Patent Application
20160354307
Technical Field
The invention relates generally to antimicrobial compositions and methods of use, particularly to ocular antimicrobial compositions for treatment of eye infections and treatment of ocular related articles.
State of the Art
Treatment of corneal disease is complicated by the difficulty in diagnosis, at both the clinical and laboratory level, of the pathogen(s) causing the infection. These pathogens take days or even weeks to culture and to grow during which time significant irreversible damage may well occur to the infected eye. Even after diagnosis, the medications available for treatment are limited, to wit: the antibiotics used in ophthalmology do not have significant activity across groups of potential pathogens and there is a lack of potent fungicidal agents and poor ocular penetration of existing agents. The paucity of effective drugs is further diminished by a growing number of multi-drug resistant organisms
Keratitis is a general term meaning any inflammation of the cornea (the clear, round dome covering the eye's iris and pupil). The risk factors for keratitis include diabetes, AIDS, trauma to the eye, contact lens wear, contaminated lens cases and solutions, topical steroid use, use of traditional eye remedies, contaminated medications and make-up and ocular surface disorders. There are approximately thirty-six million lens users in the United States with 12,000 to 15,000 cases of keratitis each year. Overnight wear of contact lenses is the overwhelming risk factor.
Fungal keratitis is notoriously difficult to treat because of poor corneal penetration of antifungal agents. The only commercially available agent is natacyn and other agents needed to treat some of the seventy varieties of fungus must be compounded. Fungal keratitis has also been observed after LASIK procedures and associated denervation, as well as after corneal transplant in which the patient's corneal nerves are compromised, foreign material is present in the form of sutures and there is a concomitant use of a topical corticosteroid. The incidence of fungal keratitis has increased due to frequent use of topical corticosteroids along with antibacterial agents.
Bacterial keratitis causes pain, reduced vision, light sensitivity and tearing or discharge from the eye, and can also cause blindness. This disease is characterized by rapid progression. Destruction of the cornea may be complete within 24-48 hours with some of the more virulent bacteria. The characteristics of this disease are corneal ulceration, stromal abscess formation, surrounding corneal edema, and anterior segment inflammation. Bacterial keratitis is a common problem in contact lens use and refractive corneal surgery.
Polymicrobial infection is not uncommon and may be caused by combinations of viruses, bacteria and fungi. These multi-pathogen infections have been found in a third of cases, the majority due to multiple bacterial species. Twenty percent of positive cultures from cases with fungal keratitis were co-infected with bacteria. The risk of polymicrobial infection was approximately three times greater with Candida yeast fungi than with infection with filamentous fungi. This finding suggests that the bacterial are protected within the biofilm produced by the Candida fungi (the most common cause of fungal infection) and may contribute to the generally poor prognosis for fungal keratitis.
Conjunctivitis may be caused by a bacterial or viral infection, allergy, environmental irritants, contact lens products, eye drops, or eye ointments. Conjunctivitis causes swelling, itching, burning, and redness of the conjunctiva, the protective membrane that lines the eyelids and covers exposed areas of the sclera, or white of the eye. Conjunctivitis can spread from one person to another and affects millions of Americans at any given time. Some forms of conjunctivitis require medical treatment. If treatment is delayed, the infection may worsen and cause corneal inflammation and a loss of vision. Corneal infections are the most serious complication of contact lens wearers.
Compliance is a factor in inability of a patient/family to administer the medication required to treat many eye infections. Enough medication is required to kill the infection and at the same time be tolerated by the eye. One difficulty in topical administration of antibiotics is that they are rapidly cleared from the pre-corneal area by tear drainage and the immediate effect of blinking. Thus, most antibiotics must be administered frequently with application rates up to hourly and through the night, and in the case of fungal disease, perhaps for weeks of duration.
