Antibacterial Organosilane

Abstract

Organosilicon quaternary ammonium compounds, their formulations, including powdered and solid formulations, and methods of use for treating infectious diseases in humans and animals.

Description

Technical field

[0001] [Cross reference to related application] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 923,372 filed October 18, 2019 and U.S. Patent Application No. 63 / 014,535 filed April 23, 2020 is.

[0002] The present disclosure provides organosilicon quaternary ammonium compounds and compositions thereof, and their use in topical medical therapy in humans and animals, and their use for disinfecting surfaces, wherein the surfaces are Applications include, but are not limited to, industrial applications, transportation applications, and domestic applications. [Background technology]

[0003] To provide novel antibacterial agents, including antifungal agents and antibiotics, for the treatment of infections, including difficult-to-treat infections, in humans and animals that do not respond or respond poorly to current therapies. is an urgent global imperative.

[0004] In September 2018, PEW Charitable Trusts reported a critical need for new antibiotics. At that time, there were only 42 antibiotics in clinical development, with an expected approval rate of less than 20%. Of those, only 15 had the potential to treat infections caused by drug-resistant Gram-negative pathogens. Only 11 antibiotics in development have the potential to treat pathogens considered a serious threat by the World Health Organization.

[0005] One way microorganisms evade current therapies is by forming biofilms. Biofilms consist of populations of microorganisms that adhere to each other and often to surrounding surfaces. Such microorganisms may be fungi, bacteria, yeasts, algae, or generally mixtures thereof. Microbial communities are surrounded by extracellular polymeric substances (EPS) (see Non-Patent Document 1), which is a mixture of polysaccharides, extracellular DNA (eDNA), and proteins, It functions as a matrix that keeps the . The biofilm matrix contributes to the overall biofilm structure and resistance phenotype (see Non-Patent Document 2 and Non-Patent Document 3). This matrix "also provides the spatial organization of biofilms from which microbes develop steep, high biodiversity and complex, dynamic, and lead to synergistic interactions” (see Non-Patent Document 4). This protective mode of growth allows microorganisms to survive in harsh environments and disperse seeded cells to colonize new microenvironments under desirable conditions.

[0006] The increase in microbial resistance to current therapeutic regimens is due, at least in part, to increased effectiveness of the primary endogenous defense mechanisms of microorganisms, particularly those in biofilms. These defenses include reduced drug uptake, efflux, enzyme inactivation, and retargeting by mutation. Microorganisms can also acquire resistance by sharing genetic material, a process called horizontal gene transfer (HGT) that is more rapid than gene selection responsible for the development of endogenous resistance. there is a possibility. Simultaneous or sequential multi-microbial infections can occur with similar organisms of different species or mixtures of bacteria and fungi. Available antimicrobial agents used for treatment often do not have significant overlapping activity across populations of candidate pathogens (Non-Patent Document 5).

[0007] The negative consequences of such biofilm interactions can result in significant medical burden such as non-healing or chronic wounds. Chronic wounds, defined as biobarrier defects that have not healed in 3 months, management of which presents a major therapeutic challenge throughout the Western world, are conditions that interfere with wound healing, such as diabetes, obesity, and obesity. The problem is that it only increases with the rising incidence of vascular disorders. Ulcers last an average of 12-13 months, recur in up to 60%-70% of patients, can lead to disability and poor quality of life, and are an important cause of morbidity ( Non-Patent Document 6). Regardless of their clinical and molecular heterogeneity, all chronic wounds are generally assigned to one of three major clinical classifications: leg ulcers, diabetic foot ulcers, or pressure ulcers. In the United States alone, such wounds affect an estimated 2.4-4.5 million people (Non-Patent Document 7). Chronic leg and foot ulcers occur in many adults with vascular disease or diabetes and result from chronic venous insufficiency, arterial disease, long-term compression, or neuropathy (Non-Patent Document 6). Diabetic foot ulcers (DFU) are responsible for 80% of non-traumatic leg amputations, with an associated 5-year mortality rate of 43%-55%.

[0008] These chronic wounds are largely believed to be severely colonized by multiple microbial communities that contribute to persistent inflammation and cessation of the healing process, reducing patient quality of life. reduce significantly. In tissue injury, microorganisms enter the wound. In wounds, the physical environment differs from the skin surface in temperature, pH, nutrient availability, and host immune effectors. In this case, microbial metabolism may be altered, thereby providing opportunities for commensal microbes to become pathogenic and community composition to fluctuate in response to host clinical factors. Once colonization occurs, these communities form biofilms within the wound and disrupt coordinated tissue regeneration processes.

[0009] Although current treatments for wounds with suspected biofilms focus primarily on targeting bacteria, the skin is also a host for resident fungi, and our environment is rich in fungal diversity. (Non-Patent Document 8). Chronic wound patients receive significantly more antibiotic prescriptions (both systemic and topical) than other age- and gender-matched patients. Many human commensal fungi or yeasts are also opportunistic pathogens and many species are known to be biofilm prolific. There is now sufficient evidence to conclude that increased biofilm species diversity correlates with increased antimicrobial resistance (9). Moreover, the use of antibiotics that target bacteria in mixed communities has been shown to increase fungal diversity in wound tissue and provide a suitable microenvironment for fungal expansion of mixed bacterial-fungal biofilms. there is

[0010] Biofilms exist in a number of additional conditions that can lead to chronic infections or recurrent infections. For example, ear infections can be the result of biofilms in humans and in animals such as dogs, cats, rabbits, and horses. In both animals and humans, infections can cause hearing loss as well as other health problems if not treated appropriately.

[0011] Corneal vision impairment is a general term for symptoms resulting from various infections that damage the cornea. Effective treatment of ocular infections with available medicines is clearly a global health priority. Fungi alone cause over one million eye infections each year, many of which lead to blindness. The eye is particularly vulnerable to fungal infections when anatomical barriers are breached. The host's immune system is often unable to fight fungal infections to prevent vision loss (see Non-Patent Document 10). The lack of potent fungicides and the poor intraocular penetration of existing antifungal agents has resulted in significant ocular morbidity. Bacteria are also a major cause of ocular infections worldwide. If not treated properly, eye infections can cause damage to eye structures, leading to visual impairment or possible blindness. Bacteria, especially Gram-positive bacteria, are associated with conjunctivitis, keratitis, endophthalmitis, blepharitis, and orbital cellulitis.

[0012] A further skin disorder that has proven difficult to treat is acne vulgaris. Acne vulgaris is caused in part by the overgrowth of the bacteria Propionibacterium acnes and inflammation induced in response to P. acnes and / or dead skin cells and skin lesions. It is a common skin condition that occurs when hair follicles become clogged with oil from the hair. It has been suggested that P. acnes cells resident in hair follicles grow as biofilms, making them particularly difficult to treat (see, eg, Non-Patent Document 11).

[0013] Biofilm formation occurs on non-living (i.e., inanimate) surfaces such as homes, workplaces, industrial areas including manufacturing plants, public areas, bathrooms, kitchens, furniture, transportation hubs and surfaces, and others that come into contact with humans or animals. It also occurs on the surface of

[0014] By way of example and not limitation, the food and medical sectors constitute a major public health problem. Biofilms provide a persistent source of pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus, which lead to serious infections such as food-borne infections and nosocomial infections. Such biofilms are also a source of material degradation and failure. It also appears that the environmental conditions commonly met in the food and medical fields also improve biofilm formation, as well as their resistance to disinfectants.

[0015] Contamination caused by biofilms can occur at all stages of food processing through food handlers, contaminated equipment, and food preparation surfaces (12). The Centers for Disease Control and Prevention (CDC) reported that 48 million foodborne illness episodes occur each year in the United States, resulting in 128,000 hospitalizations and up to 3,000 deaths (13). In the European Union, 5609 outbreaks of food poisoning were reported in 2007, including approximately 39727 human cases (11283 in France), 3291 hospitalizations and 19 deaths (7 in France). was involved (Non-Patent Document 14). In addition, healthcare-associated infections (HAIs), also known as hospital-acquired infections, commonly occur via the hands of healthcare workers, contaminated surfaces, and equipment (surgical instruments, catheters, respiratory devices, endoscopes, needles, etc.). (Non-Patent Document 15). The National Hospital Discharge Study (NHDS) estimated that between 1990 and 2002, the number of HAIs occurring in US hospitals was up to 1.7 million, of which 98,987 were fatal

[16] . ). In Europe, the number of HAIs is estimated at 3.2 million per year (Non-Patent Document 17).

[0016] Globally, a global pandemic caused by the spread of the SARS-CoV virus has occurred in recent years and continues to plague the world. The pandemic has raised public awareness around the world about the importance of sanitizing surfaces.

[0017] The problem of antimicrobial resistance has been growing in severity for decades, but fewer and fewer antibiotics and other antimicrobial agents are being developed, and many previously treatable infections are now It has become much more difficult to treat with the current arsenal of drugs and may soon become incurable. [Prior art documents] [Non-Patent Literature]

[0018] [Non-Patent Document 1] Karatan E., Watnick P. "Signals, regulatory networks, and materials that build and break bacterial biofilms" Microbiol. Mol. Biol Rev. 2009, 73:310-347 [Non-Patent Document 2] Sutherland I.W. "The biofilm matrix-An immobilized but dynamic microbial environment" Trends Microbiol. 2001, 9:222-227 [Non-Patent Document 3] Branda S.S., Vik S., Friedman L., Kolter R. "Biofilms: The matrix revisited" Trends Microbiol. 2005, 13:20-26 [Non-Patent Document 4] Flemming H.-C., Wingender J., Szewzyk U. Steinberg, P., Rice S. A., Kjelleberg, S. "Biofilms: An emergent form of bacterial life" Nature Reviews Microbiology 2016, 14:563-575 [Non-Patent Document 5] Tuft, S. "Polymicrobial infection and the eye" Br J Ophthalmol. 2006, 90(3):257-258 [Non-Patent Document 6] Richmond NA, Maderal AD, Vivas AC. Evidence-based management of common chronic lower extremity ulcers. Dermatol Ther 2013; 26:187-196 [Non-Patent Document 7] Evidence-based management of PAD & the diabetic foot. Brownrigg JR et al., Eur J Vasc Endovasc Surg. 2013 Jun; 45(6):673-81 [Non-Patent Document 8] Percival SL, McCarty SM, Lipsky B. 2015. Biofilms and wounds: an overview of the evidence. Adv Wound Care (New Rochelle) 4: 373-381. [Non-Patent Document 9] Desai JV, Mitchell AP, Andes DR. 2014. Fungal biofilms, drug resistance, and recurrent infection. Cold Spring Harb Perspect Med 4: doi:10.1101 / cshperspect.a019729 [Non-Patent Document 10] Klotz, S., Penn, C., Negvesky, G. and Butrus, S. "Fungal and Parasitic Infections of the Eye" Clin Microbiol Rev 2000, 13(4):662-685 [Non-Patent Document 11] Coenve et al., Biofilms in skin infections: Propionibacterium acnes and acne vulgaris. Infect Disorder Drug Targets. 2008 Sep; 8(3): 156-9 [Non-Patent Document 12] Verraes et al.2013 [Non-Patent Document 13] CDC 2013 [Non-Patent Document 14] EFSA 2009 [Non-Patent Document 15] Weber et al.2013 [Non-Patent Document 16] Klevens et al.2007 [Non-Patent Document 17] Suetens et al. [Outline of the invention] [Problems to be solved by the invention]

