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1.
J Pharm Sci ; 111(3): 608-617, 2022 03.
Article in English | MEDLINE | ID: mdl-34530002

ABSTRACT

Biopharmaceuticals for human use present unique challenges during manufacturing, storage, shipment, and administration. Not all drug product process development aspects can and should be studied in detail before entering in first-in human studies (FIH) due to limited resources and the need for new drug candidates to enter phase I clinical studies quickly. Whilst activities for formulation development studies are well defined in literature, there is a lack of regulatory guidance for phase appropriate process development studies for clinical supplies. This review summarizes potential process development studies for liquid protein formulations and proposes a phase appropriate testing approach.


Subject(s)
Proteins , Humans , Pharmaceutical Preparations , Proteins/therapeutic use
2.
Int J Pharm ; 495(1): 608-611, 2015 Nov 10.
Article in English | MEDLINE | ID: mdl-26387618

ABSTRACT

A comparison of lyophilized PEGylated and HESylated IFNα was carried out to investigate the influence of protein conjugation, lyoprotectants as well as storage temperature on protein stability. Results show that PEG tends to crystallize during freeze-drying, reducing protein stability upon storage. In contrast, HESylation(®) drastically improved the stability over PEGylation by remaining totally amorphous during lyophilization, with and without lyoprotectants while providing a high glass transition temperature of the freeze-dried cakes.


Subject(s)
Freeze Drying , Hydroxyethyl Starch Derivatives/chemistry , Interferon-alpha/chemistry , Polyethylene Glycols/chemistry , Protein Stability , Calorimetry, Differential Scanning , Crystallization , Drug Stability , Drug Storage , Interferon alpha-2 , Recombinant Proteins/chemistry , Temperature , Transition Temperature
3.
J Pharm Sci ; 104(2): 515-26, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25445200

ABSTRACT

Although PEGylation of biologics is currently the gold standard for half-life extension, the technology has a number of limitations, most importantly the non-biodegradability of PEG and the extremely high viscosity at high concentrations. HESylation is a promising alternative based on coupling to the biodegradable polymer hydroxyethyl starch (HES). In this study, we are comparing HESylation with PEGylation regarding the effect on the protein's physicochemical properties, as well as on formulation at high concentrations, where protein stability and viscosity can be compromised. For this purpose, the model protein anakinra is coupled to HES or PEG by reductive amination. Results show that coupling of HES or PEG had practically no effect on the protein's secondary structure, and that it reduced protein affinity by one order of magnitude, with HESylated anakinra more affine than the PEGylated protein. The viscosity of HESylated anakinra at protein concentrations up to 75 mg/mL was approximately 40% lower than that of PEG-anakinra. Both conjugates increased the apparent melting temperature of anakinra in concentrated solutions. Finally, HESylated anakinra was superior to PEG-anakinra regarding monomer recovery after 8 weeks of storage at 40°C. These results show that HESylating anakinra offers formulation advantages compared with PEGylation, especially for concentrated protein solutions.


Subject(s)
Chemistry, Pharmaceutical/methods , Hydroxyethyl Starch Derivatives/chemistry , Interleukin 1 Receptor Antagonist Protein/chemistry , Polyethylene Glycols/chemistry , Protein Stability
4.
Eur J Pharm Biopharm ; 87(2): 378-85, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24681396

ABSTRACT

Half-life extension (HLE) is becoming an essential component of the industrial development of small-sized therapeutic peptides and proteins. HESylation(®) is a HLE technology based on coupling drug molecules to the biodegradable hydroxyethyl starch (HES). In this study, we report on the synthesis, characterization and pharmacokinetics of HESylated anakinra, where anakinra was conjugated to propionaldehyde-HES using reductive amination, leading to a monoHESylated protein. Characterization using size exclusion chromatography and dynamic light scattering confirmed conjugation and the increase in molecular size, while Fourier transform infrared spectroscopy showed that the secondary structure of the conjugate was not affected by coupling. Meanwhile, microcalorimetry and aggregation studies showed a significant increase in protein stability. Surface plasmon resonance and microscale thermophoresis showed that the conjugate retained its nanomolar affinity, and finally, the pharmacokinetics of the HESylated protein exhibited a 6.5-fold increase in the half-life, and a 45-fold increase in the AUC. These results indicate that HESylation(®) is a promising HLE technology.


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Hydroxyethyl Starch Derivatives/chemical synthesis , Hydroxyethyl Starch Derivatives/pharmacokinetics , Interleukin 1 Receptor Antagonist Protein/chemical synthesis , Interleukin 1 Receptor Antagonist Protein/pharmacokinetics , Aldehydes/chemical synthesis , Aldehydes/pharmacokinetics , Amination , Animals , Anti-Inflammatory Agents/administration & dosage , Area Under Curve , Calorimetry , Chemistry, Pharmaceutical , Chromatography, Gel , Half-Life , Hydroxyethyl Starch Derivatives/administration & dosage , Injections, Intravenous , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Light , Male , Molecular Weight , Particle Size , Protein Stability , Protein Structure, Secondary , Rats, Wistar , Scattering, Radiation , Spectroscopy, Fourier Transform Infrared , Surface Plasmon Resonance , Technology, Pharmaceutical/methods
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