It was believed for many years that bacteria, unlike eukaryotic organisms, behaved as self-sufficient individuals and maintained a strictly unicellular life-style in planktonic form. During infections, bacterial mass was considered nothing more than the sum of these individuals. Our perception of bacteria as unicellular life-style was deeply rooted in the pure culture paradigm. Pure cultures were used to establish microbial causes of disease, and growth in liquid media ensured that all cells were exposed to similar conditions and behaved in the same manner. As a result, most of the measures to control pathogenic bacteria (e.g., vaccines and antimicrobial agents) have been developed based on knowledge of bacteria grown as planktonic cells. However, pure-culture planktonic growth of bacteria rarely exists in natural environments. In fact, bacteria in Nature largely reside in a complex and dynamic surface-associated community called a biofilm. It is now known that over 99% of bacteria life forms s with as few as 1% living in planktonic form.
Biofilms are generally defined as a community of sessile microbes held together by a polymeric extracellular matrix, adherent to a surface, interface or to other cells that are phenotypically distinct from their planktonic counterparts. Members of a biofilm community, which can be of the same or multiple species, show varying stages of differentiation and exchange information, metabolites, and genes with each other. As a result, members of the biofilm community are in a diversity of physiologies influenced by the unequal sharing of nutrients and metabolic byproducts, which results in subpopulations subjected to differing environmental stresses and having wit4i increased tolerance to antimicrobials and environmental stresses, the host immune system, and predatory microorganisms. Biofilm cell communities are more resistant to antibiotic and antifungal drugs than planktonic cells. Contributing factors include biofilm structural complexity, presence of extracellular matrix (ECM), metabolic heterogeneity intrinsic to biofilms, and biofilm-associated up-regulation of efflux pump genes.
Recent advances in medical biofilm research have led to an understanding that biofilms are responsible for a broad spectrum of microbial infections in the human or animal hosts and represent the prevalent form of bacterial life for tissue colonization, and they have been observed on the capsule, and in the corneal stroma.
The growing problem of antibiotic resistance is well documented in the CDC publication Antibiotic Resistance Threats in the United State, 2013. Candida is singled out in this report because this dangerous fungus is showing increasing resistance to the drugs available for treatment. With the already daunting course an ocular fungal infection already poses due to the paucity of anti-fungals that penetrate the cornea poorly, a drug resistant Candida presents a global threat to corneal health. The story is much the same with respect to other drugs used to treat eye infections: Over 30% of isolates from corneal infections were not sensitive to ciprofloxacin in India, and moxifloxacin and gatifloxacin are not reliable treatments for MRSA. Approximately 85% of MRSA strains are resistant to moxifloxacin and gatifloxacin. Resistance to fluoroquinolones is increasing.
Less well understood is a biofilm defense called antibiotic tolerance. Because of this defense “we actually never had antibiotics capable of eradicating an infection.” Lewis (2012), Persister Cells: Molecular Mechanisms Related to Antibiotic Tolerance, p. 121. A small number of cells (persisters) in a biofilm are phenotypically resistant to sudden exposure to stress brought on by high doses of antibiotics and also phagocytosis by microphages. Once an antibiotic concentration drops, surviving persisters re-establish the population, causing a relapsing chronic infection. Whether persistence and resistance represent complementary or alternative adaptions is unclear, although recent research indicates that they come from separate phenomena. Tolerance allows a population of cells to linger at the site during the decrease of antibiotic concentration which increases the probability of acquiring resistance.
The mechanism of the formation of persister cells has only recently been studied and begun to be understood. “Only a few years ago the molecular basis of persistence was still obscure. Although many genes were known to influence persister formation, they seemed so disparate and general that predicting persistence solely from genomic data would have appeared impossible.” Vogwill, et. al. (2016)J. Evol. Biol. dcl: 10.111/jeb. 12864, p. 1. “The main focus of research in antimicrobials has been on antibiotic resistance, and the basic starting experiment is to test a clinical isolate for its ability to grow in the presence of elevated levels of different antibiotics.” Persister cells are missed by this test. Lewis (2012), Persister Cells, p. 124.
