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Oxytocin is the gold standard drug for the prevention of postpartum haemorrhage, but limitations in cold chain systems in resource-constrained settings can severely compromise the quality of oxytocin product available in these environments. This study investigated the perspectives and practices of stakeholders in low and lower-middle income countries towards oxytocin, its storage requirements and associated barriers, and the quality of product available. Qualitative inquiries were undertaken in Ethiopia, India and Myanmar, where data was collected through Focus Group Discussions (FGDs) and In-Depth Interviews (IDIs). A total of 12 FGDs and 106 IDIs were conducted with 158 healthcare providers (pharmacists, midwives, nurses, doctors and obstetricians) and 40 key informants (supply chain experts, program managers and policy-makers). Direct observations of oxytocin storage practices and cold chain resources were conducted at 51 healthcare facilities. Verbatim transcripts of FGDs and IDIs were translated to English and analysed according to a thematic content analysis framework. Stakeholder awareness of oxytocin heat sensitivity and the requirement for cold storage of the drug was widespread in Ethiopia but more limited in Myanmar and India. A consistent finding across all study regions was the significant barriers to maintaining a consistent cold chain, with the lack of refrigeration facilities and unreliability of electricity cited as major challenges. Perceptions of compromised oxytocin quality were expressed by some stakeholders in each country. Knowledge of the heat sensitivity of oxytocin and the potential impacts of inconsistent cold storage on product quality is not widespread amongst healthcare providers, policy makers and supply chain experts in Myanmar, Ethiopia and India. Targeted training and advocacy messages are warranted to emphasise the importance of cold storage to maintain oxytocin quality.

Background Access to oxytocin for prevention of postpartum haemorrhage (PPH) in resource-poor settings is limited by the requirement for a consistent cold chain and for a skilled attendant to administer the injection. To overcome these barriers, heat-stable, non-injectable formulations of oxytocin are under development, including oxytocin for inhalation. This study modelled the cost-effectiveness of an inhaled oxytocin product (IHO) in Bangladesh and Ethiopia. Methods A decision analytic model was developed to assess the cost-effectiveness of IHO for the prevention of PPH compared to the standard of care in Bangladesh and Ethiopia. In Bangladesh, introduction of IHO was modelled in all public facilities and home deliveries with or without a skilled attendant. In Ethiopia, IHO was modelled in all public facilities and home deliveries with health extension workers. Costs (costs of introduction, PPH prevention and PPH treatment) and effects (PPH cases averted, deaths averted) were modelled over a 12-month program. Life years gained were modelled over a lifetime horizon (discounted at 3%). Cost of maintaining the cold chain or effects of compromised oxytocin quality (in the absence of a cold chain) were not modelled. Results In Bangladesh, IHO was estimated to avert 18,644 cases of PPH, 76 maternal deaths and 1954 maternal life years lost. This also yielded a cost-saving, with the majority of gains occurring among home deliveries where IHO would replace misoprostol. In Ethiopia, IHO averted 3111 PPH cases, 30 maternal deaths and 767 maternal life years lost. The full IHO introduction program bears an incremental cost-effectiveness ratio (ICER) of between 2 and 3 times the per-capita Gross Domestic Product (GDP) ($1880 USD per maternal life year lost) and thus is unlikely to be considered cost-effective in Ethiopia. However, the ICER of routine IHO administration considering recurring cost alone falls under 25% of per-capita GDP ($175 USD per maternal life-year saved). Conclusions IHO has the potential to expand access to uterotonics and reduce PPH-associated morbidity and mortality in high burden settings. This can facilitate reduced spending on PPH management, making the product highly cost-effective in settings where coverage of institutional delivery is lagging.

Background The use of quality injectable oxytocin effectively prevents and treats postpartum hemorrhage, the leading cause of maternal death worldwide. In low- and middle-income countries (LMICs), characteristics of oxytocin—specifically its heat sensitivity—challenge efforts to ensure its quality throughout the health supply chain. In 2019, WHO, UNFPA and UNICEF released a joint-statement to clarify and recommend that oxytocin should be kept in the cold chain (between 2 and 8 °C) during transportation and storage; however, confusion among stakeholders in LMICs persists. Objectives and methods To further support recommendations in the WHO/UNFPA/UNICEF joint-statement, this paper reviews results of oxytocin quality testing in LMICs, evaluates product stability considerations for its management and considers quality risks for oxytocin injection throughout the health supply chain. This paper concludes with a set of recommended actions to address the challenges in maintaining quality for a heat sensitive pharmaceutical product. Results Due to the heat sensitivity of oxytocin, its quality may be degraded at numerous points along the health supply chain including: At the point of manufacture, due to poor quality active pharmaceutical ingredients; lack of sterile manufacturing environments; or low-quality manufacturing processes During storage and distribution, due to lack of temperature control in the supply chain, including cold chain at the end user health facility Safeguarding the quality of oxytocin falls under the purview of national medicines regulatory authorities; however, regulators in LMICs may not adhere to good regulatory practices. Conclusions Storing oxytocin from 2 to 8 °C throughout the supply chain is important for maintaining its quality. While short temperature excursions may not harm product quality, the cumulative heat exposure is generally not tracked and leads to degradation. National and sub-national policies must prioritize procurement of quality oxytocin and require its appropriate storage and management.

