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Antimicrobial Nanoemulsions

During the 1990’s under Department of Defense, DARPA funding, scientists at the Michigan Nanotechnology Institute developed a composite material that resulted in a new class of antimicrobial agents with activity against gram–positive bacteria and spores, fungi and viruses. The  resulting antimicrobial nanoemulsions are oil-in-water droplets that range from 200-600 nm
(Fig. 1).

They are composed of oil and water and are stabilized by surfactants and alcohol. They are manufactured from ingredients which are on the Generally Recognized as Safe (GRAS) list. Active ingredients are approved for over-the-counter human applications. A high-energy state is formed in the particle using a high-speed mixer (Fig. 2).

Nano Emulsion

Figure 2: Nanoemulsion Lab

Nanoscale emulsion

Figure 1: Nanoscale emulsion technology
High energy oil-in-water emulsions (average droplets 200 nm), stabilized by surfactants. Broad-spectrum antimicrobial activity against bacteria, enveloped viruses, fungi, spores and protozoa

The active ingredient and the high energy are essential for the antimicrobial mechanism of action. Additional reduction of size is achieved by a high-pressure microfluidizer. This additional reduction of size results in more energy units per volume. Additional ingredients are added to enhance the nanoemulsion spectrum of activity or to improve its stability. The concentrated (neat) emulsions are diluted 10- to 100-fold in water, resulting in a stable final product. The dilute emulsions are milky in consistency and appearance; additional thickeners could be added to increase its viscosity and prevent running in specific applications.

The nanoemulsion has a broad spectrum activity against bacteria (e.g., E. coli, Salmonella, S. aureus), enveloped viruses (e.g., HIV, Herpes simplex), fungi (e.g., Candida, Dermatophytes), and spores (e.g., anthrax). See our section on nanoemuslion as a decontamination agent.The nanoemulsion particles are thermodynamically driven to fuse with lipid-containing organisms. This fusion is enhanced by the electrostatic attraction between the cationic charge of the emulsion and the anionic charge on the pathogen. When enough nanoparticles fuse with the pathogens, they release part of the energy trapped within the emulsion. Both the active ingredient and the energy released destabilize the pathogen lipid membrane, resulting in cell lysis and death (Fig. 3).

Figure 3: Nanoemulsion Mechanism of Action Against Microbes:
Membrane destabilization results in killing of microbe

Effect of Nanoemulsion on Vibrio Cholerae

Figure 4: Effect of Nanoemulsion on Vibrio Cholerae (El Tor stain):
Left: before emulsion; right: after emulsion

In the case of spores, additional germination enhancers are incorporated into the emulsion. Once initiation of germination takes place, the germinating spores become susceptible to the antimicrobial action of the nanoemulsion (Fig. 5).

Figure 5: Nanoemulsion Mechanism of Action Against Spores
When Bacillus spores contaminate a mucosal membrane, nutritional factors present in the damaged tissue and serum serve as germination enhancers. These germination enhancers initiate the germination of the bacillus spores and the tough outer shells of the spores then become vulnerable to the lethal effect of the nanoemulsion. This will result in disruption of the spore.

Figure 6 shows alterations of Bacillus spores induced by nanoemulsion treatment.

Alterations of Bacillus Spores induced by Nanoemulsions

Figure 6: Alterations of Bacillus Spores induced by Nanoemulsions

Dilute emulsions showed stability when stored at 40°C for over 1 year and at room temperature for over 3 years. They can also withstand several cycles of heating and cooling. This would be enough to have viable marketable products.

In animal studies, nanoemulsion proved quite effective for wound irrigation: Hamouda T, Cao Z, Tonda R, Johnson K, Wright CD, Brisker J, Baker JR Jr.  A novel surfactant nanoemulsion with broad-spectrum sporicidal activity against Bacillus species.  J Infect Dis 180(6):1939-49, 1999

Another valuable application of nanoemulsion is in the field of bioterrorism and includes decontamination of humans, surfaces and buildings following biological bio-attacks. Recently, the formulation has been enhanced to achieve killing for B. anthracis in 45-60 minutes.

An unique aspect of the nanoemulsions is their selective toxicity to microbes at concentrations that are non-irritating to skin or mucous membrane. This safety has been tested in several animal species and verified during human clinical trials. The safety margin of the nanoemulsion is due to the low level of detergent in each droplet, yet when acting in concert, these droplets have sufficient energy and surfactant to destabilize the targeted microbes without damaging healthy cells. As a result, the nanoemulsion can achieve a level of topical antimicrobial activity that has only been previously achieved by systemic antibiotics. Nanoemulsion cannot, however, be injected into the bloodstream because they will lyse red cells.

Our nanoemulsion technology has successfully transferred out of our research laboratory into commercialization at NanoBio Corp., a spin-off company from the University of Michigan, which has an exclusive license to develop and commercialize the antimicrobial emulsion for topical and mucosal applications. FDA phase II clinical trials for topical treatment of Herpes Labialis have been completed at NanoBio Corp. There have been no safety issues and the product has been well tolerated. Other applications to follow include onychomycosis, herpes labialis, genital herpes, and Methicillin-resistant Staphylococcus aureus (MRSA).

Scientsist at the Michigan Nanotechnology Institute continue work on nanoemuslion based applications. 

We are presently studying the adjuvant and / or immuno-stimulant capabilities and the mechanism of action of the nanoemulsion mixed with pathogens as adjuvant vaccines. See the Adjuvant Vaccine Development section.

We also work on formulating nanoemulsions that are non-toxic to the lung and are microbiocidal to the colonized pathogens, and simultaneously are also able to improve lung function and reduce pulmonary exacerbations due to mucus accumulation in Cystic Fibrosis or Chronic Lung Disease patients

 



 

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