Propofol is the largest selling, intravenous general anesthetic that may have several adverse effects due to its lipophilicity and need to be formulated in Intralipid. We propose to develop a patented microemulsion of propofol in which the lipophilicity of propofol is leveraged to serve dual roles as both the lipid oil core of the microemulsion and a pharmacodynamically active agent to cause anesthesia. Previously, we demonstrated that these microemulsions had favorable anesthetic properties. In summary, we synthesized propofol microemulsions and learned their physical boundary conditions and stability when subjected to environmental changes;narrowed these formulations to 5 promising microemulsions and studied their properties studied in rat;learned that some microemulsions had anesthetic kinetic properties similar to Diprivan;used the leading formulation in pig and dog to demonstrate that there are no changes in blood coagulation;demonstrated in pig that the formulation had similar pharmacokinetics to Diprivan, the FDA reference labeled drug;showed that the propofol microemulsion inhibited the growth of various species of bacteria;and constructed a plan to produce GMP-grade propofol microemulsions. To take the next step, a FDA IND must be obtained prior to beginning clinical studies. Therefore, the following Aims will be achieved:
Specific Aim #1 : Execute preclinical studies of the MicrofolTM formulation sufficient for IND submission. These studies to include: (a) 28-day acute toxicity dog study;(b) comparative single dose toxicokinetic (TK) studies and modeling in the dog of Diprivan(R) (RLD) and MicrofolTM (test article);(c) parental tolerance study in rabbits;and (d) evaluation of the test article to induce hemolysis in whole human blood.
Specific Aim #2 : Transfer manufacturing of MicrofolTM microemulsion formulation from NanoMedex'laboratories to an active pharmaceutical Ingredient (API) manufacturer for development of commercial formulation in lot sizes including full Chemistry, Manufacturing and Control (CMC) documentation of composition, process and controls.
Specific Aim #3 : Develop plan and perform all components (packaging, labeling, stability release testing) associated with final fill contract manufacturing organization (CMO) of 20L documented commercial batch of MicrofolTM.
Specific Aim #4 : Compare the pharmacokinetics, serum lipid profile, and divalent cation response in human subjects receiving MicrofolTM or Diprivan(R). Generating data to submit a successful FDA IND application is the explicit goal of the NIH SBIR Phase II CR program as detailed in the solicitation. Successful conclusion of the propofol project will allow NanoMedex Pharmaceuticals to present this microemulsion to larger Pharma for commercialization.
Propofol is the largest selling, intravenous general anesthetic that may have several adverse effects due to its lipophilicity and need to be formulated in Intralipid. We propose to develop a patented microemulsion of propofol in which the lipophilicity of propofol is leveraged to serve dual roles as both the lipid oil core of the microemulsion and a pharmacodynamically active agent to cause anesthesia. Successful conclusion of the propofol project will allow NanoMedex Pharmaceuticals to present this microemulsion to larger Pharma for commercialization.
| Morey, Timothy E; Modell, Jerome H; Garcia, Jorge E et al. (2010) Thromboelastographic and pharmacokinetic profiles of micro- and macro-emulsions of propofol in swine. Biopharm Drug Dispos 31:269-77 |