Several models theorize how persister cells escape destruction. The three-dimensional organization of the biofilm causes gradients of oxygen, pH, and nutrients, resulting in the development of different microniches, or microbial microenvironments. The cell's individual physiological adaptations to these microniches results in physiological heterogeneity. Cells near the surface of the biofilm will be exposed to more nutrients, such as salts, amino acids, proteins, sugars and oxygen and are therefore more metabolically active, while cells in the deep regions will be less active or even dormant. This heterogeneity results in a range of responses to antimicrobial agents, with metabolically active cells at the surface being rapidly killed while more internal, dormant cells are comparatively unaffected. Some theories postulate that persister cells adopt a low metabolic state or dormancy and thus become highly resistant to antibiotics. An experiment with ciprofloxacin indicated that a biofilm response was the stress release of the TisB peptide which binds to the membrane of the persister cell causing a metabolic shut down, that blocks antibiotic targets, and ensures multidrug tolerance for the surviving persisters. Another possible route to the formation of persister cells is stochastic production of a few persister cells in each generation of cells that would seem to provide evolutionary protection should the vast majority be destroyed
In some instances, the medications available for treatment are limited because the available antibiotics do not have significant activity across groups of potential pathogens and there is a lack of potent fungicidal agents. “[A]ntimicrobial drugs that specifically target biofilm-associated infections are needed.” CDC, Vol. 10, Number 1 “Fungal Biofilms and Drug Resistance. It is apparent that there is a critical need to find and identify molecules that can overcome both antibiotic resistance and tolerance and can completely destroy biofilms and persister cells.
Biofilm formation also imposes a limitation on the uses and design of ocular devices, such as intraocular lenses, posterior contact lenses, scleral buckles, conjunctival plugs, lacrimal intubation devices and orbital implants. As the evidence for the involvement of microbial biofilms in many ocular infections has become compelling. Biofilm formation begins with a transition from the planktonic form to its genetically distinct sessile state (Colonization). Developing new strategies to prevent colonization has become a priority. One way to reduce ocular related article surface contamination is to sterilize the contact lenses, intraocular lens and lens case. Products used to clean and disinfect contact lenses use heat, subsonic agitation or UV disinfection systems with cleaning solutions that include enzymes or hydrogen peroxides. These systems are intended to remove contamination on the lens. However, it has been found that fungi resist disinfection by contact lens solutions wherein they readily form biofilms. Biofilms have that cause endophthalmitis have also been found on intraocular cataract lenses and contact lenses. Contact lens cases have also been linked to microbial keratitis. Such cases provide an environment that is nutritive and protective of microorganisms that form biofilms. Some disinfectants have been shown to select for resistant antimicrobial strains, e.g., methicillin resistant Staphylococcus aureus (MRSA). MRSA/MRSE and mycobacterial infection in contact lens wear are rare but have devastating effect. Community-associated MRSA is an evolving ocular pathogen most often found in hospital patients. Finally, disinfectants are washed off and must be replaced daily. The repeated use of disinfectants that are sent down the drain poses an environmental problem.
Compliance with safety measures involving contact lens care products is a daunting problem. Patients are not compliant even though they believe and intend otherwise. Contact lens users have a tendency to re-use or top off cleaning solutions. Tap water is often used to rinse lenses or contact lens storage cases instead of sterile water. The recommendation that contact lens cases be thoroughly cleaned and air dried and then replaced every three months is routinely ignored. These non-compliance tendencies raise the risk of contact lens-related eye infections.
To address the exhaustion of biocides to the surrounding environment, a class of water-soluble antimicrobial polymers, Contact-Active Biocidal (CAB) was developed to provide a non-toxic, non-leaching surface covering for walls and counters. CAB products can be bonded to most surfaces, both porous and non-porous, for an extended period of time. As such, the CAB products provide an invisible, microbiostatic coating to prevent Colonization by reducing the number of planktonic single cell microbes that attach to the surface below the number required to form a biofilm. The CAB products are typically offered in liquid form and may be applied to desired surfaces after disinfecting the surface of a wall or counter or through a washing machine rinse cycle. Once the CAB product is applied, the compound reduces the number of new microbes that are able to attach to the surface by creating a semi-permanent coating that partially covers the surface and physically kills microorganisms on contact.
