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Browsing by Subject "formulation"

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  • Oral age-appropriate dosage forms used in pediatric randomized clinical trials : a systematic review 
    Vironen, Aleksi (2021)
    Evidence based medicines alongside with age-appropriate dosage forms are essential in enabling appropriate treatment for any patient group. Pediatric pharmacotherapy, however, is lacking age-appropriate dosage forms and research-based evidence regarding the dosing, efficacy, and safety of medicines. Orally administered drugs require manipulation to enable administration and are often used against the indications approved in the marketing authorization and summary of product characteristics (SmPC). This off-label use puts pediatric patients at risk for medicational errors and adverse drug reactions. The aim of this study was to investigate recent trends in oral dosage forms used in pediatric randomized controlled trials (RCTs), with emphasis on age appropriateness. The results could be utilized in developing evidence-based dosage forms, suitable for all pediatric patients aged 0-17 years, and manufacturable in a small scale in a hospital pharmacy. This study was conducted as a systematic review following the PRISMA Statement. The literature search was carried out from Pubmed and Scopus databases and it covered a five-year period of 2015-2020. References from the databases were entered to the Covidence systematic review platform. After removing duplicates 3333 articles were left for screening. Two independent researchers selected the articles first screening by title and abstract, and then by full text review. A qualitative content analysis was conducted on the included articles. Altogether 77 articles met the inclusion criteria. Dosage forms included were tablets (n=37), liquids (n=21), capsules (n=18) and multiparticulates (n=6). Majority of the dosage forms were conventional (n=49) compared to more advanced novel modified release and fixed-dose combination formulations (n=33). Based on our results, orally administered dosage forms used in the recent pediatric RCTs are still limited by poor acceptability, palatability, and the need to manipulate dosage forms to enable administration. These issues are similar to the ones related to the off-label use of medicine that compromise patient safety. Majority of the dosage forms included in our study were tablets, indicating a positive shift towards more safe and acceptable dosage form. Formulations were also evolving towards dispersible, extended-release and fixed-dose combinations that offer additional benefits for pediatric patients. The low number of children < 2 years old included in study populations and the poor acceptability profile reported by most studies limit our conclusions on an ideal age-appropriate dosage form. Further research is needed on unifying the guidelines used in pediatric drug development.
  • Protein aggregation (literature review) : Soluble expression of human Ciliary neurotrophic factor in Escherichia coli (experimental work) 
    Itkonen, Jaakko (2014)
    Proteins are endogenous molecules that carry out most biological functions in vivo. They are called as the biological workhorses. Proteins are made up of polypeptide chains that usually fold in the three dimensional space to adopt a native stable conformation. Stability of proteins is dependent on the interplay of environmental factors (pH, temperature, ionic strength). For most proteins, the biological function closely relates to the structural attributes of the protein. Misfolding or unfolding of proteins often result in aggregation. Protein aggregation in vivo is known to cause debilitating and fatal diseases such as Alzheimer's, Huntington's, Parkinson's and age related macular degeneration (AMD). Instability (physical and chemical) of proteins in vitro is believed to result in aggregation. This is a huge concern for the biopharmaceutical industry as it not only limits the effectiveness of the manufacturing process but also poses a great risk of fatality in vivo due to the immunogenic nature of the aggregates. Mechanisms of protein aggregation are complex and not well understood. Regulatory requirements for patient safety in biopharmaceutical products require characterization and analysis of aggregates in protein drug formulations. This review provides an overview of protein aggregation in general and highlights the different analytical methods used to characterize protein aggregates in biopharmaceuticals. Neurotrophic factors influence survival, differentiation, proliferation and death of neuronal cells within the central nervous system. Human ciliary neurotrophic factor (hCNTF) has neuroprotective properties and is also known to influence energy balance. Consequently, hCNTF has potential therapeutic applications in neurodegenerative, obesity and diabetes related disorders. Clinical and biological applications of CNTF necessitate a recombinant expression system to produce large amounts of functional protein. Previous studies have reported that recombinant expression of CNTF in Escherichia coli (E. coli) was limited by low yields and the need to refold the protein from inclusion bodies. In this report, we describe a strategy to effectively screen fusion constructs and expression conditions for soluble hCNTF production in E. coli. Most conditions tested with the codon optimized hCNTF sequence in fusion with soluble tags resulted in soluble expression of the protein. The construct 6-His-CNTF showed soluble expression in all the conditions tested. Our results suggest that codon optimization of the hCNTF sequence is sufficient for soluble expression in E. coli. The recombinant hCNTF was found to bind to CNTFRα with an EC50 = 36 nM.

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