[0019] Therefore, there is still a strong need for new antimicrobial agents. Novel safe and effective topical medicaments that treat a wide range of microbial infections are needed for the treatment of topical infections, including those involving mixed pathogen biofilms, in humans and other animals. New effective antimicrobial agents are also needed for surface disinfection in a wide range of environments, including residences, workplaces, industrial areas, transportation points, and food production and serving locations. [Means for solving the problem]

[0020] In one embodiment, it is administered to a host in need of treatment in an effective amount in a topical pharmaceutical formulation to treat a wide range of infections, including fungal infections, Gram-positive, Gram-negative, and viral infections. Novel organosilane quaternary ammonium compounds are provided that are capable of treating disease. Fungi can appear as yeast, mold, or a combination of both forms. The novel quaternary ammonium compounds and formulations described herein can treat microorganisms in biofilms, including mixed organisms.

[0021] As shown in the Examples, several non-limiting exemplary compounds described herein (e.g., Compound 1, Compound 2, and Compound 23) are effective against a wide range of difficult-to-treat microorganisms present in persistent infections. and have potent antimicrobial activity and inhibition, such microorganisms include multiple Candida species, Cladosporium herbarum, Aspergillus niger, Mycoplasma pneumoniae. , Fusarium oxysporum, Staphylococcus aureus, and Enterococcus faecalis. Such microorganisms are particularly prevalent in microbial biofilms present in chronic wounds (see, eg, Omar et al., Microbial Biofilms and Chronic Wounds. Microorganisms 2017, Mar; 5(1): 9).

[0022] Thus, in one embodiment, the organosilane quaternary ammonium compounds described herein can be used in effective amounts in topical formulations for direct application to infections or wounds, such as wounds. , for application to chronic wounds or burns, for example, in dressings, plasters, surgical packings, gauzes, wrappings, conformable foams, or films. When incorporated into an article, the organosilane quaternary ammonium compounds described herein are such that the article controls the release of the compound, or a pharmaceutically acceptable salt or composition thereof, into the surrounding area to promote microbial growth. can be incorporated to provide long-term inhibition of In some embodiments, an effective amount of selected compounds described herein are used to treat chronic wounds, such as pressure ulcers, venous ulcers, arterial wounds, neuropathic ulcers, diabetic ulcers, such as leg ulcers. It is used to treat ulcers or foot ulcers, skin lacerations, or moisture-related skin lesions (MASD), such as incontinence-related dermatitis. In some embodiments, the compounds described herein are used to treat wounds caused by burns.

[0023] In further embodiments, the quaternary ammonium compounds described herein are used to treat, for example, eye infections (including bacterial or fungal infections and dry eye due to blepharitis), ear infections, Skin infections including nail bed infections, acne vulgaris, eczema, medical implant infections, oral and periodontal infections, nasal infections, vaginal infections, anal infections, and using topical or suppository formulations It can be used in effective amounts to treat other possible infections. Furthermore, the quaternary ammonium compounds described herein can be incorporated into such devices for the purpose of reducing the risk of infection associated with the use of medical implants.

[0024] Importantly, in some embodiments, the novel organosilane quaternary ammonium compounds described herein can be provided as a stable powder or freeze-dried material, and the stable powder Alternatively, the lyophilized material can be formulated with a pharmaceutically acceptable topical carrier prior to administration. In alternative embodiments, the novel organosilane quaternary ammonium compounds described herein are used in dressings, conformable foams, or polymers used in dressings, bandages, or medical applications such as Incorporation into films for use in wound dressings or surgical packing can reduce the risk of infection. In yet another alternative embodiment, the novel organosilane quaternary ammonium compounds described herein can be incorporated into medical implants, such as orthopedic implants or dental implants. etc., but not limited to these.

[0025] In some embodiments, topical infections in humans or animals are treatable with selected organosilane quaternary ammonium compounds, wherein the selected organosilane quaternary ammonium compounds are microbial or microbial. Can be used to treat a combination or biofilms containing combinations thereof, wherein the microorganisms are, for example, Acinetobacter (Gram-negative), Pseudomonas (Gram-negative), Proteus (Gram-negative), Gram-negative Proteobacteria), Staphylococcus (Gram-positive), Streptococcus (Gram-positive), MRSA (Methicillin-resistant S. aureus), Escherichia coli (Gram-negative), Propionibacterium (Gram-positive), Klebsiella (Gram-negative), Enterococcus (Gram-positive), Haemophilius influenzae, etc., as well as fungi, such as Fusarium Fusarium, Aspergillus, Cladosporium, Curvularia, and Candida, etc., and dermatophytes such as Trichophyton, Microsporum ), and Epidermophyton.

[0026] In certain embodiments, the topical infection comprises a Candida fungal infection, such as Candida, for example C. albicans, C. auris, or C. including, but not limited to, C. glabrata, or combinations thereof.

[0027] The present invention provides novel organosilicon quaternary amine compounds having a pharmaceutically acceptable charge-neutralizing anion(s) (whether explicitly indicated in the formula or not). In certain embodiments, the charge neutralizing anion is chloride anion, fluoride anion, iodide anion, bromide anion, hydroxide anion, chlorite anion, chlorate anion, hydroxide anion, formate selected from anion, acetate, lactate, benzoate or salicylate. In exemplary embodiments, the charge-neutralizing anion is a chloride anion or a hydroxide anion.

[0028] In some embodiments, the quaternary ammonium compound has a negatively charged substituent. Negatively charged substituents may be neutralized with pharmaceutically acceptable cations, such as sodium or potassium cations.

[0029] In some embodiments, the quaternary ammonium compound is provided as a zwitterion and the positive charge of the internal quaternary amine in the compound is derived from substituents in the molecule, as further described below. neutralized by the anion

[0030] The present invention provides one or more of the novel compounds described herein for treating, preventing, inhibiting or eliminating an infectious disease in a host in need of such treatment, prevention, inhibition or elimination of an infectious disease. Also provided is a method of topical administration of an effective amount of an organosilicon quaternary amine compound, which optionally includes a pharmaceutically acceptable salt in its composition.

[0031] The invention also includes pharmaceutically acceptable compositions thereof in the form of powders, lyophilized powders, or other solid stable storage forms.

[0032] Selected compounds of the present invention are applied in effective amounts, optionally in a liquid, gel, or solid carrier, to non-living (i.e., inanimate) surfaces, such as homes, workplaces, industrial areas including manufacturing plants, Also used to disinfect microbial growth or biofilm formation, such as on public areas, bathrooms, kitchens, furniture, transportation points or surfaces, or other surfaces that come in contact with humans or animals or are in the environment of humans or animals. can do. In one embodiment, environmental surfaces commonly met in the food and medical fields also appear to improve biofilm formation, as well as their resistance to disinfectants.

[0033] In one embodiment, the present invention provides a compound of the formula: [formation] (In the formula, a is 1, 2, 3, 4, 5, 6, 7, or 8 (where methylene is C 1 ~C 4 alkyl, etc.), R. 1 are each independently C 6 ~C 22 Alkyl (which is C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 ), C 6 ~C 22 alkenyl (which is C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 ), and C 6 ~C 22 Alkanoyl (which is C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22wherein any of these methylene or aliphatic carbons are C, including branched alkyls, such as methyl 1 ~C 4 alkyl, etc.), R. 2 , R 3 , and R 4 are independently [formation] is selected from or C 2 ~C 10 alkanoic acid (which is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , or C 10 or a salt thereof, and in some embodiments, R 2 , R 3 , and R 4 are all alkanoic acids (where any of these methylene or aliphatic carbons are C 1 ~C 4 alkyl, etc.), y is 0, 1, 2, 3, or 4; each p is independently selected from 1, 2, 3, and 4; R. 6 is independently selected from hydrogen, alkyl, aryl, cycloalkyl and heterocyclyl, each of said alkyl, aryl, cycloalkyl and heterocyclyl optionally being C 1 ~C 6 Alkyl, hydroxyl, chloro, bromo, iodo, fluoro, N(R 7 ) 2 , COOR 7 , C(O)R 7 , CH 2 OR 7 , CON(R 7 ) 2 , and NO 2 having a substituent selected from R. 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are each independently hydrogen, halogen, hydroxyl, N(R 7 ) 2 , CH 2 OR 7 , CON(R 7 ) 2 , COOR 7 , C(O)R 7 , C 1 ~C 8 Alkyl, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl and aryl; R. 7 are each independently hydrogen, C 1 ~C 8 Alkyl, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl and aryl; X 1 are independent of each other, NR 17 , CH 2 , CHOH, and C(O); X 2 are each independently C 1 ~C 3 alkyl, and C 1 ~C 3 selected from hydroxyalkyl, X 3 are each independently hydroxyl, NO 2 , N(R 7 ) 2 , CH 2 OR 7 , CON(R 7 ) 2 , COOR 7 , C(O)R 7 , C 1 ~C 12 alkanoic acid, C 1 ~C 8 Alkyl, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl and aryl; X 4 are independent of each other, X 3 is selected from R. 16 are each independently C 1 ~C 4 Alkyl, C 2 ~C 4 alkenyl, C 2 ~C 4 alkynyl, and C 1 ~C 4 selected from haloalkyl, R. 17 are each independently hydrogen, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl and aryl; X - is an anion such as chloride, fluoride, iodide, bromide, hydroxide, chlorite, chlorate, formate, acetate, lactate, benzoate, or salicylate is an anion and X - If is an anion with two or more negative charges, the charge stoichiometry must be neutralized by other cations, B. + is a cation, such as an ammonium cation, potassium cation, or sodium cation, and B + If it is useful to use e.g. calcium cations, the stoichiometry must be appropriately neutralized e.g. [formation] A quaternary ammonium compound is provided.

