Technology solutions landscape
Oxytocin (chemical formula C43H66N12O12S2) is only marginally stable in an aqueous solution. However, unlike some other marginally stable drugs, it does not have to be formulated into a freeze-dried powder and then reconstituted with a diluent at the point of use.14 Oxytocin is sufficiently stable in a ready-to-use solution that requires refrigeration.15 Several research groups have developed formulation technologies that improve the temperature stability of oxytocin. A systematic review of these formulation approaches can be organized into three major groups, as discussed below and summarized in Table 1.
1. Heat-stable parenteral formulations
These formulations include the addition of metal ions and/or buffers to improve the stability of aqueous oxytocin by preventing the degradation pathways15 demonstrated that the stability of oxytocin in an aqueous solution can be improved with the addition of a combination of divalent metal salts and citrate buffer.16 This formulation, however, requires parenteral administration with a needle and syringe filled directly from an ampoule or vial or intravenous delivery. The use of a needle and syringe can be problematic in low-resource settings.
2. Heat-stable non-parenteral formulations
Spray-drying oxytocin into an ultrafine powder or particle form is another approach. It has the potential not only to achieve molecule stability but also to provide an alternative, non-parenteral delivery method. Such technology can allow for oxytocin to be inhaled and absorbed very rapidly upon delivery to the lungs, with potentially increased pharmacological action to generate uterine contractions. Research by Michelle McIntosh’s team at the McIntosh laboratory at Monash University (Australia) demonstrated that the inhalation of pharmaceutically engineered particles of oxytocin could prevent and treat postpartum hemorrhage.17 This novel solution is promising for low-resource settings.
3. Chemical modification
Because oxytocin is a peptide hormone, it is susceptible to protein degradation pathways such as oxidation, disulfide (S-S) reduction, and hydrolysis. The decomposition of oxytocin is mainly caused by deamination, oxidation, hydrolysis, and dimerization. Chemical modification can increase the stability of oxytocin; this makes the peptide hormone less susceptible to degradation pathways.15, 18 This approach delivers an analogue or derivative of oxytocin; additional research and clinical testing is required to ensure that the uterotonic properties or safety of the oxytocin has not been compromised.
Table 1. Summary of heat-stable oxytocin technologies.
|Heat-stable parenteral||Heat-stable non-parenteral||Oxytocin analogue|
|Common formulation approaches||Addition of metal ions and or buffers. Lyophilized powder for reconstitution and injection.||Spray dry oxytocin into an ultrafine powder.||Modification of oxytocin chemical structure. Use of an oxytocin derivative.|
|Development stage||Formulation development||Formulation development||Formulation development|
|Delivery route (method)||Injection (needle and syringe)||Inhalation into the lungs or mucosa||Injection (needle and syringe)|
|Bundling considerations||None||Dry powder or aerosolized inhaler||None|
|Alignment with current WHO guidelines||Recommended||Divergent||Divergent|