Nanoparticles in anesthesia
(fVA – Chris Fraker)
by Maja Hunter, Ph.D.

Christopher Fraker, Ph.D. from the University of Miami Miller School of Medicine, recently published a paper describing a new technology in the field of anesthesia – formulating an anesthetic isoflurane into nanoemulsion [1]. The impetus of his research was to improve patient safety during anesthesia administration, accelerate induction and emergence, and reduce the expenditure of extra personnel and costly machinery. A short summary of the study, results and plan is written below.

In the last few years, emulsions of halogenated ethers have emerged as a technology with potential as both induction and maintenance agents. Stable emulsions are attractive formulations for a variety of drugs due to enhanced drug solubility or due to the new mechanism of drug delivery. There is an increased interest in intravenously administrable emulsified halogenated ether, a fluid volatile anesthetic (fVA), acting as general anesthetics, as well as protective agents for ischemic conditioning. The emulsification of halogenated ethers is key since their direct injection proved to be dangerous in early studies.

An example of such fVA is isoflurane. While usually administered via inhalation, this causes airway irritation. Emulsification of isoflurane allows a different drug delivery mechanism as well as reducing the evaporation of this volatile drug. The escape of volatile anesthetic in the operating room would present a potential hazard to surgical staff.

Preparation of isoflurane nanoemulsion

The coarse emulsion was processed with a High-Pressure Homogenizer (HPH), ShearJet® HP350 from Dyhydromatics (Maynard, MA, USA), equipped with an 87.1L (87 µm) followed by a 200.2L (200 µm) Reaction Chamber® module. Temperature was held constant at 14° C during the processing using a ThermoFlex 3500 (Neslab) providing recirculated, chilled water for the heat exchanger and the hydraulics of the HPH. The coarse emulsion was processed in 5 distinct passes at 15,000-16,000 psi and then was diluted with a final 1/3 volume of saline. Nanoemulsion particle size was determined by dynamic light scattering and all manufactured emulsions used in the study were between 150-160 nm.

Results

The oily component of the emulsion reduces the evaporation of the volatile anesthetic isoflurane. Due to the slower evaporation rate, these nanoemulsions have a higher safety rate relative to pure isoflurane as shown in Figure 1. Together with the development of anesthetic isoflurane emulsion for the first time, C. A. Fraker´s team also describes the successful development and testing of a rapid Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) method for determination of isoflurane content in anesthetic nanoemulsions. The isoflurane content measurements with ATR-FTIR method are accurate and in agreement with measurements obtained with the standardly used HPLC. Moreover, the ATR-FTIR method proved to be 20 times faster and therefore has the potential to lower drug development costs in this formulation and other hydrophobic pharmaceutical nanoemulsions.

Figure 1: The evaluation of evaporative isoflurane loss from 10 mL beakers containing 2 mL of either pure isoflurane or emulsified isoflurane. Graph B represents loss in terms of total molecules lost and in graph A as percent of total isoflurane lost relative to T = 0. The emulsion was made with standard formulation concentrations (10 % v/v perfluorocarbon and isoflurane, 2 % w/v surfactant). Graphs are only for visual presentation; the values are not exact.

Future Plans

There has been tremendous success in the veterinary field trials with animals being under in 30 seconds (with just one injectable drug), and awake and fully ambulating within ten minutes. They hope to expand in veterinary medicine and move into human trials with initial results showing patients awake and fully ambulating within 15-17 minutes simply by blowing oxygen into the patient.

Dyhydromatics Technology

High-shear processing is an optimal method to create nanoemulsions. High pressure forces the premixed nanoemulsion through the microchannels of the Reaction Chamber® module. The sample stream reaches high velocities and collides with the walls of the chamber and itself. The fixed geometry of the microchannels enables consistent shear and impact forces that reduce the size of an emulsion droplet to create fine nanoemulsions. On the laboratory processor, the Reaction Chamber® module contains one microchannel and on the production processor, the Reaction Chamber® module would have a few microchannels in parallel, which is key to a linear scale up. All the energy supplied from high pressure, shear and impact forces warms up the sample and could lead to denaturation of proteins (cell lysis) or coalescence of nanoemulsion droplets if efficient cooling of the sample is not provided. Dyhydromatics ShearJet® processors have a heat exchanger installed directly after the Reaction Chamber® module. The heat exchanger cools the formulation down utilizing a chiller or chilled water, which provides an additional benefit for GMP environments since the temperature can be tightly controlled. If you are interested in our equipment or you want to learn more about our technology, don’t hesitate to reach out to our friendly customer service.

Literature

[1] M. H. Tootoonchi, R. Bradsley, T. Panagiotou, R. J. Fisher, E. A. Pretto Jr., C. A. Fraker, Rapid quantification of isoflurane in anesthetic nanoemulsions using Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR), Vibrational Spectroscopy 109 (2020). https://doi.org/10.1016/j.vibspec.2020.103095