[0034] In some embodiments, B + is K + or Na + is. In another embodiment, B + is Ca +2 or Mg +2 is.

[0035] In certain embodiments, B + is the ammonium ion, which includes NH 4 + , RNH 3 + , R 2 NH 2 + , R 3 NH + , or R 4 N. + where each R is independently C 1 ~C 8 Alkyl, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 selected from the group consisting of haloalkyl, heterocyclyl, heteroaryl, heterocycloalkyl, and aryl;

[0036] In any of the formulas provided herein, C 1 ~C 4 can have alkyl, etc., and are considered specifically disclosed for each combination.

[0037] In another aspect, the present invention provides a compound of the formula: [formation] (during the ceremony a is 1, 2, 3, 4, 5, 6, 7, or 8, where any of these methylenes are C 1 ~C 4 alkyl, etc.), X - is an anion such as chloride, fluoride, iodide, bromide, chlorite, chlorate, hydroxide, formate, acetate, lactate, benzoate, or salicylate is an anion and X - is an anion with two or more negative charges, the stoichiometry must be appropriately neutralized, R. 14 and R 15 are independently [formation] , R 2 , and R 17 wherein all other variables are as defined herein.

[0038] In another aspect, the present invention provides a compound of the formula: [formation] (during the ceremony p and q are each independently selected from 1, 2, 3, and 4; R. 5 are each independently R 2 , R 17 , and C 2 ~C 10 alkanoic acid (which is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , or C 10 wherein the acid is optionally a diacid or a salt thereof (wherein any of these methylenes include branched alkyls such as methyl) 1 ~C 4 alkyl, etc.), R. 2 are independently [formation] or R. 2 are each independently C 1 ~C 8 selected from alkanoic acids or salts thereof; R. 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are each independently hydrogen, halogen, hydroxyl, N(R 7 ) 2 , CH 2 OR 7 , CON(R 7 ) 2 , COOR 7 , C(O)R 7 , C 1 ~C 8 Alkyl, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl and aryl; R. 7 are each independently hydrogen, C 1 ~C 8 Alkyl, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl and aryl; X 1 are independent of each other, NR 17 , CH 2 , CHOH, and C(O); X 2 are each independently C 1 ~C 3 alkyl, and C 1 ~C 3 selected from hydroxyalkyl, X 3 are each independently hydroxyl, NO 2 , N(R 7 ) 2 , CH 2 OR 7 , CON(R 7 ) 2 , COOR 7 , C(O)R 7 , C 1 ~C 12 alkanoic acid, C 1 ~C 8 Alkyl, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl and aryl; X 4 are independent of each other, X 3 is selected from R. 17 are each independently hydrogen, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl and aryl; X - is an anion such as chloride, fluoride, iodide, bromide, chlorite, chlorate, hydroxide, formate, acetate, lactate, benzoate, or salicylate is an anion and X - If is an anion with two or more negative charges, the charge stoichiometry is still neutralized by other cations, B. + is a cation, such as a sodium, potassium, magnesium, calcium, or lithium cation, and B + is a cation with more than one positive charge, the charge stoichiometry is appropriately neutralized by other anions) to provide a quaternary ammonium compound.

[0039] In certain embodiments, the quaternary ammonium compound has a negatively charged moiety capable of forming pharmaceutically acceptable salts, where the cations are sodium cation, potassium cation, magnesium cations, calcium cations, cesium cations, barium cations, and lithium cations.

[0040] In one embodiment, one or more quaternary ammonium compounds of Formula I, Formula II, Formula III, or Formula IV are reacted with a polyhdroxyl compound to form Formula I', Formula II', Formula III', an oligomeric or polymeric product of formula IV' is formed, the polyhdroxyl compound being, for example, a compound selected from glycerol, or glycidol, glycerol, glycerol-propylene oxide copolymers, ethylene glycol, A glycol selected from one or more of propylene glycol, polyethylene glycol, polypropylene glycol, and polyvinyl alcohol.

[0041] In one embodiment, one or more of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compounds, polyhydroxyl by reacting with compounds of formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI' , XXXII', XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL' oligomeric or polymeric products are formed, and the polyhydroxyl compound is selected, for example, from glycerol. or a glycol selected from one or more of glycidol, glycerol, glycerol-propylene oxide copolymer, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, and polyvinyl alcohol.

[0042] In one aspect, the invention provides a powder formulation comprising at least one quaternary ammonium compound as described herein, or a combination thereof. In some embodiments the powder is a lyophilized powder.

[0043] In some embodiments, a pharmaceutical composition is provided using a quaternary ammonium compound as described herein, wherein the pharmaceutical composition comprises, by weight, about 5%, about 4%, Contains less than about 3%, about 2%, about 1%, about 0.5%, about 0.1%, or no methanol.

[0044] In some embodiments, a quaternary ammonium compound as described herein, a pharmaceutically acceptable composition thereof, or a combination thereof is an aqueous composition formed by reconstitution of a powder or solid formulation. Or administered as a glycerin solution.

[0045] In some embodiments, any mixture of quaternary ammonium compounds as described herein, or pharmaceutically acceptable compositions thereof, are suitable so long as the desired stability is obtained. be.

[0046] In some embodiments, compounds of the invention exist as mixtures of related structures. As an example and not as a limitation, primarily the following molecules: [formation] A composition consisting of [formation] may also have some molecules of These related structures can be interconverted in solution.

[0047] In certain embodiments, the compositions of any of the aspects of the invention are independently mixtures of any of the molecules herein, but indicated The structure is at least 10%, 20%, 30%, 40%, 50%, 51%, at least 60%, at least 70%, at least 80%, at least 90% of the mixture on a molar basis or by weight. , or constitute at least 95%.

[0048] As will also be appreciated by those skilled in the art, the compounds of the present invention may exist in various forms in solution and still achieve their intended purpose. Thus, in certain embodiments, the present invention is a solution of the indicated compounds, although the solution may contain a variety of related structures, with silicon side-chain groups versus silicone Overall ratios are identical to those shown. For example, in some embodiments, the invention provides [formation] , which contains various related molecules, [formation] total number of parts vs. [formation] The ratio of the moieties is about 3 to 1 on a ratio (ie, on a molar basis). In certain embodiments, about 3:1 includes any ratio from 2.6:1 to 3.4:1. In other embodiments, about 3 to 1 includes any ratio from 2.8:1 to 3.2:1. In certain embodiments, the sodium chloride (NaCl) salt can be replaced with another salt described herein. And, in another embodiment, the present invention comprises: [formation] , which contains various related molecules, [formation] total number of parts vs. [formation] The ratio of the moieties is about 2 to 1 on a ratio (ie, on a molar basis). In certain embodiments, about 2:1 includes any ratio from 1.6:1 to 2.4:1. In other embodiments, about 2:1 includes any ratio from 1.8:1 to 2.2:1. In certain embodiments, the sodium chloride (NaCl) salt can be replaced with another salt described herein.

[0049] In one embodiment, the present invention provides the following Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, and Formula XII: [formation] TIFF2022552017000018.tif185170 (in the formula, Each R 21 independently, C 1 ~C 22 Alkyl (which is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 ), C 2 ~C 22 alkenyl (which is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 ), C 2 ~C 22 Alkanoyl (which is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 ), and -alkyl-aryl, wherein R 21 is optionally substituted with 1, 2, or 3 substituents, the substituents independently being C 1 ~C 6 alkyl, halogen, and [formation] is selected from R. 22 , R 23 , and R 24 are independently [formation] is selected from R. 25are each independently R 22 , R 17 , and C 2 ~C 10 alkanoic acid (which is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , or C 10 wherein the acid is optionally a diacid or a salt thereof; R. 31 is C 6 ~C 22 Alkyl (which is C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 ), C 6 ~C 22 alkenyl (which is C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 ), C 6 ~C 22 alkynyl (which is C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 ), and C 6 ~C 22 alkenylalkynyl (which is C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 can be ) and Each R 32 is independently hydrogen, [formation] is selected from In certain embodiments, each R 32 is independently hydrogen, [formation] is selected from R. 33 are each independently hydroxyl, hydrogen, C 1 ~C 6 selected from alkyl and halogen; R. 34 and R 35 are independently [formation] , R 22 , and R 17 is selected from Each R 36 is independently hydrogen, [formation] is selected from X 5 is selected from heterocycle, cycloalkyl, alkyl, aryl, heteroaryl, alkenyl, haloalkyl, and alkynyl; wherein the remaining variables are as defined herein).

[0050] In certain embodiments, the compounds of the invention are [formation] or a pharmaceutically acceptable salt thereof.

[0051] In certain embodiments, R 22 , R 23 , and R 24 are independently [formation] is selected from

[0052] In certain embodiments, R 22 , R 23 , and R 24 are independently [formation] is selected from

[0053] In certain embodiments, each R 36 is hydrogen.

[0054] In certain embodiments, each R 32 is -CH 2 -SO 3 is H.

[0055] In one embodiment of the invention, formulas XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, or XXI: [formation] TIFF2022552017000029.tif174170TIFF2022552017000030.tif184170 (in the formula, o is 1 or 2; n is each independently selected from 0, 1, and 2; m is each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 is selected from m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 and Q is -CR 104 R. 104 - is R. 101 and R 102 are both hydrogen, or In an alternative embodiment, R 101 and R 102 are each independently selected from hydrogen and ethyl; R. 103 are independently [formation] is selected from Each R 104 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, and haloalkyl; R. 105 is hydrogen or -CH 2 CH 2 OH) are provided.

[0056] In certain embodiments of the quaternary ammonium compounds of Formulas XIII through XXI, Formulas XXIII through XXXIII, and Formulas XXXV through XL, variables m are each independently 6, 7 , 8, 9, 10, 11, 12, 13, 14, 15, and 16. In certain embodiments of the quaternary ammonium compounds of formulas XIII through XXI, m is 14. In certain embodiments of the quaternary ammonium compounds of Formulas I through XXI, m is independently selected from 12-16.

[0057] In certain embodiments, the ammonium compound of Formula XIII, XIV, XV, XVI, or XVII in solution is in equilibrium with other quaternary ammonium compounds of Formula XIII, XIV, XV, XVI, or XVII. be. In another embodiment, the quaternary ammonium compounds of Formulas XIII, XVIII, XIX, XX, and XXI are in equilibrium. For example, in one embodiment the following compounds may be in equilibrium: [formation]

[0058] Due to the instability of the silicon-oxygen bond, these structures are such that mixtures of formulas XIII, XIV, XV, XVI, and XVII or mixtures of formulas XIII, XVIII, XIX, XX, or XXI may exist. , may interconvert by breaking and forming bonds.