The effective life of the CAB product, however, is relatively short. Moreover, once applied, it is difficult to determine at what time the biological activity becomes diminished and the CAB is no longer maintaining a disinfected surface. An undisclosed problem is a CAB that is not regularly cleaned can be expected to fill with dust and debris which works counter to its claimed purpose. Most CAB products used as coverings for ocular related article surfaces have not been a commercial success.
There is a desperate need in medicine for newer compounds with novel mechanisms of action, greater antimicrobial activity and less cytotoxicity. Therefore, it is desired to provide a composition that address the above concerns, namely, providing an effective substitute for antibiotics and antifungals in treating eye infections; better antifungal agents that work rapidly, penetrate more efficiently into ocular tissues and have fewer medical failures, protecting against infection inadvertently delivered by contact lenses, lens cases and contaminated fluids that are used to disinfect or treat the eye; reducing use of toxic compounds that pollute the environment and reduce the likelihood of microbial development of antibiotic resistance in biofilms.
The present disclosure relates to broad spectrum antimicrobial compositions, and, in particular, to antimicrobial compositions comprising organosilanes including 3-(trihydroxysilyl)propyldimethyloctadecyl ammonium chloride and methods of use for treating ocular infections; destruction and removal of biofilms and inhibiting the formation of biofilms on eyes, lenses or other devices to be placed in the eye and in lens cases or other containers or repositories for such lenses or devices. These compositions combine both antibacterial and antifungal properties and accordingly are particularly useful when rapid intense topical therapy is required before identification of the pathogen causing the infection can be made or when dealing with a polymicrobial infection.
The antimicrobial compositions inactivate, disrupt and destroy pathogens that cause, inter alia: corneal inflammation, endophthalmitis, anterior segment infection and inflammation, keratitis, scleral buckle infection, corneal ulceration, stromal abscess formation, lacrimal system infections, periorbital infections and infections in the corneal stroma (any of which can cause loss of vision and blindness), and methods of using the same. Use of such compositions is intended by direct application to the eye, to cure eye infections; inhibit re-infection; also to disinfect and create an antimicrobial barrier against the population of infectious microorganisms on ocular related articles, such as intraocular cataract lenses, contact lenses and other devices to be placed or used in or on the eye; and disinfect and provide a barrier against re-infection of lens cases and similar storage devices. The disclosed antimicrobial compositions may be placed topically onto the conjunctiva and cornea. In some embodiments, the organosilane is 3-(trihydroxysilyl) quaternary ammonium chloride. In a preferred embodiment, the formulation includes a pharmaceutically acceptable topical carrier and a delivery system, which is applied directly into the infected eye of an animal or human. The rapid bonding quality of the composition inhibits premature clearing by tearing and permits low concentration of the active ingredient at an effective level of minimal irritation to tissues.
The antimicrobial compositions described herein may be used for treatment of ocular articles relating to the eye, inter alia contact lenses, lens cases, protective shields that contact the sclera or cornea, suture material, for some embodiments the delivery system is a pad, cloth or other material treated with the antimicrobial composition herein, which is inserted into the lens case or other container in a manner so as to surround and be proximate to the lens or other ocular device stored therein. In some embodiments the treated cloth may be used as a wipe to clean the lenses or other devices to be placed into or on the eye. As part of this cleaning process, some of the antimicrobial composition will be deposited on the lenses or other devices and will provide a barrier against infection from other microorganisms that may be encountered on the surface of the eye or from other sources of contamination that may come into contact with the eye. In some embodiments the pad to enclose the contact lens within the case is treated with the organosilane and further enhanced with a dating system to limit duration of usage. In some embodiments, the concentration of organosilane is less than about 0.1 percent by weight. In some embodiments, the concentration of the organosilane is in the range of from about 0.1 to about 1.0 percent by weight. In some embodiments, the concentration of the organosilane is in the range of from about 1.0 to about 5.0 percent by weight and percent by weight. In some embodiments the concentration of the organosilane is greater than about 5.0 percent by weight.
