Abstract
Oxytocin, a cyclic nine amino acid neurohypophyseal hormone therapeutic, is effectively used in the control of postpartum hemorrhaging (PPH) and is on the WHO List of Essential Medicines. However, oxytocin has limited shelf life stability in aqueous solutions, particularly at temperatures in excess of 25 °C and injectable aqueous oxytocin formulations require refrigeration (<8 °C). This is particularly problematic in the hot climates often found in many developing countries where daytime temperatures can exceed 40 °C and where reliable cold-chain storage is not always achievable. The purpose of this study was to develop N-terminal amine targeted PEGylation strategies utilizing both linear PEG and polyPEG "comb" polymers as an effective method for stabilizing solution formulations of this peptide for prolonged storage in the absence of efficient cold-chain storage. The conjugation chemistries investigated herein include irreversible amine targeted conjugation methods utilizing NHS ester and aldehyde reductive amination chemistry. Additionally, one reversible conjugation method using a Schiff base approach was explored to allow for the release of the native peptide, thus, ensuring that biological activity remains unaffected. The reversibility of this approach was investigated for the different polymer architectures, alongside a nonpolymer oxytocin analogue to monitor how pH can tune native peptide release. Elevated temperature degradation studies of the polymer conjugates were evaluated to assess the stability of the PEGylated analogues in comparison to the native peptide in aqueous formulations to mimic storage conditions in developing nations and regions where storage under appropriate conditions is challenging.
Highlights
There is an unacceptably large difference in the death of mothers during child birth between the developed and developing world
N-Succinimidyl 2-bromo-2methylpropionate was synthesized in one step by reacting Nhydroxysuccinimide with 2-bromoisobutyryl bromide in a high yield with little purification required.[79]
As degradation remained very low with oxytocin-conjugate recoveries remaining around 100%. These results prove very promising in showing that the conjugation of poly(ethylene glycol) (PEG) onto oxytocin via the N-terminal amine can prove beneficial for reducing degradation and extending shelf life stability at high temperatures
Summary
There is an unacceptably large difference in the death of mothers during child birth between the developed and developing world. Maternal mortality in developing regions is still 14× higher than in the developed regions. Since 1990, worldwide maternal mortality rates have improved; rates are still unacceptably high in developing nations that will account for 99% of the maternal deaths that occur in 2016. Postpartum hemorrhaging (PPH) is one such complication, manifesting as excessive and uncontrolled bleeding due to insufficient contraction of the uterus after delivery. It is understood that in developing countries, where home births are common and access to well-resourced health care facilities and professionals are limited, that obstetric hemorrhage continues to be a leading cause of maternal deaths and, sadly, a conservative estimate is that over 140000 women per year die needlessly of complications arising from PPH
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