[0059] In another aspect of the invention, a compound of formula XXII, XXIII, XXIV, XXV, XXVI, or XXVII: [formation] TIFF2022552017000034.tif194170 (where R 106 are each independently hydrogen, hydroxy, and C 1 ~C 6 alkoxy, with all other variables as defined herein).

[0060] In one embodiment, the quaternary ammonium compound of Formula XXII, XXIII, or XXIV in solution is in equilibrium with other quaternary ammonium compounds of Formula XXII, XXIII, or XXIV. For example, in one embodiment the following compounds may be in equilibrium: [formation]

[0061] In one embodiment, quaternary ammonium compounds of Formula XXV, XXVI, or XXVII in solution are in equilibrium with other quaternary ammonium compounds of Formula XXV, XXVI, or XXVII. By way of example and not by way of limitation, the following compounds may be in equilibrium: [formation]

[0062] Because of the instability of the silicon-oxygen bond, these structures may exist in mixtures of Formula XXII, XXIII, or XXIV, or in mixtures of Formula XXV, XXVI, or XXVII. As such, they may interconvert by breaking and forming bonds.

[0063] In another aspect of the invention, formula XXVIII, XXIX, or XXX: [formation] (In the formula, R 107 and R 108 are each independently C 1 ~C 6 alkoxy, with all other variables as defined herein).

[0064] In one embodiment, compounds of Formula XXVIII, XXIX, or XXX are in equilibrium with other compounds of Formula XXVIII, XXIX, or XXX. For example, in one embodiment the following compounds may be in equilibrium: [formation]

[0065] Due to the lability of the silicon-oxygen bond, these structures may interconvert by bond scission and formation such that mixtures of Formula XXVIII, Formula XXIX, or Formula XXX may exist. .

[0066] In another aspect of the invention, formula XXXI or XXXII: [formation] (In the formula, R A teeth, [formation] and A are each independently [formation] is selected from p' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; All other variables are as defined herein).

[0067] Due to the lability of the silicon-oxygen bond, these structures may interconvert by bond scission and formation such that mixtures of Formula XXXI or Formula XXXII may exist.

[0068] In another embodiment, the present invention provides Formula XXXIII: [formation] (where all other variables are as defined herein, q', r, and s are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) quaternary ammonium compounds.

[0069] In one embodiment q', r and s are the same.

[0070] In another aspect of the invention, formula XXXIV, XXXV, or XXXVI: [formation] (In the formula, X is [formation] is selected from M is selected from hydrogen, sodium, potassium, cesium, or lithium; all other variables are as defined herein).

[0071] In one embodiment, compounds of Formula XXXIV, XXXV, or XXXVI are in equilibrium with other compounds of Formula XXXIV, XXXV, or XXXVI. For example, in one embodiment the following equilibrium may exist: [formation]

[0072] Due to the lability of the silicon-oxygen bond, these structures may interconvert by bond scission and formation such that mixtures of formulas XXXIV, XXXV, or XXXVI may exist.

[0073] In another aspect of the invention there is provided a quaternary ammonium compound of formula XXXVII, XXXVIII, or XXXIX: [formation]

[0074] In one embodiment, a quaternary ammonium compound of Formula XXXVII, XXXVIII, or XXXIX is in equilibrium with another quaternary ammonium compound of Formula XXXVII, XXXVIII, or XXXIX. For example, in one embodiment the following compounds may be in equilibrium: [formation]

[0075] Due to the lability of the silicon-oxygen bond, these structures may interconvert by bond cleavage and formation such that mixtures of formulas XXXVII, XXXVIII, or XXXIX may exist.

[0076] The present invention contemplates, inter alia, antimicrobial compositions containing one or more compounds of Formula XXXVII, XXXVIII, or XXXIX and a suitable carrier.

[0077] The present invention also includes a method of treating an infection using an effective amount of a quaternary ammonium compound of formula XXXVII, XXXVIII, or XXXIX in a host in need of such treatment.

[0078] In another alternative embodiment, formula XL: [formation] (In the formula, R A is as defined above and t is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each Z is independently [formation] is selected from Each L is independently [formation] is selected from R. 124 and R 125 are each independently hydrogen, ethyl, [formation] is selected from T is a monovalent capping group, which can optionally be derived from the curing agent, where all other variables are as defined herein) There is provided an oligomeric or polymeric quaternary ammonium compound of

[0079] The curing agent in Formula XL can be any pharmaceutically acceptable compound.

[0080] In certain embodiments, the oligomeric or polymeric curing agent as described herein is diethylenetriamine (DTA), triethylenetetramine (TTA), tetraethylenepentamine (TEPA), dipropenediamine (DPDA), Diethylaminopropylamine (DEAPA), Amine 248, N-Aminoethylpiperazine (N-AEP), Lamiron C-260, Araldit HY-964, Menthanediamine (MDA), Isophoronediamine (IPDA), S Cure 211, S Cure 212, Wandamine HM, 1,3BAC, m-Xylylenediamine (m-XDA), Shawamine X, Amine Black, Shawamine Black, Shawamine N, Shawamine 1001, Shawamine 1010, Metaphenylene Diamine (MPDA), diaminodiphenylmethane (DDM), diaminodiphenylsulfone (DDS), piperidine, N,N-dimethylpiperidine, triethylenediamine, 2,4,6-tris(dimethylaminomethyl)phenol (DMP-30), benzyl dimethylamine (BDMA), and 2-(dimethylaminomethyl)phenol (DMP-10); imidazoles such as 2-methylimidazole, 2-ethyl-4-methylimidazole, 1-cyanoethyl-2-undecylimidazolium tri Melitate, and epoxy-imidazole adducts, etc.; liquid polymercaptan or polysulfide resins; or acid anhydrides such as phthalic anhydride, trimellitic anhydride, pyromellitic anhydride, benzophenonetricarboxylic anhydride, ethylene glycol. Bistrimellitate, glycerol trimellitate, maleic anhydride, tetrahydrophthalic anhydride, methyltetrahydrophthalic anhydride, endomethylenetetrahydrophthalic anhydride, methylendomethylenetetrahydrophthalic anhydride, methylbutenyltetrahydrophthalic acid Anhydride, dodecenylsuccinic anhydride, hexahydrophthalic anhydride, hexahydrophthalic anhydride, hexahydro-4-methylphthalic anhydride, succinic anhydride, methylcyclohexenedicarboxylic anhydride, alkylstyrene-maleic anhydride Including copolymers, chlorendic anhydride, and polyazelaic acid polyanhydride.

[0081] In another aspect of the invention, Formula A: [formation] (In the formula, Each R 109 are each independently selected from halo, hydroxyl, and alkoxy, all other variables being as defined herein; and Formula B, C, D, E, F, G, H, or J: [formation] (where all other variables are as defined herein) and one or more compounds of A product formed by reacting is provided.

[0082] In another aspect of the invention, compounds B' are provided, which are formed by the reaction of one or more compounds of formula A with one or more compounds of formula B. In one embodiment, compound B' is an oligomeric or polymeric compound having one or more Formula B units and one or more Formula A units.

[0083] In another aspect of the invention, compounds C' are provided, which are formed by reaction of one or more compounds of formula A with one or more compounds of formula C. In one embodiment, compound C' is an oligomeric or polymeric compound having one or more Formula C units and one or more Formula A units.

[0084] In another aspect of the invention, compounds D' are provided, which are formed by reaction of one or more compounds of formula A with one or more compounds of formula D. In one embodiment, compound D' is an oligomeric or polymeric compound having one or more Formula D units and one or more Formula A units.

[0085] In another aspect of the invention, compounds E' are provided, which are formed by reaction of one or more compounds of formula A with one or more compounds of formula E. In one embodiment, compound E' is an oligomeric or polymeric compound having one or more Formula E units and one or more Formula A units.

[0086] In another aspect of the invention, compounds F' are provided, which are formed by reaction of one or more compounds of formula A with one or more compounds of formula F. In one embodiment, compound F' is an oligomeric or polymeric compound having one or more Formula F units and one or more Formula A units.

[0087] In another aspect of the invention, compounds G' are provided, which are formed by the reaction of one or more compounds of formula A with one or more compounds of formula G. In one embodiment, compound G' is an oligomeric or polymeric compound having one or more Formula G units and one or more Formula A units.

[0088] In another aspect of the invention, compounds H' are provided, which are formed by reaction of one or more compounds of formula A with one or more compounds of formula H. In one embodiment, compound H' is an oligomeric or polymeric compound having one or more formula H units and one or more formula A units.

[0089] In another aspect of the invention, compound J' is provided, which compound J' is formed by reaction of one or more compounds of formula A with one or more compounds of formula J. In one embodiment, compound J' is an oligomeric or polymeric compound having one or more Formula J units and one or more Formula A units.

[0090] In another aspect of the invention, compounds K' are provided, which are formed by reaction of one or more compounds of formula A with one or more compounds of formula K. In one embodiment, compound K' is an oligomeric or polymeric compound having one or more units of formula K and one or more units of formula A.

[0091] In another aspect of the invention, compounds L' are provided, which are formed by the reaction of one or more compounds of formula A with one or more compounds of formula L. In one embodiment, compound L' is an oligomeric or polymeric compound having one or more Formula L units and one or more Formula A units.

[0092] In another aspect of the invention, compounds M' are provided, which are formed by reaction of one or more compounds of formula A with one or more compounds of formula M. In one embodiment, compound M' is an oligomeric or polymeric compound having one or more formula M units and one or more formula A units.

[0093] In another embodiment, the compounds of the invention are oils, which can be administered topically as the pure compound. Oils are optionally mixed with excipients, carriers, or diluents as described herein to maintain long shelf life without solidifying. For example, the oils of the present invention can be mixed with ionic liquids, organic solvents, or aqueous solutions to maintain the oil form. Non-limiting examples of oils that can be mixed with the compounds of the present invention include coconut oil, rice bran oil, and vegetable oils. In certain embodiments, a mixture of a compound of the present invention and additional oil forms a shelf-stable oily composition that can be administered topically to a patient in need thereof.

[0094] In certain embodiments, a compound of the invention (optionally as an oil) is administered directly to the wound. By way of example and not limitation of how the compound can be administered, dripping, pouring, tapping, or otherwise onto an open wound, a covered wound, or as part of a negative pressure wound therapy regimen. and administering the drug in the manner of For example, the compounds of the invention can be applied to a sponge and inserted into the wound, after which the surrounding skin is sealed with a membrane, pierced with a small suction tube, and pulled from atmospheric pressure by the small suction tube. Creates a low vacuum and draws out exudates.