In some embodiments, the carrier is a compound that includes buffers; sodium chloride; potassium; sugars including disaccharides, such as lactose, monosaccharides, such as dextrose and glucose, and polyols such as mannitol; surfactants; enhancers; saline; and water. Buffers may include boric acid or sodium borate to maintain the pH of the composition in the range of from about 7 to about 8. In some embodiments, when a gel or ointment is desired, the organosilane is mixed with a carrier that may include isotonic saline, in the range of from about 1 to about 2% t polyvinyl alcohol, 1% alpha-methylcellulose, a mixture of white petrolatum-mineral oil ointment or another properly constituted ophthalmic gel, ointment, mineral oil, lanolin or petrolatum.
In some embodiments, the composition also includes an enzyme of bacterial origin, preferably from a Bacillus or Actinomyces, or from fungal sources or genetically engineered from non-alkaline cellulases by modifying the protein to function in an alkaline pH. In some embodiments, the enzyme is a proteolytic keratinase or a protein hydrolase. In some embodiments, the enzyme is an enzyme acting upon a substrate comprising N-acyl homoserine lactone. In some embodiments, the enzyme is an alginate lyase. In some embodiments the enzyme is a cellulose such as carboxymethyl cellulose or a gluconase. In some embodiments, the enzyme is a glycoside hydrolase such as DispersinB. In some embodiments, the enzyme is an amylase or a protease. In some embodiments, the enzyme is Deoxyribonuclease (DNase I.)
Disclosed is a method of providing a non-toxic antimicrobial treatment to inhibit, remove and destroy a biofilm, the method comprising the steps of applying and adhering an antimicrobial composition that includes an organosilane to the cornea by liquid drops or gel or ointment. The antimicrobial composition penetrates the biofilm in some embodiments aided by the use of enzymes and accompanied by other antibiotic and or antifungal compounds designed to destroy intractable colonies together with any disbursed planktonic pathogens. Disclosed is a method of treating an eye infection, the method comprising steps of topically applying the antimicrobial composition containing an organosilane to an infected cornea; thereby penetrating and killing infectious pathogens and biofilms.
In some embodiments for treatment of ocular related articles, the method further comprises the step of placing the treated ocular related article in close proximity to an area of microbial colonization. Disclosed is a method of providing a non-toxic antimicrobial treatment to a container or case for ocular lenses or devices, the method comprising the steps of applying a liquid composition containing an organosilane to the interior surfaces of the case or container by spray, brushing, dipping or other method of application.
The foregoing and other features and advantages of the present invention will be apparent from the following more detailed description of the particular embodiments of the invention.
Some of the embodiments will be described in detail, with reference to the following figures, wherein like designations denote like members:
FIG, 2 is a schematic diagram showing a general chemical structure of an organosilane molecule: 3-(trihydroxysilyl)propyldimethyloctadecyl ammonium chloride according to the invention;
A detailed description of the hereinafter described embodiments of the disclosed apparatus and method are presented by way of example and not meant to be limiting. Although certain embodiments are shown and described in detail, it should be understood that various changes and modifications may be made without departing from the scope of the appended claims. The scope of the present disclosure will in no way be limited to the number of constituting components, the materials thereof, the shapes thereof, the relative arrangement thereof, etc., and are disclosed simply as an example of embodiments of the present disclosure.
As a preface to the detailed description, it should be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents, unless the context clearly dictates otherwise. Some general definitions are provided for the terms used herein. “Organosilane” means a compound of the family of compounds comprising the elements of silicon, oxygen, and carbon with a C—Si covalent bond and a nitrogen atom in a quaternary ammonium configuration. “Organosilane” also includes any quaternary ammonium salt of an organosilane. “Microbial cell” and “microbe” are used interchangeable and are understood to mean any single-celled planktonic organism. “Biofilms” are multicellular communities usually held together by an extracellular polymeric substance (EPS), ranging from capsular material to cell lysate. In a structure that imposes diffusion limits, environmental microgradients arise to which individual bacteria adapt their physiologies, resulting in the gamut of physiological diversity. Additionally, the proximity of cells within the biofilm creates the opportunity for coordinated behaviors through cellcell communication using diffusible signals, the most well documented being quorum sensing (QS). The cells growing in a EPS biofilm are physiologically distinct from planktonic cells, which, by contrast, are single-cells that may float or swim in a liquid medium. Microparticle may also refer to a solid compound comprising the particle that is, itself, coated with the organosilane for purposes of becoming imbedded in the EPS of a-mature biofilm.
