options such as a route-of-administration switch from low concentration intravenous (IV) to high concentration subcutaneous (SC) delivery while reducing dependence on the cold chain.

bioengineering↗

bioRxiv2021

Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies

When properly deployed, the immune system can eliminate deadly pathogens, eradicate metastatic cancers, and provide long-lasting protection from diverse diseases. Unfortunately, realizing these remarkable capabilities is inherently risky as disruption to immune homeostasis can elicit dangerous complications or autoimmune disorders. While current research is continuously expanding the arsenal of potent immunotherapeutics, there is a technological gap when it comes to controlling when, where, and how long these drugs act on the body. Here, we explore the ability of a slow-releasing injectable hydrogel depot to reduce the problematic dose-limiting toxicities of immunostimulatory CD40 agonist (CD40a) while maintaining their potent anti-cancer efficacy. We leverage a previously described polymer-nanoparticle (PNP) hydrogel system that exhibits shear-thinning and yield-stress properties that we hypothesized would improve locoregional delivery of the CD40a immunotherapy. Using PET imaging, we demonstrate that prolonged hydrogel-based delivery redistributes CD40a exposure to the tumor and the tumor draining lymph node (TdLN), thereby reducing weight loss, hepatotoxicity, and cytokine storm associated with standard treatment. Moreover, CD40a-loaded hydrogels mediate improved local cytokine induction in the TdLN and improve treatment efficacy in the B16F10 melanoma model. PNP hydrogels, therefore, represent a facile, drug-agnostic method to ameliorate immune-related adverse effects and explore locoregional delivery of immunostimulatory drugs.

bioengineering↗

bioRxiv2021

Engineering Insulin Cold Chain Resilience to Improve Global Access

There are 150 million people with diabetes worldwide who require insulin replacement therapy and the prevalence of diabetes is rising fastest in middle and low-income countries. Current formulations require costly refrigerated transport and storage to prevent loss of insulin integrity. This study shows the development of simple "drop-in" amphiphilic copolymer excipients to maintain formulation integrity, bioactivity, pharmacokinetics and pharmacodynamics for over 6 months when subjected to severe stressed aging conditions that cause current commercial formulation to fail in under 2 weeks. Further, when these copolymers are added to Humulin R (Eli Lilly) in original commercial packaging they prevent insulin aggregation for up to 4 days at 50 {degrees}C compared to less than 1 day for Humulin R alone. These copolymers demonstrate promise as simple formulation additives to increase the cold chain resilience of commercial insulin formulations, thereby expanding global access to these critical drugs for treatment of diabetes.

bioengineering↗

bioRxiv2021

Ultra-fast insulin-pramlintide co-formulation for improved glucose management in diabetic rats

Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, we use amphiphilic acrylamide copolymers to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 hours under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 hours. The faster pharmacokinetics of monomeric insulin in this co-formulation resulted in increased insulin-pramlintide overlap of 75 {+/-} 6% compared to only 47 {+/-} 7% for separate injections. The co-formulation resulted in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats the co-formulation reduced deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.

bioengineering↗