IntroductionOxytocin, administered via injection, is recommended by WHO for the prevention and treatment of postpartum haemorrhage. However, the susceptibility of oxytocin injection to thermal degradation has led WHO and UNICEF to recommend cold-chain storage of all oxytocin products. Nevertheless, some oxytocin products supplied to the global market are labelled for storage at ≤25°C, often with a shorter shelf-life relative to products labelled for refrigeration. Differences in labelled storage requirements can lead to uncertainties among stakeholders around the relative stability of oxytocin products and specifically whether ≤25°C products are more resistant to degradation. Such confusion can potentially influence policies associated with procurement, distribution, storage and the use of oxytocin in resource-poor settings.ObjectivesTo compare the stability of oxytocin injection ampoules formulated for storage at ≤25°C with those labelled for refrigerated storage.DesignAccelerated and temperature cycling stability studies were performed with oxytocin ampoules procured by the United Nations Population Fund (UNFPA) from four manufacturers.MethodUsing oxytocin ampoules procured by UNFPA, accelerated stability (up to 120 days) and temperature cycling (up to 135 days between elevated and refrigerated temperatures) studies were performed at 30°C, 40°C and 50°C. Oxytocin content was quantified using a validated HPLC-UV method.ResultsAll ampoules evaluated exhibited similar stability profiles under accelerated degradation conditions with the exception of one product formulated for ≤25°C storage, where the rate of degradation increased at 50°C relative to other formulations. Similar degradation trends at elevated temperatures were observed during temperature cycling, while no significant degradation was observed during refrigerated periods of the study.ConclusionOxytocin ampoules formulated for non-refrigerated storage demonstrated comparable stability to those labelled for refrigerated storage and should not be interpreted by stakeholders as offering a more stable alternative. Furthermore, these products should not be procured for use in territories with high ambient temperatures, where all oxytocin injection products should be supplied and stored under refrigerated conditions.

Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the prevention and treatment of postpartum haemorrhage. The requirement for parenteral administration by trained healthcare providers and the need for the drug solution to be maintained under cold-chain storage limit the use of oxytocin in the developing world. In this study, a spray-dried ultrafine formulation of oxytocin was developed with an optimal particle size diameter (1-5 µm) to facilitate aerosolised delivery via the lungs. A powder formulation of oxytocin, using mannitol, glycine and leucine as carriers, was prepared with a volume-based median particle diameter of 1.9 µm. Oxytocin content in the formulation was assayed using high-performance liquid chromatography-mass spectroscopy and was found to be unchanged after spray-drying. Ex vivo contractility studies utilising human and ovine uterine tissue indicated no difference in the bioactivity of oxytocin before and after spray-drying. Uterine electromyographic (EMG) activity in postpartum ewes following pulmonary (in vivo) administration of oxytocin closely mimicked that observed immediately postpartum (0-12 h following normal vaginal delivery of the lamb). In comparison to the intramuscular injection, pulmonary administration of an oxytocin dry powder formulation to postpartum ewes resulted in generally similar EMG responses, however a more rapid onset of uterine EMG activity was observed following pulmonary administration (129 ± 18 s) than intramuscular injection (275 ± 22 s). This is the first study to demonstrate the potential for oxytocin to elicit uterine activity after systemic absorption as an aerosolised powder from the lungs. Aerosolised oxytocin has the potential to provide a stable and easy to administer delivery system for effective prevention and treatment of postpartum haemorrhage in resource-poor settings in the developing world.

PurposeNiclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization.MethodsWe characterized the plasma and pulmonary pharmacokinetics of three ascending doses of nebulized niclosamide in sheep, compare it to intravenous niclosamide for compartmental PK modelling, and to the human equivalent approved 2 g oral dose to investigate in the pulmonary exposure of different niclosamide delivery routes. Following a single-dose administration to five sheep, niclosamide concentrations were determined in plasma and epithelial lining fluid (ELF). Non-compartmental and compartmental modeling was used to characterize pharmacokinetic profiles. Lung function tests were performed in all dose groups.ResultsAdministration of all niclosamide doses were well tolerated with no adverse changes in lung function tests. Plasma pharmacokinetics of nebulized niclosamide behaved dose-linear and was described by a 3-compartmental model estimating an absolute bioavailability of 86%. ELF peak concentration and area under the curve was 578 times and 71 times higher with nebulization of niclosamide relative to administration of oral niclosamide.ConclusionsSingle local pulmonary administration of niclosamide via nebulization was well tolerated in sheep and resulted in substantially higher peak ELF concentration compared to the human equivalent oral 2 g dose.

