Excipient Innovation Through Precompetitive Research

Yu, Yinan; Taraban, Marc B.; Briggs, Katharine T.; Brinson, Robert G.; Marino, John P.

doi:10.1007/s11095-021-03157-y

Cited by 7 publications

(6 citation statements)

References 10 publications

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“…In general, quantitative NMR analysis often relies on some linearity between an NMR parameter and the solute amount. 23,24 As we have shown previously, 14,25 in the absence of aggregation, R 2 ( 1 H 2 O) shows a linear dependence on the concentration of a solute. In the presence of aggregates, the concentration dependence of R 2 ( 1 H 2 O) deviates from linearity.…”

mentioning

confidence: 54%

“…Indeed, under conditions of controlled stress, such as heat-induced protein aggregation at fixed temperature but with variable exposure time, one might observe a fairly linear dependence of Z-average R h on the percentage content of protein aggregates. 14,15 In our previous paper, 16 we demonstrated that the water proton transverse relaxation rate R 2 ( 1 H 2 O) could be used to detect the presence of monoclonal antibody (mAb) aggregates generated by different stresses. Compared to SEC, MFI, and DLS, the water proton NMR (wNMR) approach was consistently sensitive to changes in protein aggregate populations, both soluble and insoluble aggregates and subvisible particles.…”

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confidence: 99%

“…However, wNMR could perform an analysis in a sealed vial and could be successfully used as a noninvasive and nondestructive tool for simple and fast quantitative analysis of protein aggregates within a wide size range. 14,16 On the other hand, solute NMR, which is capable of providing detailed structural data on a protein, is invasive, requiring transferring protein solutions into NMR tubes and often involving 13 C-and 15 N-enrichments, prolonged 2D-and 3D-NMR data collection, 17 enzymatic digestion of the sample, and complex principal component analysis (PCA). 18 However, not all advanced high-field NMR techniques used to study protein dynamics are necessarily based on the complex solution structure analysis.…”

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confidence: 99%

“…In the presence of aggregates, the concentration dependence of R 2 ( 1 H 2 O) deviates from linearity. 14 This suggests that R 2 ( 1 H 2 O) cannot disentangle the effects of changes in the protein concentration and the formation of the protein aggregates. 26 Therefore, to monitor aggregation effects on R 2 ( 1 H 2 O), total protein concentration should be kept constant.…”

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confidence: 99%

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Use of Water Proton NMR to Characterize Protein Aggregates: Gauging the Response and Sensitivity

Taraban

DePaz²,

Lobo³

et al. 2019

Anal. Chem.

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Water proton transverse relaxation rate R 2(1H2O) measurements by NMR stand out as a powerful noninvasive tool to detect protein aggregates, including subvisible particles in biopharmaceutical formulations. To understand the applicability of water proton NMR (wNMR), we studied the response and sensitivity of wNMR to the aggregates of a monoclonal antibody (mAb) within a wide size range at different aggregate levels, for three different physical stresses: freeze–thaw cycling, heating, and agitation. We compared the sensitivity and response of wNMR with those observed by conventional techniques of size exclusion chromatography (SEC), microflow imaging (MFI), and dynamic light scattering (DLS). Our findings showed that wNMR detects mAb aggregates within wide aggregate levels and in a wide range of aggregate sizes. wNMR was sensitive to an increase in soluble protein aggregates in the range of <1.0%. In most cases, wNMR demonstrated linear response toward the aggregate fraction. Nonlinearity of such response potentially points to the presence of larger size aggregates that possibly rearrange and/or dissociate upon dilution. The results demonstrate the potential of wNMR as a quantitative and noninvasive analytical tool for characterizing protein aggregates in biopharmaceutical formulations.

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confidence: 54%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Use of Water Proton NMR to Characterize Protein Aggregates: Gauging the Response and Sensitivity

Taraban

DePaz²,

Lobo³

et al. 2019

Anal. Chem.

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“…153 In addition, the transport and distribution of many biological therapies requires what is termed the 'cold-chain', that is they must remain refrigerated or frozen during each step of the physical delivery process, from the manufacturing location to the clinical administration site. 154 This can be particularly problematic when considering restrictions associated with therapeutic distribution in low-and middle-income countries, as highlighted by the recent and on-going distribution of vaccines for COVID-19. 155 Finally, storage and shelf life are also a major consideration for all therapeutic agents developed.…”

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confidence: 99%

Advancements in antimicrobial nanoscale materials and self-assembling systems

et al. 2022

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Deep Eutectic Solvents for Subcutaneous Delivery of Protein Therapeutics

et al. 2023

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Proteins are among the most common therapeutics for the treatment of diabetes, autoimmune diseases, cancer, and metabolic diseases, among others. Despite their common use, current protein therapies, most of which are injectables, have several limitations. Large proteins such as monoclonal antibodies (mAbs) suffer from poor absorption after subcutaneous injections, thus forcing their administration by intravenous injections. Even small proteins such as insulin suffer from slow pharmacokinetics which poses limitations in effective management of diabetes. Here, a deep eutectic‐based delivery strategy is used to offer a generalized approach for improving protein absorption after subcutaneous injections. The lead formulation enhances absorption of mAbs after subcutaneous injections by ≈200%. The same composition also improves systemic absorption of subcutaneously injected insulin faster than Humalog, the current gold‐standard of rapid acting insulin. Mechanistic studies reveal that the beneficial effect of deep eutectics on subcutaneous absorption is mediated by their ability to reduce the interactions of proteins with the subcutaneous matrix, especially collagen. Studies also confirm that these deep eutectics are safe for subcutaneous injections. Deep eutectic‐based formulations described here open new possibilities for subcutaneous injections of therapeutic proteins.

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Excipient Innovation Through Precompetitive Research

Cited by 7 publications

References 10 publications

Use of Water Proton NMR to Characterize Protein Aggregates: Gauging the Response and Sensitivity

Use of Water Proton NMR to Characterize Protein Aggregates: Gauging the Response and Sensitivity

Advancements in antimicrobial nanoscale materials and self-assembling systems

Deep Eutectic Solvents for Subcutaneous Delivery of Protein Therapeutics

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