NanoMedex Propofol Microemulsions: Preclinical Studies to FDA IND Application

DESCRIPTION (provided by applicant): Propofol is the largest selling, intravenous general anesthetic with domestic annual sales in excess of $500 million due to several favorable characteristics of this anesthetic and has an expected annual growth rate of 19%. However, a primary drawback of propofol (2,6-diisopropylphenol) revolves around this drug's extreme lipophilicity that necessitates dispersion in a soybean macroemulsion (i.e., Intralipid 10%). This requirement causes several possible adverse drug outcomes (e.g., rapid bacterial growth, severe stinging pain on injection). In SBIR Phase I activities, NanoMedex proposed that these adverse reactions caused by the Intralipid formulation could be prevented by using an alternative formulation of microemulsion-based nanoparticles to construct clear, thermodynamically stable formulations of propofol. To that end, NanoMedex demonstrated in SBIR Phase I the physical boundary parameters to synthesize these formulations, that these formulations had differential release rates in response to dilution, that these NanoMedex propofol formulations had differential anesthetic kinetics in rat, and that one NanoMedex formulation and Diprivan (the commercial formulation) were bioequivalent to cause anesthesia in dog. In SBIR Phase II, NanoMedex seeks to expand on these findings to demonstrate the following Specific Aims leading to an US Food and Drug Administration Investigational New Drug application and GMP-grade propofol formulations. Specific Aim 1. Determine the propensity of propofol microemulsions (NMDX) and a macroemulsion (Diprivan) to cause stinging on injection into a rat tail vein. Specific Aim 2. Characterize the ability of microbes to survive and grow in different anesthetic solutions (NMDX formulations, Diprivan, Intralipid, and Baxter PPI). Specific Aim 3. In swine, determine the pharmacokinetics of a propofol bolus and infusion as well as and dose-response relationship to cause hemolytic and/or thrombotic changes due to propofol microemulsions (NMDX) and macroemulsion (Diprivan). Specific Aim 4. Determine the stability of a GMP-manufactured, NanoMedex propofol microemulsion and macroemulsion (Diprivan) to changes in time, light, temperature, oxygen, and vibration. GMP-grade propofol formulations will be custom-synthesized in an FDA-approved plant with appropriate regulatory oversight using external contractors. At the conclusion of SBIR Phase II, NanoMedex, Inc. will have applied for an FDA IND, secured external financing via private investors to conduct FDA Phase I studies, and begun planning for an abbreviated new drug application. Successful conclusion of the propofol project will allow NanoMedex, Inc. to present this propofol microemulsion to large Pharma for additional Phase ll/lll studies and commercialization.