[0095] In another aspect, an anti-infective composition is provided, the composition comprising one or more quaternary as described herein in an amount effective to treat, prevent, or eliminate an infection. ammonium compounds, or pharmaceutically acceptable compositions thereof, and a suitable carrier.

[0096] In certain embodiments, pharmaceutically acceptable carriers include aqueous or glycerol solutions such as water, saline, or phosphate-buffered saline.

[0097] In certain embodiments, the glycerin solution is selected from glycerol, glycidol, glycerol-propylene oxide copolymer, ethylene glycol, propylene glycol, polyethylene glycol, or polypropylene glycol, or combinations thereof.

[0098] In another aspect, a kit is provided comprising a vial containing a sterile aqueous solution and a vial containing a quaternary ammonium compound as described herein and a dispensing device.

[0099] In another aspect, a kit is provided comprising a powder formulation comprising a quaternary ammonium compound as described herein or a pharmaceutically acceptable salt thereof, a sterile aqueous solution, and a dispensing device. . In some embodiments the powder is a lyophilized powder.

[0100] In some embodiments, the dispensing device is a syringe.

[0101] In another aspect, a kit is provided, comprising a sterile aqueous solution and a quaternary ammonium compound as described herein, one selected from solketal, epichlorohydrin, and polyvinyl alcohol. Including with the above compounds.

[0102] In another aspect, a kit is provided comprising a sterile aqueous or glycerin solution and a quaternary ammonium compound as described herein, glycerol, glycidol, glycerol-propylene oxide copolymer, ethylene. With one or more compounds selected from glycol, propylene glycol, polyethylene glycol, and polypropylene glycol.

[0103] In some embodiments, the present invention provides compounds as described herein, or pharmaceutically acceptable compositions thereof, which treat, prevent, inhibit, or treat infectious diseases. Effective amounts are useful for treating, preventing, inhibiting, or eliminating infections in hosts in need thereof.

[0104] In one aspect, a method of treating, preventing, inhibiting or eliminating an infectious disease is provided, as further described herein, wherein the method requires treating, preventing, inhibiting or eliminating an infectious disease. administering to a host an effective amount of one or more quaternary ammonium compounds, or pharmaceutically acceptable compositions thereof, as described herein.

[0105] In some embodiments, the host is human.

[0106] In another embodiment, the host is a mammal, such as a dog, cat, horse, cow, or pig.

[0107] In another aspect, the invention provides a method of administering one or more compounds of the invention, or a pharmaceutically acceptable composition thereof, in an effective amount useful for treating, inhibiting, eliminating, or preventing the above infectious diseases. I will provide a.

[0108] In some embodiments, the infection is a mixed infection comprising bacterial, fungal, and viral species.

[0109] In some embodiments, one or more quaternary ammonium compounds of the present invention, or compositions thereof, are effective to treat or prevent infection in chronic wounds. Used in hosts in need of treatment or prophylaxis.

[0110] In some embodiments, the chronic wound is a diabetic ulcer, eg, a diabetic ulcer, such as a diabetic leg ulcer or a diabetic foot ulcer.

[0111] In another embodiment the chronic wound is a decubitus ulcer.

[0112] In some embodiments the chronic wound is a pressure ulcer.

[0113] In some embodiments the chronic wound is a venous ulcer.

[0114] In some embodiments the chronic wound is an arterial ulcer.

[0115] In some embodiments the chronic wound is a neuropathic ulcer.

[0116] In some embodiments the chronic wound is a skin tear.

[0117] In some embodiments, the chronic wound is moisture-related skin damage (MASD), eg, incontinence-related dermatitis.

[0118] In some embodiments, the compounds described herein are used to treat wounds caused by burns.

[0119] In another embodiment, the infection in chronic wounds is caused by biofilms.

[0120] In some embodiments, one or more quaternary ammonium compounds of the invention, or compositions thereof, are used to treat ocular infections in a host in need of treating, preventing, or eliminating ocular infections. It is used in a prophylactically or remedially effective amount.

[0121] In some embodiments, the eye infection is keratitis.

[0122] In another embodiment, the eye infection is bacterial keratitis, eg, keratitis caused by Staphylococcus aureus or Pseudomonas aeruginosa.

[0123] In another embodiment, the eye infection is fungal keratitis, eg, keratitis caused by Fusarium spp., Aspergillus spp., Candida spp., or Curvularia spp. In some embodiments, the eye infection is Acanthamoebic keratitis.

[0124] In another embodiment, the eye infection is viral keratitis, eg, herpes simplex virus (HSV) keratitis.

[0125] In another embodiment, the eye infection is bacterial conjunctivitis, eg, conjunctivitis caused by Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, or Pseudomonas aeruginosa.

[0126] In another embodiment, the eye infection is viral conjunctivitis, eg, conjunctivitis caused by adenoviruses or enteroviruses.

[0127] In another embodiment, eye infections are polymicrobial, which makes diagnosis and treatment more difficult. For example, when bacteria are associated with Acanthamoeba keratitis, the risk of neovascularization and prolonged healing is high.

[0128] In another embodiment, the ocular infection is a sequential infection with one or more opportunistic organisms that can also cause the infection. For example, herpetic corneal ulcers may provide a favorable microenvironment for the establishment of bacterial or fungal pathogens.

[0129] In another aspect, an ophthalmic composition is provided comprising an effective amount of one or more quaternary ammonium compounds of the invention and an ophthalmically acceptable carrier.

[0130] In some embodiments, the ophthalmic composition does not contain any by-products or additives such as alcohol.

[0131] In some embodiments, the ophthalmic composition is substantially free of methanol. In some embodiments, the infection to be treated is an eye infection.

[0132] In another embodiment, the infection to be treated is an ear infection, eg, an inner ear, outer ear, or middle ear infection.

[0133] In some embodiments, the infection to be treated is a skin infection.

[0134] In some embodiments, the infection to be treated is a nail infection, eg, a fungal nail infection.

[0135] In some embodiments, the infection to be treated is an infection of the vaginal mucosal tissue, eg, vulvar candidiasis.

[0136] In some embodiments, the infection is in a chronic wound or ulcer, and the ulcer is, for example, a leg ulcer or a diabetic ulcer, such as a diabetic leg ulcer or a diabetic foot ulcer, including but not limited to: Not limited.

[0137] In another aspect, a method of treating an ear infection in a host in need thereof is provided, the method comprising administering one or more quaternary ammonium compounds of the present invention, or compositions thereof, to including administering in an effective amount.

[0138] In some embodiments, one or more quaternary ammonium compounds of the invention, or compositions thereof, are used to treat, treat, prevent, or eliminate ear infections in a host in need thereof. It is used in a prophylactically or remedially effective amount.

[0139] In some embodiments, the ear infection is an inner ear infection (otitis labyrinth).

[0140] In some embodiments, the ear infection is an outer ear infection (otitis externa).

[0141] In another embodiment, the ear infection is middle ear infection (otitis media).

[0142] In some embodiments, the ear infection is caused by bacteria or fungi.

[0143] In another embodiment, the ear infection is caused by both bacteria and fungi.

[0144] In another embodiment, the infection is caused by a biofilm, which may contain a combination of bacterial and fungal cells. In another embodiment, the infection is caused by a biofilm that may contain a combination of bacterial and fungal cells and one or more viruses.

[0145] In another aspect, a method of treating an ocular infection in a host in need thereof is provided, the method comprising one or more quaternary ammonium compounds described herein, or including administering the composition in an effective amount.

[0146] In another aspect, there is provided a method of treating onychomycosis, ie, a fungal nail infection, in a host in need thereof, the method being described herein. administering an effective amount of one or more of the described quaternary ammonium compounds, or compositions thereof.

[0147] In some embodiments, one or more quaternary ammonium compounds of the present invention, or compositions thereof, are used to treat, prevent, or eliminate onychomycosis in a host in need thereof. It is used in an amount effective to treat, prevent, or eliminate.

[0148] In another aspect, there is provided a formulation for treating onychomycosis in a host in need thereof, the formulation comprising one or more quaternary ammonium compounds described herein. in an effective amount in a carrier suitable for delivery to the nail bed. In some embodiments, the carrier is dimethylsulfoxide.

[0149] In some embodiments, one or more quaternary ammonium compounds described herein are administered as an aqueous, glycerol, or dimethylsulfoxide solution, which solution comprises one or more quaternary It was formed by reconstitution from a powder formulation of an ammonium compound. In some embodiments the powder is a lyophilized powder.

[0150] In another embodiment, methods of treating or preventing infections in chronic wounds in a host in need thereof are provided, which methods are described herein. administering one or more quaternary ammonium compounds, or compositions thereof, in an effective amount.

[0151] In another embodiment, a method of treating or preventing a vaginal infection in a host in need of such treatment or prevention is provided, the method comprising one or more of the methods described herein. administering the quaternary ammonium compound, or composition thereof, in an effective amount.

[0152] In some embodiments, one or more quaternary ammonium compounds of the present invention, or compositions thereof, are used to treat or prevent vaginal infections in a host in need thereof. used in amounts effective for

[0153] In some embodiments, the vaginal infection is vulvovaginal candidiasis.

[0154] In some embodiments, the vaginal infection, eg, vulvovaginal candidiasis, is a fungal infection caused by Candida species.

[0155] In some embodiments, the vaginal infection is bacterial vaginosis.

[0156] In some embodiments, the vaginal infection, e.g., vulvovaginal candidiasis, is Lactobacilli, Bacteroides, Peptostreptococcus, Fusobacterium, and / or It is a bacterial infection caused by the genus Eubacterium.

[0157] In another aspect, a method of treating a dermatological disorder in a host in need thereof is provided, the method comprising one or more quaternary ammonium compounds described herein, or including administering the composition in an effective amount.

[0158] In an alternative embodiment, the infectious disease to be treated is a dermatological disorder.

[0159] In certain embodiments, dermatological disorders are, for example, acne vulgaris, acne cystic, eczema, folliculitis, and skin infections.

[0160] In certain embodiments, the dermatological disorder, eg acne vulgaris, is caused by the Gram-positive bacteria Propionibacterium acnes and / or Staphylococcus epidermidis.

[0161] In certain embodiments, the dermatological disorder, eg, eczema (atopic dermatitis), eczema herpes, eczema vaccinae, or eczema coxsackie, is caused by a bacterial or viral infection.

[0162] In certain embodiments, the dermatological disorder, eg, eczema (atopic dermatitis), is caused by bacteria, eg, staphylococcal or streptococcal bacteria such as Staphylococcus aureus.

[0163] In certain embodiments, the dermatological disorder, eg, eczema (atopic dermatitis), is caused by a virus, eg, herpes simplex virus and / or Molluscum contagiosum virus.