Background Pulmonary-delivered gene therapy promises to mitigate vaccine safety issues and reduce the need for needles and skilled personnel to use them. While plasmid DNA (pDNA) offers a rapid route to vaccine production without side effects or reliance on cold chain storage, its delivery to the lung has proved challenging. Conventional methods, including jet and ultrasonic nebulizers, fail to deliver large biomolecules like pDNA intact due to the shear and cavitational stresses present during nebulization. Methods In vitro structural analysis followed by in vivo protein expression studies served in assessing the integrity of the pDNA subjected to surface acoustic wave (SAW) nebulisation. In vivo immunization trials were then carried out in rats using SAW nebulized pDNA (influenza A, human hemagglutinin H1N1) condensate delivered via intratracheal instillation. Finally, in vivo pulmonary vaccinations using pDNA for influenza was nebulized and delivered via a respirator to sheep. Results The SAW nebulizer was effective at generating pDNA aerosols with sizes optimal for deep lung delivery. Successful gene expression was observed in mouse lung epithelial cells, when SAW-nebulized pDNA was delivered to male Swiss mice via intratracheal instillation. Effective systemic and mucosal antibody responses were found in rats via post-nebulized, condensed fluid instillation. Significantly, we demonstrated the suitability of the SAW nebulizer to administer unprotected pDNA encoding an influenza A virus surface glycoprotein to respirated sheep via aerosolized inhalation. Conclusion Given the difficulty of inducing functional antibody responses for DNA vaccination in large animals, we report here the first instance of successful aerosolized inhalation delivery of a pDNA vaccine in a large animal model relevant to human lung development, structure, physiology, and disease, using a novel, low-power (<1 W) surface acoustic wave (SAW) hand-held nebulizer to produce droplets of pDNA with a size range suitable for delivery to the lower respiratory airways.

Pulmonary immunization has gained increased recognition as a means of triggering both a mucosal and systemic immune response without the use of needles. The appropriate formulation of antigens in a dry, solid state can result in improved stability, thereby removing cold-chain storage complications associated with conventional liquid-based vaccines. The particulate nature of dry powder vaccines could also induce a better immune response. This review describes our current understanding of pulmonary immunization, including possible barriers facing the development of pulmonary vaccines, and discusses recent advances in spray-drying technologies applicable to the production of dry powder formulations for pulmonary vaccine delivery.

Abstract Background: Pulmonary immunization has recently gained increased interest as a means to induce both systemic and mucosal immunity while eliminating issues associated with the use of needles in parenteral vaccination. However, in contrast to the inhaled delivery of small molecule drugs, a dry powder carrier platform that is readily adaptable to the incorporation of biomacromolecules (e.g., vaccine antigens) as a common standard is lacking. Spray-dried trehalose with leucine has previously been characterized and demonstrated to produce highly aerosolizable powders containing an amorphous glassy matrix suitable for stabilization of biomacromolecules. This study aimed to further extend the understanding in the use of this formulation as a dry powder carrier platform in an in vivo setting, using influenza antigen as a model, for pulmonary delivery of biomacromolecules. Methods: Spray-dried influenza vaccine was produced using previously established spray-drying conditions. The formulations were characterized to examine the impact of influenza antigen on the solid-state properties of the spray-dried powders. The optimal vaccine formulation was then selected for in vivo immunogenicity study in rats to evaluate the efficacy of the reconstituted spray-dried vaccine compared to liquid vaccine administered via pulmonary and subcutaneous routes. Results: The formation of amorphous glassy matrix and morphology of the spray-dried particles, within the protein concentration range used in the study, was not affected by the incorporation of the influenza antigen. However, the amount of proteins incorporated increased water content and reduced the glass transition temperature (Tg) of the formulation. Nevertheless, the spray-dried vaccine induced strong mucosal and systemic immunity comparable to liquid vaccine after pulmonary and subcutaneous immunization without causing any inflammation to the lung parenchyma. Conclusions: The study demonstrated the usability of the spray-dried carrier as a promising platform for pulmonary delivery of influenza vaccine. The potential utility of this delivery system for other biomacromolecules may also be further explored.

Researchers found that oxytocin concentrations in ampules remained stable after exposure to freezing temperatures. These results should reassure health care workers and skilled birth attendants that oxytocin ampules can be safely used even if temporarily frozen during transportation or storage. To the Editor: Postpartum hemorrhage is a major cause of maternal death worldwide, particularly in developing countries. 1 Oxytocin ampules are included on the World Health Organization list of essential medicines used in the active management of the third stage of labor to prevent postpartum hemorrhage. Refrigerated storage minimizes the degradation of oxytocin, 2 but the ampules are also labeled with instructions against freezing during storage. Although data are lacking on the effects of freezing, there has been concern that oxytocin, a peptide, may be unstable with freezing. Freeze sensitivity is a recognized problem in some vaccines, such as tetanus toxoid and . . .