The objective of this program is to develop of a clinical prototype, semi-solid drug formulation and auto-injector pen that deliver microliter volumes of a glucagon dose without reconstitution for hypoglycemic emergencies. To assess the feasibility of this objective, it is necessary to first demonstrate that glucagon can be formulated into an ultra- concentrated, semi-solid formulation and second, that glucagon in a semi-solid formulation is bioavailable and bioactive following subcutaneous delivery. If successful, these experiments will lead to development of a simple, portable, glucagon delivery system for use in a Phase 1/2 safety-pharmacokinetics study. The first Specific Aim of this proposed project is to develop a prototype formulation of human glucagon that meets defined criteria for functionality in the delivery device, dissolution in an in vitro model of interstitial fluid and demonstration of short-term, accelerated stability of the glucagon formulation. The second Specific Aim is the successful in vivo delivery of formulations in clinically relevant doses in a rat model. Formulations will be judged by 1) >80% dissolution of glucagon in simulated interstitial fluid and 2) <10% residual drug in the device after administration. In addition, one (1) months of chemical and physical stability (>95% API content and equivalent viscosity to day 0) of the solid glucagon formulation will be deemed successful. Effective subcutaneous delivery of glucagon will be assessed by measurement of the drug in the blood using radioimmunoassay. Bioavailability of >80% relative to a control subcutaneous injection of aqueous-reconstituted glucagon in a rat model will be deemed successful. Meeting these criteria will justify further development of this novel glucagon delivery system.
The current standard of care for hypoglycemic emergencies-- the glucagon Emergency Kit requires a diabetic's caregiver to reconstitute the peptide powder contained in a vial using a 1 mL prefilled syringe and to assure complete solubilization prior to injection. A patient friendly, ready-to-use auto-injector Glucagon Pen will reduce caregiver and patient fear and risk, costs of 911 calls and emergency room visits.
| Fang, Wei-Jie; Qi, Wei; Kinzell, John et al. (2012) Effects of excipients on the chemical and physical stability of glucagon during freeze-drying and storage in dried formulations. Pharm Res 29:3278-91 |