[0164] In certain embodiments, the dermatological disorder, eg, skin infection, is caused by Staphylococcus aureus (S. aureus).

[0165] In some embodiments, an effective amount of one or more quaternary ammonium compounds of the invention, or compositions thereof, treats, prevents, or eliminates the infections described herein. is the amount required for

[0166] In another aspect, methods of treating biofilms or microbial contamination of non-living (i.e., inanimate) surfaces are provided, the methods comprising one or more quaternary ammonium compounds described herein, or including using the mixture in an effective amount.

[0167] In some embodiments, the non-living (i.e., inanimate) surface comprises one or more of the quaternaries described herein for the removal and / or prevention of recurrence of bacterial biofilms or bacterial contamination. directly treated with a solution containing ammonium compounds, or mixtures thereof.

[0168] In some embodiments, the bacterial biofilm or bacterial contamination is caused by Staphylococcus aureus.

[0169] In some embodiments, the bacterial biofilm or bacterial contamination is caused by methicillin-resistant Staphylococcus aureus (MRSA).

[0170] In some embodiments, the bacterial biofilm or bacterial contamination is caused by Pseudomonas aeruginosa.

[0171] In some embodiments, the non-living (i.e., inanimate) surface comprises one or more of the quaternaries described herein for the removal of and / or prevention of recurrence of fungal biofilms or fungal contamination. directly treated with a solution containing ammonium compounds, or mixtures thereof.

[0172] In some embodiments, the fungal biofilm or fungal contamination comprises a Candida fungal infection, where the Candida is, for example, C. albicans, C. auris, or C. glabrata, or mixtures thereof. , but not limited to.

[0173] In some embodiments, the non-living (i.e., inanimate) surface comprises one or more of the quaternaries described herein for the removal and / or prevention of recurrence of viral biofilms or viral contamination. directly treated with a solution containing ammonium compounds, or mixtures thereof.

[0174] In some embodiments, the viral biofilm or viral contamination is caused by SARS Coronavirus 2 (COVID-19).

[0175] In some embodiments, the non-living (i.e., inanimate) surface comprises one or more of the materials described herein for the removal and / or prevention of recurrence of multi-microbial biofilms or multi-microbial contamination. It is treated directly with a solution containing a quaternary ammonium compound, or mixtures thereof.

[0176] In some embodiments, the multi-microbial biofilm or multi-microbial contamination comprises bacterial species, fungal species, and viral species.

[0177] In some embodiments, one or more quaternary ammonium compounds described herein, or mixtures thereof, are effective as antimicrobial hand sanitizers, or surface disinfectant sprays, foams, liquids, gels, or solids. can be blended in quantity.

[0178] In some embodiments, a method of providing enhanced antimicrobial activity to a skin surface is provided, the method comprising administering an effective amount of a quaternary ammonium compound or composition thereof described herein Including.

[0179] In some embodiments, the antibacterial activity is against bacteria.

[0180] In some embodiments, the antibacterial activity is against fungi.

[0181] In some embodiments, the antibacterial activity is against viruses.

[0182] In some embodiments, the antimicrobial activity is against multiple microorganisms, including combinations of bacterial, fungal, and / or viral microorganisms.

[0183] In some embodiments, the antimicrobial hand sanitizer is optionally combined with a thickening agent.

[0184] In some embodiments, the antimicrobial hand sanitizer is optionally combined with alcohol.

[0185] In other embodiments, the quaternary ammonium compound is provided in a carrier that does not contain any alcohol.

[0186] In some embodiments, an antimicrobial hand sanitizer is optionally combined with a skin conditioner.

[0187] In some embodiments, the antimicrobial hand sanitizer is optionally combined with perfume.

[0188] In some embodiments, quaternary ammonium compounds are provided in which at least one hydrogen has been replaced with deuterium.

[0189] Accordingly, the invention includes at least the following features: (a) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compounds; (b) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, used in the treatment of bacterial, fungal and / or viral infections; XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL a quaternary ammonium compound of (c) formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, in the manufacture of a medicament for the treatment of bacterial, fungal and / or viral infections; XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or the use of one or more quaternary ammonium compounds of XL; (d) A method of manufacturing a medicament for therapeutic use to treat bacterial, fungal and / or viral infections, comprising formulas I, II, III, IV, V, VI, VII, VIII, IX , X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV , XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL, in an effective amount, in the preparation of (e) A method of treating a bacterial, fungal, and / or viral infection comprising administering to a host in need of treatment of a bacterial, fungal, and / or viral infection a formula I, II, III, IV, V , VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX administering an effective amount of one or more quaternary ammonium compounds of XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL; (f) A method of treating a bacterial, fungal, and / or viral infection comprising administering to a host in need of treatment of a bacterial, fungal, and / or viral infection the formula I, II, III, IV, V , VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX administering an effective amount of one or more quaternary ammonium compounds of XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL; (g) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, comprising an effective amount of one or more quaternary ammonium compounds of XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL; an antimicrobial composition comprising a pharmaceutically acceptable excipient; (h) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, A lyophilized powder comprising one or more quaternary ammonium compounds of XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL powder or solid formulations, including formulations; (i) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, a lyophilized powder of one or more quaternary ammonium compounds of XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL a kit comprising a powder or solid formulation containing (j) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, a sterile aqueous solution comprising one or more quaternary ammonium compounds of XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL; a kit comprising a dispensing device; (k) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, a process of synthesizing a quaternary ammonium compound of XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL; (l) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII as mixtures of enantiomers, including racemates, or diastereomers (where relevant), XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, the quaternary ammonium compound of XXXIX, or XL; (m) enantiomers or diastereomers, including isolated enantiomers or diastereomers (i.e. greater than 85%, 90%, 95%, 97%, or 99% purity) (where relevant); systematically biased forms of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compounds; (n) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, containing an effective amount of one or more quaternary ammonium compounds of XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL a process of preparing a therapeutic product, (o) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compound, glycerol, glycerol-propylene oxide copolymer a product formed by reacting with one or more compounds of coalescence, solketal, glycidol, or epichlorohydrin; (p) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV for use in the treatment of bacterial, fungal and / or viral infections , XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or a product formed by reacting a quaternary ammonium compound of XL with one or more compounds of a glycerol-propylene oxide copolymer, solketal, glycidol, or epichlorohydrin; (q) formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, in the manufacture of a medicament for the treatment of bacterial, fungal and / or viral infections; XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or the use of a product formed by reacting a quaternary ammonium compound of XL with one or more compounds of glycerol, glycerol-propylene oxide copolymer, solketal, glycidol, or epichlorohydrin; (r) A method of manufacturing a medicament for therapeutic use to treat bacterial, fungal and / or viral infections, comprising formulas I, II, III, IV, V, VI, VII, VIII, IX , X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV , XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL with one or more compounds of glycerol, glycerol-propylene oxide copolymer, solketal, glycidol, or epichlorohydrin. a method, characterized in that an effective amount of the product is used in the manufacture; (s) A method of treating a bacterial, fungal, and / or viral infection comprising administering to a patient in need of treatment of a bacterial, fungal, and / or viral infection a formula I, II, III, IV, V , VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX , XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compounds of glycerol, glycerol-propylene oxide copolymer, solketal, glycidol, or epichlorohydrin. a method comprising administering an effective amount of a product formed by reacting with one or more compounds; (t) A method of treating a bacterial, fungal, and / or viral infection comprising administering to a patient in need of treatment of a bacterial, fungal, and / or viral infection a formula I, II, III, IV, V , VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX , XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compounds of glycerol, glycerol-propylene oxide copolymer, solketal, glycidol, or epichlorohydrin. a method comprising administering an effective amount of a product formed by reacting with one or more compounds; (u) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compound, glycerol, glycerol-propylene oxide copolymer an antimicrobial composition comprising an effective amount of a product formed by reacting with one or more compounds of coalescing, solketal, glycidol, or epichlorohydrin, and comprising a pharmaceutically acceptable excipient; (v) Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compounds with glycerol, glycidol, glycerol-propylene oxide Copolymers, including lyophilized powders, including products formed by reacting with one or more compounds of ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, solketal, glycidol, or epichlorohydrin. powder formulation or solid formulation, (w) formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compound, glycerol, glycerol-propylene oxide copolymer Powder or solid formulations, including lyophilized powders, sterile aqueous solutions, and dispensing devices of products formed by reacting with one or more compounds of coalescence, solketal, glycidol, or epichlorohydrin. kit, (x) Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compound, glycerol, glycerol-propylene oxide copolymer a kit comprising a sterile aqueous or glycerin solution comprising a product formed by reacting with one or more compounds of coalescence, solketal, glycidol, or epichlorohydrin, and a dispensing device; (y) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compounds with glycerol, glycidol, glycerol-propylene oxide A process of preparing a therapeutic product formed by reacting with one or more compounds of copolymers, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, solketal, glycidol, or epichlorohydrin; (z) Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL compound dressings, plasters, surgical packings, films, wrappers, comfortable foams, or other types of materials; (aa) formula I, for the treatment of skin infections, wounds or ulcers, for example but not limited to leg ulcers or diabetic ulcers such as diabetic leg ulcers or diabetic foot ulcers; II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL dressings, plasters, surgical packings, films, wrappers, or forms incorporating compounds use of comfortable foam or other types of materials; (bb) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI ', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', oligomeric or polymeric products of XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL'; (cc) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X' for use in the treatment of bacterial, fungal and / or viral infections , XI', XII', XIII', XIV', XV', XVI', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII oligomeric or polymeric products of ', XXVIII', XXIX', XXX', XXXI', XXXII', XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL'; (dd) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X in the manufacture of a medicament for the treatment of bacterial, fungal and / or viral infections ', XI', XII', XIII', XIV', XV', XVI', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL' oligomeric or polymeric products use in effective amounts; (ee) A method of manufacturing a medicament for therapeutic use in treating bacterial, fungal and / or viral infections, comprising formulas I', II', III', IV', V', VI' , VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI', XVII', XVIII', XIX', XX', XXI', XXII', XXIII ', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL' oligomeric or polymeric product is used for the production, (ff) A method of treating a bacterial, fungal and / or viral infection comprising administering to a host in need of treatment of a bacterial, fungal and / or viral infection: IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI', XVII', XVIII', XIX', XX' , XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', XXXIII', XXXIV', XXXV', XXXVI', XXXVII a method comprising administering an effective amount of an oligomeric or polymeric product of ', XXXVIII', XXXIX', or XL'; (gg) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI ', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', An antimicrobial composition comprising an effective amount of an oligomeric or polymeric product of XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL' and comprising a pharmaceutically acceptable excipient thing, (hh) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI ', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', powders or solid formulations, including lyophilized powders, comprising oligomeric or polymeric products of XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL', or combinations thereof; (ii) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI ', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', Powder or solid formulations, including lyophilized powders, sterile aqueous solutions, and applicators of oligomeric or polymeric products of XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL' and a kit containing (jj) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI ', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', a kit comprising a sterile aqueous or glycerin solution containing the oligomeric or polymeric product of XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL' and a dispensing device; (kk) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI ', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', a process of preparing a therapeutic product containing an oligomeric or polymeric product of XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL'; (ll) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI ', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', Dressings, plasters, surgical packings, films, packaging, comfortable, incorporating compounds of XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL' foam or other type of material, (mm) Formula I' for treating skin infections, wounds, or ulcers such as, but not limited to, leg ulcers, or diabetic ulcers, such as diabetic leg ulcers or diabetic foot ulcers. , II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI', XVII', XVIII ', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', XXXIII', XXXIV', Dressings, plasters, surgical packings, films, wrappings, comfortable foams, or other materials incorporating XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL' compounds the use of materials of a kind, and (nn) Formulas I', II', III', IV', V', VI', VII', VIII', IX', X', XI', XII', XIII', XIV', XV', XVI ', XVII', XVIII', XIX', XX', XXI', XXII', XXIII', XXIV', XXV', XXVI', XXVII', XXVIII', XXIX', XXX', XXXI', XXXII', medical or dental implants incorporating compounds of XXXIII', XXXIV', XXXV', XXXVI', XXXVII', XXXVIII', XXXIX', or XL'; (oo) Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, an effective amount of one or more quaternary ammonium compounds of XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL, Methods of treating biofilms or microbial contamination by administration to living (i.e., inanimate) surfaces, and (pp) Used as a disinfectant for inanimate surfaces including, but not limited to, home surfaces, workplaces, industrial areas, transportation areas or carriers, kitchens, bathrooms, furniture, etc., optionally for suitable applications. An antimicrobial quaternary compound of the invention together in a suitable carrier. [Brief description of the drawing]

