SBIR-STTR Award

Domestic propofol sales exceed $500 million annually and continue to increase due to a shift towards ambulatory surgery. This intravenous anesthetic exists as an oil and necessitates dispersion in a soybean macroemulsion (i.e., Intralipid). This formulation (e.g., Diprivan) has a number of disadvantages overcome with a microemulsion formulation. The present investigators hypothesize that the lipophilicity of propofol can be leveraged to construct oil-in-water microemulsions in which propofol serves dual roles as both the active pharmaceutical and the core oil component of the nanoparticles. Furthermore, the investigators hypothesize that the relaxation constant of the microemulsion can be modified so that nanoparticles reach the central circulation before releasing active drug to cause general anesthesia. Three specific aims are proposed herein to test the feasibility of this approach. Specific Aim 1: Synthesize microemulsion-based nanoparticle systems of propofol with varying concentrations of biologically-friendly surfactants (proprietary information, see B.5) in order to modify the relaxation rate of the nanoparticles and, thereby, drug release rate and time to cause general anesthesia. Specific Aim 2: Using a randomized, crossover design in dog and rat, demonstrate that propofol-based nanoparticles causes general anesthesia and pharmacokinetic indices similar to that caused by a commercially available formulation (e.g., Diprivan), but without associated pain on injection. Specific Aim 3: In dog, conduct a preliminary safety investigation emphasizing possible effects on hemolysis and coagulation as assessed by thromboelastography. Although the specific aims are sharply focused, this technology is applicable to a broad number of lipophilic pharmaceuticals. The goals allude to the possibility of using nanoparticles to infuse caustic or lipophilic drugs previously reserved for central venous catheters via a peripheral intravenous cannula. In addition, these objectives integrate well into the core competency of NanoMedex, Inc. to disperse lipophilic drugs using nanotechnology and into NanoMedex's business strategy wherein all nanoparticle constituents are currently off patent and previously intravenously infused into humans.

Thesaurus Terms:
emulsion, intravenous anesthesia, technology /technique development general anesthesia, hemolysis, hydropathy, pharmacokinetics, surfactant, viscosity dog, laboratory rat, mass spectrometry

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