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Pharmaceutics
Special Issues
Developing Peptide and Protein Drug Formulations
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Developing Peptide and Protein Drug Formulations

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 14997

Special Issue Editors

Prof. Dr. Hristo Svilenov

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Guest Editor
Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
Interests: protein formulation; protein drugs; peptide drugs
Prof. Dr. Pernille Harris

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Guest Editor
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark
Interests: protein protein interactions; protein structure

Special Issue Information

Dear Colleagues,

We are delighted to announce the preparation of a Special Issue on the development of peptide and protein drug formulations.

The formulation development is what transforms a biologically active peptide or a protein into a stable and safe biotherapeutic. However, selecting the right formulation for a new protein is not an easy task. A sound formulation development strategy is based on extensive knowledge about the physicochemical stability of different peptides and proteins combined with cutting-edge analytical methods to assay the stability of the active biomolecules in different formulations.

The aim of this Special Issue is to collect articles focusing on the latest trends and outstanding challenges related to the formulation development of therapeutic peptides and proteins. Both original research articles and reviews are welcome. The core research areas are (i) studies on the formulation development of proteinaceous molecules with therapeutic relevance, (ii) mechanistic insights into the stability of peptides and proteins, and (iii) novel analytical approaches with application to peptide and protein drugs.

We look forward to receiving your contributions.

Prof. Dr. Hristo Svilenov
Prof. Dr. Pernille Harris
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein drugs
  • peptide drugs
  • formulation development
  • physicochemical properties
  • analytical methods
  • biotherapeutics

Published Papers (4 papers)

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Research

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22 pages, 10879 KiB  
Article
Combining Molecular Dynamics Simulations and Biophysical Characterization to Investigate Protein-Specific Excipient Effects on Reteplase during Freeze Drying
by Suk Kyu Ko, Gabriella Björkengren, Carolin Berner, Gerhard Winter, Pernille Harris and Günther H. J. Peters
Pharmaceutics 2023, 15(7), 1854; https://doi.org/10.3390/pharmaceutics15071854 - 30 Jun 2023
Viewed by 1402
Abstract
We performed molecular dynamics simulations of Reteplase in the presence of different excipients to study the stabilizing mechanisms and to identify the role of excipients during freeze drying. To simulate the freeze-drying process, we divided the process into five distinct steps: (i) protein–excipient [...] Read more.
We performed molecular dynamics simulations of Reteplase in the presence of different excipients to study the stabilizing mechanisms and to identify the role of excipients during freeze drying. To simulate the freeze-drying process, we divided the process into five distinct steps: (i) protein–excipient formulations at room temperature, (ii) the ice-growth process, (iii)–(iv) the partially solvated and fully dried formulations, and (v) the reconstitution. Furthermore, coarse-grained (CG) simulations were employed to explore the protein-aggregation process in the presence of arginine. By using a coarse-grained representation, we could observe the collective behavior and interactions between protein molecules during the aggregation process. The CG simulations revealed that the presence of arginine prevented intermolecular interactions of the catalytic domain of Reteplase, thus reducing the aggregation propensity. This suggests that arginine played a stabilizing role by interacting with protein-specific regions. From the freeze-drying simulations, we could identify several protein-specific events: (i) collapse of the domain structure, (ii) recovery of the drying-induced damages during reconstitution, and (iii) stabilization of the local aggregation-prone region via direct interactions with excipients. Complementary to the simulations, we employed nanoDSF, size-exclusion chromatography, and CD spectroscopy to investigate the effect of the freeze-drying process on the protein structure and stability. Full article
(This article belongs to the Special Issue Developing Peptide and Protein Drug Formulations)
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12 pages, 2002 KiB  
Article
Micro-Scale Vacuum Compression Molding as a Predictive Screening Tool of Protein Integrity for Potential Hot-Melt Extrusion Processes
by Katharina Dauer and Karl G. Wagner
Pharmaceutics 2023, 15(3), 723; https://doi.org/10.3390/pharmaceutics15030723 - 22 Feb 2023
Viewed by 2161
Abstract
Hot-melt extrusion (HME) is used for the production of solid protein formulations mainly for two reasons: increased protein stability in solid state and/or long-term release systems (e.g., protein-loaded implants). However, HME requires considerable amounts of material even at small-scale (>2 g batch size). [...] Read more.
Hot-melt extrusion (HME) is used for the production of solid protein formulations mainly for two reasons: increased protein stability in solid state and/or long-term release systems (e.g., protein-loaded implants). However, HME requires considerable amounts of material even at small-scale (>2 g batch size). In this study, we introduced vacuum compression molding (VCM) as a predictive screening tool of protein stability for potential HME processing. The focus was to identify appropriate polymeric matrices prior to extrusion and evaluation of protein stability after thermal stress using only a few milligrams of protein. The protein stability of lysozyme, BSA, and human insulin embedded in PEG 20,000, PLGA, or EVA by VCM was investigated by DSC, FT-IR, and SEC. The results from the protein-loaded discs provided important insights into the solid-state stabilizing mechanisms of protein candidates. We demonstrated the successful application of VCM for a set of proteins and polymers, showing, in particular, a high potential for EVA as a polymeric matrix for solid-state stabilization of proteins and the production of extended-release dosage forms. Stable protein-polymer mixtures with sufficient protein stability after VCM could be then introduced to a combination of thermal and shear stress by HME and further investigated with regard to their process-related protein stability. Full article
(This article belongs to the Special Issue Developing Peptide and Protein Drug Formulations)
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16 pages, 4295 KiB  
Article
Computational and Experimental Evaluation of the Stability of a GLP-1-like Peptide in Ethanol–Water Mixtures
by Lok Hin Lui, Raphael Egbu, Thomas Graver, Gareth R. Williams, Steve Brocchini and Ajoy Velayudhan
Pharmaceutics 2022, 14(7), 1462; https://doi.org/10.3390/pharmaceutics14071462 - 14 Jul 2022
Viewed by 2736
Abstract
Aggregation resulting from the self-association of peptide molecules remains a major challenge during preformulation. Whereas certain organic solvents are known to promote aggregation, ethanol (EtOH) is capable of disrupting interactions between peptide molecules. It is unclear whether it is beneficial or counterproductive to [...] Read more.
Aggregation resulting from the self-association of peptide molecules remains a major challenge during preformulation. Whereas certain organic solvents are known to promote aggregation, ethanol (EtOH) is capable of disrupting interactions between peptide molecules. It is unclear whether it is beneficial or counterproductive to include EtOH in formulations of short peptides. Here, we employed molecular dynamics simulations using the DAFT protocol and MARTINI force field to predict the formation of self-associated dimers and to estimate the stability of a GLP-1-like peptide (G48) in 0–80% aqueous EtOH solutions. Both simulation and experimental data reveal that EtOH leads to a remarkable increase in the conformational stability of the peptide when stored over 15 days at 27 °C. In the absence of EtOH, dimerisation and subsequent loss in conformational stability (α-helix → random coil) were observed. EtOH improved conformational stability by reducing peptide–peptide interactions. The data suggest that a more nuanced approach may be applied in formulation decision making and, if the native state of the peptide is an α-helix organic solvent, such as EtOH, may enhance stability and improve prospects of long-term storage. Full article
(This article belongs to the Special Issue Developing Peptide and Protein Drug Formulations)
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Review