[0190]

Figure 1

Figure 2

[0191] In one embodiment, it is administered in a topical formulation to a host in need thereof in an effective amount to treat a wide range of infections, including fungal infections, gram-positive, gram-negative, and viral infections. Novel organosilane quaternary ammonium compounds that can be treated are provided. Fungi can appear as yeast, mold, or a combination of both forms. The novel quaternary ammonium compounds and formulations described herein can treat microorganisms in biofilms, including mixed organisms.

[0192] Thus, in one embodiment, the organosilane quaternary ammonium compounds described herein can be used in effective amounts in topical formulations for direct application to infections or wounds, such as wounds. , for application to chronic wounds or burns, for example, in dressings, plasters, surgical packings, gauzes, wrappings, conformable foams, or films. When incorporated into an article, the organosilane quaternary ammonium compounds described herein are such that the article controls the release of the compound, or a pharmaceutically acceptable salt or composition thereof, into the surrounding area to promote microbial growth. can be incorporated to provide long-term inhibition of In some embodiments, an effective amount of a selected compound described herein is used to treat chronic wounds, such as pressure ulcers, venous ulcers, arterial wounds, neuropathic ulcers, diabetic ulcers, such as leg ulcers. or to treat foot ulcers, skin lacerations, or moisture-related skin lesions (MASD), such as incontinence-related dermatitis. In some embodiments, the compounds described herein are used to treat wounds caused by burns.

[0193] Importantly, in some embodiments, the novel organosilane quaternary ammonium compounds described herein can be provided as stable powders or freeze-dried materials, which stable powders or Lyophilized materials can be formulated with a pharmaceutically acceptable topical carrier prior to administration. In alternative embodiments, the novel organosilane quaternary ammonium compounds described herein are used in dressings, conformable foams, or polymers used in dressings, bandages, or medical applications such as wound dressings. Incorporation into films for use in dressings or surgical packing can reduce the risk of infection. In yet another alternative embodiment, the novel organosilane quaternary ammonium compounds described herein can be incorporated into medical implants, such as orthopedic implants or dental implants. but not limited to these.

[0194] In some embodiments, a topical human or animal infection is treatable with a selected organosilane quaternary ammonium compound, wherein the selected organosilane quaternary ammonium compound comprises a microorganism, or a combination of microorganisms. or combinations thereof, wherein the microorganisms are, for example, Acinetobacter (Gram negative), Pseudomonas (Gram negative), Proteus (Gram negative Proteobacteria), Staphylococcus (Gram-positive), Streptococcus (Gram-positive), MRSA (methicillin-resistant S. aureus), Escherichia coli (Gram-negative), Propionibacterium (Gram-positive), Klebsiella (Gram-negative), Enterococcus (Gram-positive), Haemophilius influenzae, etc., as well as fungi, such as Fusarium ( Fusarium, Aspergillus, Cladosporium, Curvularia, and Candida, etc., and dermatophytes such as Trichophyton, Microsporum , and Epidermophyton, etc.

[0195] Selected compounds of the present invention are applied in effective amounts, optionally in a liquid, gel, or solid carrier, to non-living (i.e., inanimate) surfaces, such as homes, workplaces, industrial areas including manufacturing plants, Also used to disinfect microbial growth or biofilm formation, such as on public areas, bathrooms, kitchens, furniture, transportation points or surfaces, or other surfaces that come in contact with humans or animals or are in the environment of humans or animals. can do. In one embodiment, environmental surfaces commonly met in the food and medical fields also appear to improve biofilm formation, as well as their resistance to disinfectants.

[0196] definition Compounds are described using their full name. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0197] The quaternary ammonium compounds, of any of the formulas described herein, are racemates, enantiomers, enantiomeric mixtures, diastereomers, diastereomeric mixtures, tautomers, Isomers such as rotamers are included as if each were specifically described.

[0198] The terms "a" and "an" do not express limitations in quantity, but rather the presence of at least one of the items referred to. The term "or" means "and / or." Unless otherwise specified herein, recitation of ranges of values ​​is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each Individual values ​​are incorporated herein by reference as though they were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is merely intended to better describe the invention and, unless stated otherwise, indicates limitations on the scope of the invention. not a thing Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0199] The present invention provides compounds of Formulas I, II, III, IV, V, VI wherein at least one atom is substituted with a desired isotope and which has that isotope in excess of its natural abundance, i.e., is enriched. , VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI , XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, or XL quaternary ammonium compounds. Isotopes are atoms having the same atomic number but different mass numbers, ie, the same number of protons but different numbers of neutrons.

[0200] Examples of isotopes that can be incorporated into the quaternary ammonium compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as, respectively, 2 H. 3 H. 11 C. 13 C. 14 C. 15 N, 17 O 18 O 18 F. 36 Cl, and 125 I. In one non-limiting embodiment, an isotopically labeled quaternary ammonium compound is subjected to metabolic studies ( 14 C), kinetic tests (e.g., 2 H or 3 H), in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients. be able to. For details, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled quaternary ammonium compounds of the invention and their prodrugs generally facilitate the procedures disclosed in the Schemes or in the Examples and Preparations described below from non-isotopically labeled reagents. can be prepared by substituting isotopically labeled reagents available in

[0201] As a general and non-limiting example, isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in the structure described that yields the desired result. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C may be used.

[0202] Isotopic substitution, eg, deuterium substitution, can be partial or total. Partial deuterium replacement means that at least one hydrogen is replaced with deuterium. In certain embodiments, the isotope is at least about 90%, 95%, or 99% or more enriched for the isotope at any location of interest. In one non-limiting embodiment, deuterium is at least about 90%, 95%, or 99% enriched at the desired locations.

[0203] In one non-limiting embodiment, the substitution of one or more hydrogen atoms for deuterium atoms is represented by formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, Available in either XXXVIII, XXXIX, or XL. In one non-limiting embodiment, the hydrogen atom to deuterium atom substitution is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , X 1 , X 2 , X 3 , X 4 or within any other variable defined herein. For example, if any of these groups are methyl, ethyl, or methoxy, or have methyl, ethyl, or methoxy, for example through substitution, the alkyl residue can be deuterated (non-limiting In embodiments, CDH 2 , CDs 2 H, CD 3 , CH 2 CDs 3 , CDs 2 CDs 3 , CHDCH 2 D, CH 2 CDs 3 , CHDCHD 2 , OCDH 2 , OCD 2 H or OCD 3 etc.). In certain other embodiments, when two substituents are taken together to form a ring, an unsubstituted carbon can be deuterated.

[0204] The quaternary ammonium compounds of the present invention may be provided in any suitable form, such as liquids, gels, aerosols or solids, or adsorbed onto a carrier.

[0205] The quaternary ammonium compounds of the present invention may or may not form solvates with solvents (including water). Accordingly, in one non-limiting embodiment, the present invention includes solvated forms of the compounds. The term "solvate" denotes a molecular complex of the compounds of the invention (including salts thereof) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, saline, dimethylsulfoxide (DMSO), glycols (including propylene glycol), acetone, and other common organic solvents. The term "hydrate" denotes a molecular complex comprising a quaternary ammonium compound of the invention and water. Pharmaceutically acceptable solvates according to the present invention include solvents such as D 2 O, d 6 -acetone, d 6 Including those that may be isotopically substituted such as -DMSO. Solvates can be liquid or solid.

[0206] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH 2 is attached through the carbon of the keto (C=O) group.

[0207] The term "Group I" is used herein to refer to Group I alkali metals, specifically lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), and francium (Fr). "Group II" herein refers to Group II alkaline earth metals, specifically beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), and radium (Ra). "Group III" refers herein to aluminum. "Transition metal" refers herein to any element contained in the lanthanides and actinides of the d and f blocks of the periodic table. Also included are post-transition metals, specifically gallium, indium, tin, thallium, and lead.

[0208] "Aryl" denotes an aromatic group having only carbon in the aromatic ring or rings. In some embodiments, aryl groups have from 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring atoms, but do not have heteroatoms as ring members. . If indicated, the aryl group may be further substituted with carbon or non-carbon atoms or groups. Such substitution may involve condensation with a 3- to 7-membered saturated cyclic group, which is optionally one or two independently selected from N, O, and S. heteroatoms and by condensation form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In some embodiments, aryl groups are pendant groups. Examples of pendant rings are phenyl groups substituted with phenyl groups. In some embodiments, aryl groups are optionally substituted as described above.

