Development of a thermostable oxytocin microneedle patch.

Oxytocin is a nonapeptide hormone used in labor to initiate uterine contractions and to prevent and treat postpartum hemorrhage. Oxytocin is currently administered by injection and requires refrigerated transport and storage, which limits access, especially during home birth in developing countries. Here, we propose a thermostable, simple-to-administer microneedle (MN) patch for rapid delivery of oxytocin suitable for use by healthcare workers with limited training, like traditional birth attendants. Oxytocin (10 IU, 16.8 µg) coated onto stainless steel MN arrays was released into skin within 1-5 min after manual insertion. Among tested excipients, polyacrylic acid was best at stabilizing oxytocin stored at 75% relative humidity, with no significant loss for up to 2 months at 40 °C. Under desiccated conditions, MNs coated with formulations containing trehalose in a mixture of citrate buffer and ethanol retained 75% oxytocin potency at 40 °C for 12 months; the commercial oxytocin product Pitocin® was reduced to 35% potency under these conditions. These findings support development of MN patches for oxytocin administration with improved ease of use, extended thermostability and simplified logistics to enable greater access to this life-saving medicine.

Rapid Absorption of Dry-Powder Intranasal Oxytocin.

PURPOSE: To probe the suitability of a dry-powder oxytocin formulation containing a carrier (µco™; SNBL, Ltd.) for intranasal (IN) administration to treat post-partum hemorrhage in the developing world. Specifically, to investigate (1) whether IN administration can achieve rapid systemic absorption in cynomolgus monkeys, and (2) whether the formulation exhibits sufficient physical and chemical stability. This study was conducted to support Merck for Mothers, Merck's 10-year global initiative to end preventable maternal deaths. METHODS: A partial-crossover pharmacokinetic (PK) study in cynomolgus monkeys (n = 6) was utilized to compare in vivo absorption of dry-powder IN oxytocin at three dose levels against an IM injection of an aqueous oxytocin formulation. Particle size distribution, delivered dose and chemical assay were monitored over a 12 month stability study. RESULTS: IN administration of oxytocin resulted in short (5 min) Tmax and good dose linearity in AUC and Cmax over the dose range tested (10-80 IU per animal). The relative bioavailability (BA) of IN oxytocin to IM injection was approximately 12%. The 80 IU formulation exhibited good physical stability and consistent dosing. After 12 months at 30°C/65%RH, pouched samples retained 86.0% of their original assay value. CONCLUSIONS: The PK and stability data suggests that IN administration of oxytocin formulated in the µco™ carrier may represent a viable option for rapid systemic absorption in humans and a product compatible with resource-scarce regions.

Characterization of a low-level unknown isomeric degradation product using an integrated online-offline top-down tandem mass spectrometry platform.

An integrated online-offline platform was developed combining automated online LC-MS fraction collection, continuous accumulation of selected ions (CASI), and offline top-down electron capture dissociation (ECD) tandem mass spectrometry experiments to identify a low-level, unknown isomeric degradant in a formulated drug product during an accelerated stability study. By identifying the diagnostic ions of the isoaspartic acid (isoAsp), the top-down ECD experiment showed that the Asp9 in exenatide was converted to isoAsp9 to form the unknown isomeric degradant. The platform described here provides an accurate, straightforward, and low limit of detection method for the analysis of Asp isomerization as well as other potential low-level degradants in therapeutic polypeptides and proteins. It is especially useful for unstable and time-sensitive degradants and impurities.