Designing the Optimal Formulation for Biopharmaceuticals: A New Approach Combining Molecular Dynamics and Experiments

Arsiccio, Andrea; Paladini, Andrea; Pattarino, Franco; Pisano, Roberto

doi:10.1016/j.xphs.2018.09.002

Cited by 18 publications

(9 citation statements)

References 60 publications

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“…These for instance include alcohols, amino acids, and organic solvents. Optimization of the quantity of the suitable lyoprotectants, taking into account sample-specific quality attributes, such as isotonicity, rheological features, desired residual water content, and morphology, is often based on the trial-and-error approach, which requires a vast amount of experimental data . Furthermore, according to the opinion of Patel et al the ambiguity in understanding the specific quality attributes of the FD sample challenges the optimization of the freeze-drying process, which is why they should be more properly defined.…”

Section: Introductionmentioning

confidence: 99%

“…Due to the complexity of freeze-drying, there are few studies that explore the process starting from the microscopic aspect by simulating the molecular level interactions between the active component, water, and used lyoprotectants utilizing different in silico models. ,, Understanding the behavior of the used lyoprotectants, such as the conformation and hydrogen bonding ability, could open new opportunities in the designing of formulations for freeze-drying and even in optimizing the desired water content for the biologics. Molecular dynamics (MD) simulations have been suggested as a new approach to explain and predict outcomes of the freeze-drying processes, which could minimize the time and costs compared with the optimization based only on the obtained experimental data.…”

Section: Introductionmentioning

confidence: 99%

“…9,12,17 Understanding the behavior of the used lyoprotectants, such as the conformation and hydrogen bonding ability, could open new opportunities in the designing of formulations for freeze-drying and even in optimizing the desired water content for the biologics. Molecular dynamics (MD) simulations have been suggested as a new approach to explain and predict outcomes of the freeze-drying processes, 12 which could minimize the time and costs compared with the optimization based only on the obtained experimental data.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Insights on Successful Reconstitution of Freeze-Dried Nanofibrillated Cellulose Hydrogel

Koivunotko

Merivaara

Niemelä

et al. 2021

ACS Appl. Bio Mater.

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The diversity and safety of nanofibrillated cellulose (NFC) hydrogels have gained a vast amount of interest at the pharmaceutical site in recent years. Moreover, this biomaterial has a high potential to be utilized as a protective matrix during the freeze-drying of heat-sensitive pharmaceuticals and biologics to increase their properties for long-term storing at room temperature and transportation. Since freeze-drying and subsequent reconstitution have not been optimized for this biomaterial, we must find a wider understanding of the process itself as well as the molecular level interactions between the NFC hydrogel and the most suitable lyoprotectants. Herein we optimized the reconstitution of the freeze-dried NFC hydrogel by considering critical quality attributes required to ensure the success of the process and gained insights of the obtained experimental data by simulating the effects of the used lyoprotectants on water and NFC. We discovered the correlation between the measured characteristics and molecular dynamics simulations and obtained successful freeze-drying and subsequent reconstitution of NFC hydrogel with the presence of 300 mM of sucrose. These findings demonstrated the possibility of using the simulations together with the experimental measurements to obtain a more comprehensive way to design a successful freeze-drying process, which could be utilized in future pharmaceutical applications.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Insights on Successful Reconstitution of Freeze-Dried Nanofibrillated Cellulose Hydrogel

Koivunotko

Merivaara

Niemelä

et al. 2021

ACS Appl. Bio Mater.

