Persistent topical antimicrobial compositions and methods of using the same
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Publication Number
US-11369578-B2
Publication Date
2022-06-28
Expiration Date
Abstract
The present disclosure relates to nanoemulsion compositions with certain surfactant blend ratios that impart enhanced permeability. Such compositions are useful for topical, mucosal and intranasal applications and allow for the greater delivery of one or more active agents to the application site to prevent infection by a microorganism.
Core Innovation
The invention is a method for preventing or reducing the risk of microbial infection at a target site in a subject by administering a long-acting antimicrobial nanoemulsion to the target site. Following a single application, the nanoemulsion kills about 99.9% or more of microorganisms present at the target site at the time of administration and additionally kills 99.9% of microorganisms exposed to the target site for at least about 4 hours after administration. The nanoemulsion is administered topically, mucosally, ocularly, or nasally.
The nanoemulsion comprises droplets having an average or mean diameter of less than about 1 micron and includes an aqueous phase, an oil phase comprising at least one pharmaceutically acceptable oil, at least one pharmaceutically acceptable organic solvent, at least one nonionic surfactant, and a quaternary ammonium compound selected from cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, dioctadecyl dimethyl ammonium chloride, octenidine dihydrochloride, or a combination thereof. The concentration of the quaternary ammonium compound and nonionic surfactant is in a ratio of about 1:2 to about 1:18.
The disclosure describes the nanoemulsion as persistent and long-acting, including continued antimicrobial killing after administration and retention of killing after washing or flushing. It is also described as providing enhanced permeability/substantivity on skin and mucosa/ocular/nasal surfaces, enabling additional delivery of therapeutic agents, and exhibiting stability at elevated temperatures and retained integrity after autoclaving.
Claims Coverage
The independent claim family centers on one method for preventing or reducing the risk of microbial infection using a long-acting antimicrobial nanoemulsion that provides about 99.9% killing after a single application and continued killing for at least about 4 hours. The identified inventive features include sub-micron droplet structure, a defined oil-in-water composition, and a constrained quaternary ammonium-to-nonionic surfactant ratio, with dependent refinements for microorganism selection, stability, dosage forms, and post-application handling.
Long-acting antimicrobial nanoemulsion administration for infection prevention
A method for preventing or for reducing the risk of microbial infection at a target site in a subject, comprising administering topically, mucosally, ocularly, or nasally a long-acting antimicrobial nanoemulsion to the target site, wherein following a single application the nanoemulsion kills about 99.9% or more of microorganisms present at the target site at the time of administration and additionally the nanoemulsion kills 99.9% of microorganisms exposed to the target site for at least about 4 hours after administration.
Sub-micron oil-in-water nanoemulsion composition with defined phases and surfactant system
The nanoemulsion comprises droplets having an average or mean diameter of less than about 1 micron and comprises an aqueous phase, an oil phase comprising at least one pharmaceutically acceptable oil, at least one pharmaceutically acceptable organic solvent, at least one nonionic surfactant, and a quaternary ammonium compound selected from cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, dioctadecyl dimethyl ammonium chloride, octenidine dihydrochloride, and combinations thereof.
Quaternary ammonium-to-nonionic surfactant concentration ratio for prolonged killing
The concentration of the quaternary ammonium compound and nonionic surfactant is in a ratio of about 1:2 to about 1:18.
Microorganism-specific targeting by microorganism selection
The microorganism is selected from viruses and/or bacteria, including coronaviruses characterized by SARS-CoV-2 genome polynucleotides, immunogenic SARS-CoV-2 genome fragments, or polynucleotides with specified sequence identity to the polynucleotide comprising the SARS-CoV-2 genome sequence, and selecting among specified coronavirus genera/species groups.
Nanoemulsion droplet size ceiling in nanometer ranges
Nanoemulsion particles have an average or mean diameter at or below specified nanometer ranges, including about 350 nm.
Delivery and performance thresholds for the nanoemulsion
Diluting the nanoemulsion to form a formulation containing about 0.5% to about 60% nanoemulsion with criteria for delivery of the quaternary ammonium compound into tissue and performance thresholds based on the concentration ratio of the quaternary ammonium compound to nonionic surfactant, viscosity, zeta potential, entrapping in the oil phase, and mean droplet size stability after centrifugation.
Stability and dosage form requirements
A nanoemulsion that is non-toxic and/or thermostable and meets specified stability durations at various temperatures, may be autoclaved while retaining structural and/or chemical integrity, and is formulated in specified topical, liquid/solid/semisolid, or nasal spray dosage forms.
Optional flushing after administration while retaining killing activity
After topical administration of a nanoemulsion, flushing the target site at least once within 4 hours using water or another liquid while retaining 99.9% microbial killing activity.
Preventing infection caused by contact with the target site
The method prevents or reduces the risk of microbial infection in the subject caused by contact of the microorganism with the target site of the subject.
Across the identified claim set, coverage is directed to a single-application, long-acting antimicrobial nanoemulsion method for topical, mucosal, ocular, or nasal infection prevention that provides about 99.9% killing at administration and continued 99.9% killing for at least about 4 hours. The inventive elements include sub-micron droplet nanoemulsion structure, a defined oil-in-water composition with aqueous phase, pharmaceutically acceptable oil, organic solvent, nonionic surfactant, and a specified quaternary ammonium compound, together with a constrained quaternary ammonium-to-nonionic surfactant ratio of about 1:2 to about 1:18.
Stated Advantages
Prevents or reduces the risk of microbial infection at the target site caused by contact of the microorganism with the target site.
Kills about 99.9% or more of microorganisms present at the target site at the time of administration following a single application.
Additionally kills 99.9% of microorganisms exposed to the target site for at least about 4 hours after administration.
Retains 99.9% microbial killing activity when the target site is flushed at least once within 4 hours after topical administration.
Provides long-acting antimicrobial effect characterized as persistent and continuing after washing or flushing.
Provides enhanced permeability/substantivity on skin and mucosa/ocular/nasal surfaces.
Enables delivery of additional therapeutic agents on the administered surfaces.
Allows formulations to be stable at elevated temperature and to be autoclaved while retaining structural and/or chemical integrity.
Documented Applications
Topical, mucosal, ocular, or nasal prevention or reduction of microbial infection risk at a target site in a subject.
Use for prolonged antimicrobial killing and extended microbial exposure killing for at least about 4 hours after a single application.
Topical administration followed by flushing of the target site within 4 hours while retaining 99.9% microbial killing activity.
Use with microorganisms including enveloped viruses and gram+/- bacteria, with documented examples including SARS-CoV-2 and human coronavirus 229E, influenza B, and influenza A virus, and bacterial targets including MRSA and Staphylococcus aureus and other listed gram+/- bacteria.
Protection in connection with an intranasal influenza challenge.
Delivery/permeation enhancement for an additional therapeutic agent associated with mucin permeation and rat serum increases.
Formulation use as a topical or nasal spray dosage form, including soap, hand sanitizer, lotion, cream, and spray dosage form examples.
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