The antimicrobial action of composition 100 is provided by the organosilane compound. An organosilane is a molecule comprised of a silicone atom covalently bonded to carbon. Organosilanes in general may be amphiphilic, having both water-soluble and lipid soluble components. Organosilane 102 has a hydrophilic “cap” having a silicon-tri-hydroxy “head,” and a hydrophobic “tail” comprising an eighteen or twenty-atom linear carbon chain. The head and tail are joined at a nitrogen atom bonded with two additional methyl groups to create a (cationic) quaternary ammonium group. The methoxy or hydroxy head groups facilitate enzymatically or chemically binding the organosilane to a surface 140. Surface 140 includes the non-limiting examples of biological surfaces, such as corena or mucosa, or non-biological surfaces—whether porous or non-porous—such as a lens or lens case, for example. The hydrophilic quaternary ammonium group, in particular the positive charge of the nitrogen atom, allows for ionic attraction between the negatively-charged cell wall membranes of bacteria and fungi. Microbial cells having a negative ionic charge are drawn to the organosilane electrostatically by the cationic quaternary ammonium groups of the organosilane. Amphiphilic quaternary ammonium compounds, including but not limited to organosilane 102, effect microbial killing by the cationic N+ atom ionically is attracted to negatively charged sites on lipopolysaccharides and constituent proteins of the bacterial cell wall causing perturbation and cell wall weakening with leakage. The carbon chains of the organosilane in proximity to the microbial cell wall engage and may then penetrate the weakened cell wall, destroying the microbe. This cell killing mechanism is advantageous for several reasons. Organosilane 102 is not altered or consumed by its interaction with the targeted cell. Residual organosilane remains covalently bound to the treated substrate-eliminating the need for frequent regular re-application and-minimizing release of large amounts of a frequently-applied compound into the environment.
In various embodiments of the invention, other compounds are added to composition 100. For some embodiments wherein composition 100 is used in a biological system, a carrier, 103 is added. In some embodiments, a carrier is added which may include surfactants, buffers, and/or sodium chloride with water to form aqueous solutions. In some embodiments, a gel or ointment formulation contains a carrier in a hydrophilic base prepared from compounds such as lanolin, mineral oil or polymers. For some embodiments wherein composition 100 is used to kill microorganisms in a biofilm, whether in a biologic or non-biologic environment, composition 100 further comprises a cellulase enzyme. In some embodiments, composition 100 further comprises other enzymes or compounds to interfere with quorum sensing utilized by microorganisms growing in a biofilm. In some embodiments, composition 100 comprises an agent to enhance viscosity. In some embodiments, composition 100 comprises an agent to promote trans-epithelial delivery of un-bound composition 100 through the cornea or mucosal surfaces. The manner and method of mixing these and other ingredients is well known to those skilled in the state of the art.
In some embodiments, composition 100 further comprises nutrients such as, phosphate, sugars, proteins, oxygen and nitrogen. Sugars include monosaccharides, disaccharides and polyols. Monosaccharides are particularly useful. The addition of nutrients effectively feeds the biofilm promoting delay in persister cell formation leading to dormancy and encourages persister activation thus making the active microbe easier to kill by an organosilane that benefits from a strong negative charge on the microbial cell wall. Nutrients appear to induce stress which aids in accomplishing this reversal of dormancy.