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52 pages, 2030 KiB  
Review
Alternative Excipients for Protein Stabilization in Protein Therapeutics: Overcoming the Limitations of Polysorbates
by Angel J. Castañeda Ruiz, Maryam A. Shetab Boushehri, Tamara Phan, Stefan Carle, Patrick Garidel, Julia Buske and Alf Lamprecht
Pharmaceutics 2022, 14(12), 2575; https://doi.org/10.3390/pharmaceutics14122575 - 23 Nov 2022
Cited by 15 | Viewed by 6881
Abstract
Given their safety and efficiency in protecting protein integrity, polysorbates (PSs) have been the most widely used excipients for the stabilization of protein therapeutics for years. In recent decades, however, there have been numerous reports about visible or sub-visible particles in PS-containing biotherapeutic [...] Read more.
Given their safety and efficiency in protecting protein integrity, polysorbates (PSs) have been the most widely used excipients for the stabilization of protein therapeutics for years. In recent decades, however, there have been numerous reports about visible or sub-visible particles in PS-containing biotherapeutic products, which is a major quality concern for parenteral drugs. Alternative excipients that are safe for parenteral administration, efficient in protecting different protein drugs against various stress conditions, effective in protein stabilization in high-concentrated liquid formulations, stable under the storage conditions for the duration of the product’s shelf-life, and compatible with other formulation components and the primary packaging are highly sought after. The aim of this paper is to review potential alternative excipients from different families, including surfactants, carbohydrate- and amino acid-based excipients, synthetic amphiphilic polymers, and ionic liquids that enable protein stabilization. For each category, important characteristics such as the ability to stabilize proteins against thermal and mechanical stresses, current knowledge related to the safety profile for parenteral administration, potential interactions with other formulation components, and primary packaging are debated. Based on the provided information and the detailed discussion thereof, this paper may pave the way for the identification or development of efficient excipients for biotherapeutic protein stabilization. Full article
(This article belongs to the Special Issue Developing Peptide and Protein Drug Formulations)
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