Heat-Stable Dry Powder Oxytocin Formulations for Delivery by Oral Inhalation

Abstract

In this work, heat stable dry powders of oxytocin (OT) suitable for delivery by oral inhalation were prepared. The OT dry powders were prepared by spray drying using excipients chosen to promote OT stability including trehalose, isoleucine, polyvinylpyrrolidone, citrate (sodium citrate and citric acid), and zinc salts (zinc chloride and zinc citrate). Characterization by laser diffraction indicated that the OT dry powders had a median particle size of 2 μm, making them suitable for delivery by inhalation. Aerodynamic performance upon discharge from proprietary dry powder inhalers was evaluated by Andersen cascade impaction (ACI) and in an anatomically correct airway (ACA) model, and confirmed that the powders had excellent aerodynamic performance, with respirable fractions up to 77% (ACI, 30 L/min). Physicochemical characterization demonstrated that the powders were amorphous (X-ray diffraction) with high glass transition temperature (modulated differential scanning calorimetry, MDSC), suggesting the potential for stabilization of the OT in a glassy amorphous matrix. OT assay and impurity profile were conducted by reverse phase HPLC and liquid chromatography-mass spectrometry (LC-MS) after storage up to 32 weeks at 40°C/75%RH. Analysis demonstrated that OT dry powders containing a mixture of citrate and zinc salts retained more than 90% of initial assay after 32 weeks storage and showed significant reduction in dimers and trisulfide formation (up to threefold reduction compared to control).

Safety, Tolerability and Pharmacokinetics of Single Doses of Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-blind, Phase 1 Study

“…1) and recent data support a minimum 30 month shelf-life at 25 °C (approved by the UK Medicines & Healthcare products Regulatory Agency for clinical supply). An in vitro preclinical study further demonstrated that dry powder formulations of oxytocin suitable for oral inhalation can be prepared and are stable after extended storage under tropical and subtropical conditions ( Fabio et al, 2015 ). The potential for an IH powder form of oxytocin was also demonstrated in an in vivo preclinical study, which showed that administration of an ultra-fine oxytocin powder to the airways of postpartum sheep led to rapid absorption and comparable uterine electromyographic activity to that observed with IM administration ( Prankerd et al, 2013 ).…”

Cationic, amphiphilic dextran nanomicellar clusters as an excipient for dry powder inhaler formulation

“…The efficiency of the spray drying method is superior to fluid energy mill aided micronization in generating larger population of inhalable particles. Mankind Corporation reported a spray dried oxytocin DPI formulation having 77% of FPF at 30 L/min flow rate [56].…”

The effect of trehalose, antioxidants, and acetate buffer concentration on oxytocin stability

“…These include divalent metal ions in citrate and aspartate buffer solutions, 22–24,28 and dextrose and sodium chloride injection solutions 26 . Dry powder formulations have also been tested with excipients including trehalose, isoleucine, and polyvinylpyrrolidone along with citrate and zinc salts in an effort to make the solid state oxytocin stable in extreme hot climates 29 . Although some of these excipients have resulted in the enhancement of oxytocin stability, there is still room for further improvement.…”