Development of clonidine hydrochloride injections for epidural intrathecal administration

The purpose of this study was to describe and document the development of several concentrations of clonidine hydrochloride injection for evaluation as epidural and intrathecal injections in clinical trials for the control of intractable pain. Bulk clonidine hydrochloride prepared under Good Manufacturing Practices conditions was formulated as simple aqueous solutions in 0.9% sodium chloride injection having concentrations of 0.15, 0.5 and 1.5 mg/mL. The low concentration served as the starting concentration for low drug delivery, with the highter concentrations needed to accommodate increasing rates of drug delivery. All three concentrations exhibited natural pH values of about 6 to 6.5 and were adjusted to a target pH of 6.5 with sodium hydroxide, if necessary. The measured osmolalities were about 285 mOsm/kg, nearly isotonic. The injections were filtered through 0.22 micormeter filters and packaged in 20mL, Type-1, flint glass vials with rubber stoppers. The vials were terminally sterilized by autoclaving at 121 deg C and 15 psi for 30 minutes. Using a stability-indicating, high-performance liquid chromatography analytical technique based on the official USP method, we observed no loss of clonidine hydrochloride in any of the development vials at the concentrations of 0.15, 0.5 and 1.5 mg/mL after preparation and autoclaving. Similarly, shelf-life studies on two small batches each of the 0.15- and 0.5-mg/mL concentrations have shown little or no loss of clonidine hydrochloride after three months' storage at 37 deg C and for up to 24 months at 4 and 23 deg C. Shelf-life studies are continuing. Clonidine hydrochloride 0.15-, 0.5-, and 1.5-mg/mL injections have been developed as epidural and intrathecal injections in clinical trials to control intractable pain. The injections are easily formulated and stable during compounding and storage.