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“…In addition, using high-quality excipients with no residual contamination can inhibit protein and excipients degradation as well as subsequent ISR including injection pain. Using molecular dynamics simulation before formulation design has been suggested in a recent study for easier assessment of the interactions between different formulation components ( 145 ). More research is needed towards the development of buffer-free and preservative-free formulations.…”

Section: Discussionmentioning

confidence: 99%

New insight into the importance of formulation variables on parenteral growth hormone preparations: potential effect on the injection-site pain

2022

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Reducing injection-site pain (ISP) in patients with chronic conditions such as growth hormone deficiency is a valuable strategy to improve patient compliance and therapeutic efficiency. Thus understanding different aspects of pain induction following subcutaneous injection of biotherapeutics and identifying the responsible factors are vital. Here we have discussed the effects of formulation’s viscosity, concentration, osmolality, buffering agents, pH, and temperature as well as injection volume, dosing frequency, and different excipients on ISP following subcutaneous injection of commercially available recombinant human growth hormone products. Our literature review found limited available data on the effects of different components of parenteral rhGH products on ISP. This may be due to high cost associated with conducting various clinical trials to assess each excipient in the formulation or to determine the complex interactions of different components and its impact on ISP. Recently, conducting molecular dynamics simulation studies before formulation design has been recommended as an alternative and less-expensive approach. On the other hand, the observed inconsistencies in the available data is mainly due to different pain measurement approaches used in each study. Moreover, it is difficult to translate data obtained from animal studies to human subjects. Despite all these limitations, our investigation showed that components of parenteral rhGH products can significantly contribute to ISP. We suggest further investigation is required for development of long acting, buffer-free, preservative-free formulations. Besides, various excipients are currently being investigated for reducing ISP which can be used as alternatives for common buffers, surfactants or preservatives in designing future rhGH formulations.

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“…The β-parameter , profile was computed starting from the rdf for all those systems containing excipients and/or TBA, i.e., all the simulations type #2–5. The β-parameter profile is defined as, β ( r ) = n Solute ( r ) / n Solvent ( r ) n Solute ( ∞ ) / n Solvent ( ∞ ) where n solute ( r ) and n solvent ( r ) represent, respectively, the number of solute (excipients/TBA) or solvent (water) molecules at distance r from the protein’s surface, while n solute ( ∞ ) and n solvent ( ∞ ) refer to the number of solute and solvent molecules in the system.…”

Section: Methodsmentioning

confidence: 99%

Mechanistic Investigation of tert-Butanol’s Impact on Biopharmaceutical Formulations: When Experiments Meet Molecular Dynamics

Rospiccio,

Casucci,

Arsiccio

et al. 2023

Mol. Pharmaceutics

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The use of tert-butyl alcohol for the lyophilization of pharmaceuticals has seen an uptick over the past years. Its advantages include increased solubility of hydrophobic drugs, enhanced product stability, shorter reconstitution time, and decreased processing time. While the mechanisms of protein stabilization exerted by cryo-and lyo-protectants are well known when water is the solvent of choice, little is known for organic solvents. This work investigates the interactions between two model proteins, namely, lactate dehydrogenase and myoglobin, and various excipients (mannitol, sucrose, 2-hydroxypropyl-β-cyclodextrin and Tween 80) in the presence of tert-butyl alcohol. We thermally characterized mixtures of these components by differential scanning calorimetry and freeze-drying microscopy. We also spectroscopically evaluated the protein recovery after freezing and freeze-drying. We additionally performed molecular dynamics simulations to elucidate the interactions in ternary mixtures of the herein-investigated excipients, tert-butyl alcohol and the proteins. Both experiments and simulations revealed that tert-butyl alcohol had a detrimental impact on the recovery of the two investigated proteins, and no combination of excipients yielded a satisfactory recovery when the organic solvent was present within the formulation. Simulations suggested that the denaturing effect of tert-butyl alcohol was related to its propensity to accumulate in the proximity of the peptide surface, especially near positively charged residues.

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Designing the Optimal Formulation for Biopharmaceuticals: A New Approach Combining Molecular Dynamics and Experiments

Cited by 18 publications

References 60 publications

Molecular Insights on Successful Reconstitution of Freeze-Dried Nanofibrillated Cellulose Hydrogel

Molecular Insights on Successful Reconstitution of Freeze-Dried Nanofibrillated Cellulose Hydrogel

New insight into the importance of formulation variables on parenteral growth hormone preparations: potential effect on the injection-site pain

Mechanistic Investigation of tert-Butanol’s Impact on Biopharmaceutical Formulations: When Experiments Meet Molecular Dynamics

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