Referring to the drawings,
In the example embodiment shown in
In some embodiments involving treatment of an eye wherein an invasive microbial infection is present, an anti-inflammatory compound may be desirable as a useful therapeutic adjunct. Invasive microbial infection normally creates an inflammatory response. Inflammation creates swelling, increases pain and/or itching, and, if marked or accompanied by rubbing of the eye, may interfere with healing. Therefore, treatment with a topical or systemic anti-inflammatory compound may be useful. In some embodiments, composition 100 further comprises an anti-inflammatory molecule. Some non-limiting examples of such anti-inflammatory compounds include steroids, such as triamcinolone diacetate, hydrocortisone, beta methasone valerate, and beta methasone diproprionate; non-steroidal anti-inflammatories, resorcinol, and methyl resorcinol
Some antibiotics and enzymes function optimally within a relatively narrow pH range. Accordingly, some embodiments of composition 100 add a buffer to the treating composition at concentration levels sufficient to maintain the pH range required for optimal activity of the components of the composition. The particular buffer is selected based upon the conditions present on the ocular surface 140. Buffers to maintain ambient pH within a desired range include, but are not limited to, boric acid, sodium borate, citrates, sulfonates, carbonates, and phosphates. The preferred buffering compound and concentration of same useful for maintaining a desired pH range are dependent on ambient micro-environmental conditions at the treated area and known to those skilled in the art.
Composition 100 additionally comprises a carrier 108. Carrier 108, in some embodiments, is a compound that holds the various sub-components of composition 100 in suspension or solution. The specific compound used is chosen based upon the characteristics necessary for the end-use application of composition 100. For example, if composition 100 is to be used to treat a non-biological surface, such as a lens case, carrier 108 may comprises a substance with relatively high volatility, such as ethyl alcohol or isopropyl alcohol or a similar low-molecular weight alcohol, or water. If composition 100 is to be used on a biological surface, such as a cornea, carrier 108 may be an emollient, non-ionic surfactant, viscosity enhancer, salt or sugar-containing solution or other suitable compound. Non-limiting examples include excipients, such as cetyl alcohol, tyloxapol, methyl paraben, white petroleum, propylene glycol, mineral oil, liquid lanolin, cottonseed oil or a polymer liquid-gel. The carrier may, in some embodiments, be employed to form composition 100 into a gel, lotion, ointment, liquid solution, or liquid suspension, according to the intended end-use of composition 100.
The concentration of organosilane 102 by weight of composition 100 is also selected according to the desired end-use of composition 100. In situations where high antimicrobial activity is needed for treating a non-biological surface, higher concentrations of organosilane provide a higher density of adherent organosilane molecules on surface 140. In effect, the “forest” of aliphatic hydrocarbon molecular “tails” is thicker. Additionally, higher organosilane concentrations create a higher cationic charge density, resulting in both stronger electrostatic microbial attractive forces and detergent effects on the microbial phospholipid cell membrane. Because some organosilane molecules become separated from surface 140 with each wiping or cleaning, a higher concentration of organosilane 102 in composition 100, in some embodiments, allows composition 100 to act as a surface antiseptic for a longer period of time. Concentrations of organosilane 102 in composition 100 of up to and over 5% by weight may be used, however, when used in concentrations of over about 3%, polymerization of organosilane 102 within composition 100 prior to application on surface 140 increases through intermolecular cross-linking via—S—O—S—covalent bonds. In applications to biological surfaces, such as a cornea, are to be treated using composition 100, composition shedding through tear shedding and corneal epithelium mitosis requires appropriate re-application of composition 100, in some applications. The risk of developing resistance to an antimicrobial composition, regardless of the reaction mechanism of the compound, theoretically increases with increasing environmental encounters between biofilms and other microbes, and the antimicrobial composition. It is prudent, therefore, to strive to minimize the amount of an antimicrobial composition within the general environment. Accordingly, in the aforementioned and other situations wherein frequent re-application of composition 100 is necessary, lower concentrations of organosilane 102, about 0.1% by weight and lower in composition 100, are useful by lowering the overall amount of organosilane 102 ultimately discharged into the environment. Notwithstanding the theory, it is believed that the risk to the environment and/or causing biofilm mutations by use of these formulations is minimal.
Because in some embodiments, composition is a non-leaching composition that is bound to surface of an ocular related article, such as a gauze pad, felt, cotton or fabric patch, the area may be treated without ever placing or applying the antimicrobial composition directly into the eye. The electrostatic properties of composition 100 comprising an organosilane or and/or additional cationic detergent or other substance may attract and draw nearby microbes to the cationic composition, thereby reducing the concentration of microbes in the area of the eye sought to be protected from microbial colonization and/or infection and possible biofilm formation. In some embodiments, treated article is placed in contact with the eye to treat the infection. In these instances, the positive-negative electrical attraction between the wall of the microbial cells and the formulation in the treated article tends to attract microbes, killing them and maintaining the detritus on the treated article, to be disposed of safely.
