Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles

Zee, Nicholas J. Van; Lodge, Timothy P.

doi:10.1021/acsabm.0c01173

Cited by 11 publications

(17 citation statements)

References 47 publications

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“…Common classes of linear polymers used as excipients are cellulose-based, , polyvinylpyrrolidones, , poly(ethylene oxide), and poly(acrylic acid) . Many have been well studied with respect to the micro- and nanoscale interactions with APIs during dissolution. − However, the exploration of these important materials has been limited in the chemical and architectural scope. This has hindered the development of effective excipient–API pairs and, hence, the performance and commercialization of numerous important drug candidates.…”

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confidence: 99%

“…This has been attributed to the balancing of three synergistic effects: ( i ) inhibition of crystallization by NIPAm repeat units, ( ii ) enhanced solubility imparted by the DMA at the optimal ratio of 65:35 NIPAm:DMA, and ( iii ) formation of nanoaggregates that host the drug during dissolution . Tactics to further increase excipient efficacy generally rely on improving the rate of dissolution, self-assembly, and colloidal stability of drug-rich nanoparticles, which form during the dissolution process . Previous work increased the strength of polymer–API noncovalent interactions with such polyacrylamide copolymers by increasing the density of polymer chains within a defined volume such as the corona of block copolymer micelles or using nanogel architectures.…”

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confidence: 99%

“…41 Tactics to further increase excipient efficacy generally rely on improving the rate of dissolution, self- assembly, and colloidal stability of drug-rich nanoparticles, which form during the dissolution process. 16 Previous work increased the strength of polymer−API noncovalent interactions with such polyacrylamide copolymers by increasing the density of polymer chains within a defined volume such as the corona of block copolymer micelles 43 or using nanogel 44 architectures. Bottlebrush polymers offer a robust design space, decoupling the variables of polymer chain chemistry, density, and end-group functionality from the typical constraints of micelle self-assembly, as a synthetically tunable macromolecular scaffold.…”

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Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness

et al. 2021

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Bottlebrush polymers have great potential as vehicles to noncovalently sequester, stabilize, and deliver hydrophobic small molecule actives. To this end, we synthesized a poly(Nisopropylacrylamide-stat-N,N-dimethylacrylamide) bottlebrush copolymer using ring-opening metathesis polymerization and developed a facile method to control the thermoresponsive properties using postpolymerization modification. Six increasingly hydrophilic end-groups were installed, yielding cloud point temperature control over a range of 22−42 °C. Solubility enhancement of the antiseizure medication, phenytoin, increased significantly with the hydrophilicity of the end-group moiety. Notably, carboxylated bottlebrush copolymers solubilized formulations with higher drug loadings than linear copolymers because they exist as unimolecular nanoparticles with a synthetically defined density of polymer chains that are more stable in solution. This work provides the first investigation of bottlebrush polymers for hydrophobic noncovalent sequestration and solubilization of pharmaceuticals.

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Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness

et al. 2021

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“…In recent years, many efforts have been made to stabilize amorphous drug nanoparticles formed from liquid–liquid or glass–liquid phase separation − as it is a potential approach to obtain amorphous drug nanoparticles. However, due to a lack of knowledge about the destabilization process, stable amorphous drug nanoparticles have not been successfully obtained by design yet.…”

Section: Resultsmentioning

confidence: 99%

Transition from Amorphous Cyclosporin A Nanoparticles to Size-Reduced Stable Nanocrystals in a Poloxamer 407 Solution

et al. 2021

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Amorphous drug nanoparticles usually exhibit low storage stability. A comprehensive understanding of the molecular states and physicochemical properties of the product is indispensable for designing stable formulations. In the present study, an amorphous cyclosporin A (CyA) nanosuspension with a mean particle size of approximately 370 nm was prepared by wet bead milling with poloxamer 407 (P407). Interestingly, the prepared amorphous CyA nanoparticles were transformed into uniform CyA nanocrystals with a reduced mean particle size of approximately 200 nm during storage at 25 °C. The CyA nanocrystals were stably maintained for at least 1 month. The particle morphologies and molecular structures of the CyA nanosuspensions before and after storage were thoroughly characterized by cryogenic transmission electron microscopy and magic-angle spinning nuclear magnetic resonance spectroscopy, respectively. They revealed that the freshly prepared amorphous CyA nanoparticles (∼370 nm) were secondary particles composed of aggregated primary particles with an estimated size of 50 nm. A portion of P407 was found to be entrapped at the gaps between the primary particles due to aggregation, while most of P407 was dissolved in the solution either adsorbing at the solid/liquid interface or forming polymeric micelles. The entrapped P407 is considered to play an important role in the destabilization of the amorphous CyA nanoparticles. The resultant CyA nanocrystals (∼200 nm) were uniform single crystals of Form 2 hydrate and showed corner-truncated bipyramidal features. Owing to the narrow particle size distribution of the CyA nanocrystals, the rate of Ostwald ripening was slow, giving long-term stability to the CyA nanocrystals. This study provides new insights into the destabilization mechanism of amorphous drug nanoparticles.

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“…While this instability is beneficial due to the increased dissolution rate, relative ASD instability incurs a practical challenge of crystallization out of the amorphous state during shelf life [ 24 ]. An ideal ASD must strike a delicate balance between sufficient API saturation within the carrier and recrystallization [ 25 ]. Predicting the stability and miscibility of a given API within a carrier and the resulting solubility and dissolution rate of the mixture ( Figure 1 B) is of paramount importance to guide pharmaceutical formulation and production decisions.…”

Section: Introductionmentioning

confidence: 99%

Molecular Simulation and Statistical Learning Methods toward Predicting Drug–Polymer Amorphous Solid Dispersion Miscibility, Stability, and Formulation Design

Walden¹,

Bundey²,

Jagarapu³

et al. 2021

Molecules

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Amorphous solid dispersions (ASDs) have emerged as widespread formulations for drug delivery of poorly soluble active pharmaceutical ingredients (APIs). Predicting the API solubility with various carriers in the API–carrier mixture and the principal API–carrier non-bonding interactions are critical factors for rational drug development and formulation decisions. Experimental determination of these interactions, solubility, and dissolution mechanisms is time-consuming, costly, and reliant on trial and error. To that end, molecular modeling has been applied to simulate ASD properties and mechanisms. Quantum mechanical methods elucidate the strength of API–carrier non-bonding interactions, while molecular dynamics simulations model and predict ASD physical stability, solubility, and dissolution mechanisms. Statistical learning models have been recently applied to the prediction of a variety of drug formulation properties and show immense potential for continued application in the understanding and prediction of ASD solubility. Continued theoretical progress and computational applications will accelerate lead compound development before clinical trials. This article reviews in silico research for the rational formulation design of low-solubility drugs. Pertinent theoretical groundwork is presented, modeling applications and limitations are discussed, and the prospective clinical benefits of accelerated ASD formulation are envisioned.

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Role of Polymer Excipients in the Kinetic Stabilization of Drug-Rich Nanoparticles

Cited by 11 publications

References 47 publications

Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness

Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness

Transition from Amorphous Cyclosporin A Nanoparticles to Size-Reduced Stable Nanocrystals in a Poloxamer 407 Solution

Molecular Simulation and Statistical Learning Methods toward Predicting Drug–Polymer Amorphous Solid Dispersion Miscibility, Stability, and Formulation Design

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