In some embodiments, as shown in
The use of composition 100, as an antimicrobial on a non living surface is prone to deactivation and creation of the very condition that it intends to prevent. This is because cellular debris from killed microbes may adhere to the hydrophilic “tail” of organosilane after death and new approaching microbes can adhere and proliferate on this debris, 135, some embodiments of composition 100 may be self-deactivating. Additionally, biologic exudates such as mucopolysaccharides, inorganic dust and other particulate matter and cellular material from dead microbes may eventually fill and clog the microscopic bed of composition 100, thus forming a favorable local microenvironment for the development of new biofilms. The microscopic bed of composition 100 may then become a biofilm that use of composition 100 is intended to prevent.
In addition to proteolytic keratinases, some embodiments of composition 100 comprise other enzymes. For example, N-acyl homoserine lactone is a bacterially-produced amino sugar acting as a hormone involved in quorum sensing, wherein a population of bacteria limits its growth density and other population-based characteristics, such as gene regulation of enzyme systems and the expression of flagella versus pili. Enzymes acting upon an N-acyl homoserine lactone substrate destroy and substrate and thereby temporarily disrupt bacterial signaling systems in a biofilm, acting as an adjunct to proteolytic keratinases and other components of composition 100, in some embodiments, such disruption may cause the existing biofilms to break apart and interfere with new biofilm formation. . In some embodiments, the enzyme is an alginate lyase. In some embodiments the enzyme is a cellulase such as carboxymethyl cellulase or a gluconase In some embodiments, the enzyme is a glycoside hydrolase such as DispersinB. In some embodiments, the enzyme is an amylase or a protease. In some embodiments, the enzyme is Deoxyribonuclease (DNase I.)
In some embodiments as shown in
In some embodiments as shown in
Exceptional results can be obtained with organosilane compounds for treatment of human and animal eye infection, creating antiseptic coatings for tissues, and methods of using the same disclosed in this description of several embodiments of the invention. The disclosed composition provides a durable treatment of a biological or non-biologic surface, minimizes leaching of antimicrobial into the environment, minimizes opportunities for development of microbial resistance due to its combined physical and electrostatic mechanisms of action, is safe and effective in treating resistant invasive infections of the eye and surrounding tissues, and may be applied directly to articles such as lens cases and containers.
The embodiments and examples set forth herein were presented in order to best explain the present invention and its practical application and to thereby enable those of ordinary skill in the art to make and use the invention. However, those of ordinary skill in the art will recognize that the foregoing description and examples have been presented for the purposes of illustration and example only. The description as set forth is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the teachings above.
This application claims priority to earlier U.S. Provisional Patent Application entitled “PRODUCT AND DELIVERY SYSTEM FOR ANTIMICROBIAL TREATMENT OF INFECTIONS OF THE EYE AND OF PATHOGENS CONTAMINATING OCULAR DEVICES AND METHODS OF USE,” Ser. No. 62/201,693, filed Aug. 6, 2015; and further, this application is a continuation-in-part of the earlier U.S. Utility Patent Application entitled “PRODUCT AND METHOD FOR TREATMENT OF A BIOFILM, INCLUDING CONTROL OF SUBSTRATE COLONIZATION AND TREATMENT OF INFECTION,” Ser. No. 14/716,589, filed May 19, 2015, which claims priority to earlier U.S. Provisional Patent Application entitled “ANTIMICROBIAL POLYMER PRODUCTS AND DELIVERY SYSTEM FOR INFECTION CONTROL AND METHOD OF USING THE SAME,” Ser. No. 62/200,403, filed May 19, 2014, the disclosures of which are hereby incorporated entirely herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62000403 | May 2014 | US | |
| 62201963 | Aug 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14716589 | May 2015 | US |
| Child | 15231236 | US |