[0209] "Alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, an alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. . In one non-limiting embodiment, alkyl contains 1 to about 8 carbon atoms. In certain embodiments, alkyl is C 1 ~C 2 , C 1 ~C 3 , C 1 ~C 4 , C 1 ~C 5 , or C 1 ~C 6 is. As used herein, designated ranges refer to alkyl groups with each member of the range recited as an independent species. For example, C 1 ~C 6 The term alkyl denotes a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, each of which is described as a separate species. intended to mean For example, C 1 ~C 4 The term alkyl denotes a straight or branched chain alkyl group having 1, 2, 3 or 4 carbon atoms, each of which is intended to be described as a separate species. do. Examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane. , 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In alternative embodiments, alkyl groups are optionally substituted. The term "alkyl" also includes cycloalkyl or carbocyclic groups. For example, where a term containing "alk" is used, "cycloalkyl" or "carbocyclic" may be part of the definition, unless the context clearly dictates otherwise. For example, without limitation, terms such as alkyl, haloalkyl, etc., may all be said to include cyclic forms of alkyl, unless the context clearly dictates otherwise.

[0210] "Hydroxyalkyl" refers herein to any of the alkyl groups described above, substituted with at least one hydroxyl substituent.

[0211] "Alkanoic acid" as used herein refers to any carboxylic acid in which R is alkyl, where alkyl is as defined herein. Further, the alkanoic acid can be a diacid and / or a halogen such as chloride, bromide, fluoride, iodide, hydroxyl, N(R 7 ) 2 , NO 2 , alkyl, alkenyl and the like.

[0212] An "alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at any stable point along the chain. As used herein, specified ranges refer to alkenyl groups with each member of the range listed as a separate species as described above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. In alternative embodiments, alkenyl groups are optionally substituted. The term "alkenyl" also includes cycloalkyl or carbocyclic groups having at least one point of unsaturation.

[0213] An "alkynyl" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. As used herein, specified ranges refer to alkynyl groups with each member of the range listed as a separate species as described above for the alkyl moiety. Examples of alkynyl include ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, Examples include, but are not limited to 4-hexynyl and 5-hexynyl. In alternative embodiments, alkynyl groups are optionally substituted. The term "alkynyl" also includes cycloalkyl or carbocyclic groups having at least one point of unsaturation.

[0214] "Halo" and "halogen" are fluorine, chlorine, bromine or iodine.

[0215] A "haloalkyl" is a branched or straight chain alkyl group substituted with one or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl, but are not limited to these. "Perhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced with halogen atoms. Examples include, but are not limited to trifluoromethyl and pentafluoroethyl.

[0216] The terms "heterocyclyl" or "heterocycle" as used herein have at least one ring atom a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur and the remaining ring atoms are C and 3 to about 12, more typically 3, 5, 6, 7 to 12 optionally substituted at one or more ring atoms independently with one or more substituents as described above Refers to a saturated or partially unsaturated (ie, having one or more double and / or triple bonds in the ring without aromaticity) carbocyclic radical of 10 ring atoms. Heterocycle is a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or 6 to 10 rings bicycles having members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), such as bicyclo[4,5], [5, 5], [5,6] or [6,6] systems. In some embodiments, the only heteroatoms are nitrogen. In some embodiments, the only heteroatoms are oxygen. In some embodiments, the only heteroatom is sulfur. Heterocycles are described in Paquette, Leo A., "Principles of Modern Heterocyclic Chemistry" (W. A. ​​Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7 and 9, "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), especially Vol. 13, 14, 16, 19 and 28, and J. Am. Chem. Soc. (1960) 82 :5566. Examples of heterocycles include pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl , dihydrofuranyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinylimidazolinyl, imidazolidinyl, 2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2 .1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo (azabicyco)[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl, quinolidinyl, N-pyridyl urea and pyrrolopyrimidine. . Spiro moieties are also included within the scope of this definition. Examples of heterocyclic groups in which 1 or 2 ring carbon atoms are substituted with oxo (=O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclyl groups herein are optionally substituted independently with one or more substituents described herein.

[0217] A "heterocycloalkyl" is a saturated ring group. It may have, for example, 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, and the remaining ring atoms are carbon. In typical embodiments, nitrogen is the heteroatom. Monocyclic heterocycloalkyl groups typically have from 3 to about 8 ring atoms, or from 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl and pyrrolinyl.

[0218] The term "carrier," as applied to the compositions / combinations of the present invention, denotes a diluent, excipient, or vehicle with which the active compound is provided.

[0219] A "patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of any of the infectious diseases as described herein. In some embodiments, the host is human. "Patient" or "host" or "subject" also refers to, for example, mammals, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.

[0220] A "therapeutically effective amount" of a composition / combination of the invention means an amount effective, when administered to a host, to provide therapeutic benefit, e.g., amelioration of symptoms or reduction or reduction of the disease itself. In some embodiments, a therapeutically effective amount is sufficient to prevent exacerbation, cause regression, cause healing, or inhibit, eliminate, or prevent infection in a host in need thereof. amount.

[0221] As used herein, a "salt" is a derivative of a disclosed compound in which the parent compound is added by forming an inorganic or organic, non-toxic, acid or base addition salt of itself. Qualified. Salts of the compounds of the present invention can be synthesized from the parent compound, which possesses either basic or acidic moieties, by conventional chemical procedures. Generally, such salts are formed by reacting the free acid form of the compound with a stoichiometric amount of a suitable base (e.g., sodium hydroxide, carbonate, sodium bicarbonate, Ca, Mg, or K bicarbonate, etc.), or They can be prepared by reacting the free base form of the compound with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water, or in an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where permissible. Salts of the compounds of the present invention further include solvates of the compounds and compound salts.

[0222] Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Salts include, for example, conventional non-toxic salts and quaternary ammonium salts of the parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and organic acids such as acetic acid, propionic acid, succinic acid, Glycolic Acid, Stearic Acid, Lactic Acid, Malic Acid, Tartaric Acid, Citric Acid, Ascorbic Acid, Pamoic Acid, Maleic Acid, Hydroxymaleic Acid, Phenylacetic Acid, Glutamic Acid, Benzoic Acid, Salicylic Acid, Mesylic Acid, Esylic Acid, Besylic Acid, Sulfanilic Acid , 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 ) n’ Examples include salts prepared from -COOH (wherein n' is 0 to 4) and the like, or salts prepared using different acids that generate the same counterion. Further lists of suitable salts are found, for example, in Remington's Pharmaceutical Sciences, 17 th 20 ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0223] In typical embodiments, the positive charges in the formulas described herein are paired with one or more negatively charged ions, such as chloride ions.

[0224] chemistry "Alkyl" embodiment In some embodiments, "alkyl" is C 1 ~C 10 Alkyl, C 1 ~C 9 Alkyl, C 1 ~C 8 Alkyl, C 1 ~C 7 Alkyl, C 1 ~C 6 Alkyl, C 1 ~C 5 Alkyl, C 1 ~C 4 Alkyl, C 1 ~C 3 alkyl, or C 1 ~C 2 is alkyl.

[0225] In some embodiments, an "alkyl" has 1 carbon.

[0226] In some embodiments, an "alkyl" has 2 carbons.

[0227] In some embodiments, an "alkyl" has 3 carbons.

[0228] In some embodiments, an "alkyl" has 4 carbons.

[0229] In some embodiments, an "alkyl" has 5 carbons.

[0230] In some embodiments, an "alkyl" has 6 carbons.

[0231] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0232] Further non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0233] Further non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0234] Further non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0235] Further non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0236] In some embodiments, "alkyl" is "substituted alkyl."

[0237] In some embodiments, "alkenyl" is "substituted alkenyl."

[0238] In some embodiments, "alkynyl" is "substituted alkynyl."

[0239] "Haloalkyl" embodiment In some embodiments, "haloalkyl" is C 1 ~C 10 haloalkyl, C 1 ~C 9 haloalkyl, C 1 ~C 8 haloalkyl, C 1 ~C 7 haloalkyl, C 1 ~C 6 haloalkyl, C 1 ~C 5 haloalkyl, C 1 ~C 4 haloalkyl, C 1 ~C 3 haloalkyl, and C 1 ~C 2 is haloalkyl.

[0240] In some embodiments, a "haloalkyl" has 1 carbon.

[0241] In some embodiments, a "haloalkyl" has 1 carbon and 1 halogen.

[0242] In some embodiments, a "haloalkyl" has 1 carbon and 2 halogens.

[0243] In some embodiments, a "haloalkyl" has 1 carbon and 3 halogens.

[0244] In some embodiments, a "haloalkyl" has 2 carbons.

[0245] In some embodiments, a "haloalkyl" has 3 carbons.

[0246] In some embodiments, a "haloalkyl" has 4 carbons.

[0247] In some embodiments, a "haloalkyl" has 5 carbons.

[0248] In some embodiments, a "haloalkyl" has 6 carbons.

[0249] Non-limiting examples of "haloalkyl" include: [formation] are mentioned.

[0250] Further non-limiting examples of "haloalkyl" are: [formation] are mentioned.

[0251] Further non-limiting examples of "haloalkyl" are: [formation] are mentioned.

[0252] Further non-limiting examples of "haloalkyl" are: [formation] are mentioned.

[0253] Although silane quaternary amine compounds have been previously described for biocidal applications, their use is limited to industrial and agricultural applications such as textiles, clothing, construction materials, food packaging, adhesives, among others. , shingles, fiberglass, plastics, agricultural products, paints, coatings and surface treatments, carpets, wood, water purification systems, and laundry additives, and medical applications such as medical supplies and surgical gloves. rice field. Additionally, many of these silane quaternary amine compounds are typically sold in methanol, which can be toxic for pharmaceutical and other medical applications (U.S. Pat. 3,560,385, 3,794,736, 5,954,869, and 8,999,357).

[0254] These quaternary ammonium compounds do not decompose to form components that are overly toxic to the host. They can be used in remote areas to treat people and animals not currently receiving adequate antimicrobial health care approaches.

[0255] The quaternary ammonium compounds described herein have improved stability compared to other organosilanes, such as 3-(trihydroxysilyl)-N-propyl-N,N-dimethyloctadecylammonium chloride. and provides improved shelf life due to reduced levels of polymerization and subsequent formation of insoluble polysilsequioxane materials, both in solid form and in solution. In addition, the formulations of the present invention are substantially free of alcohols such as methanol, ethanol, etc., and / or other undesired minor amounts of volatile organics.

[0256] The quaternary ammonium compounds of the present invention do not produce by-products such as methanol upon hydrolysis. The powders or other solid formulations, e.g., lyophilized powders, of the present invention are substantially free of methanol, ethanol, and / or other undesired minor amounts of volatile organic compounds, provided that (i) such or (ii) use vacuum drying during processing, without other organosilane antimicrobial agents such as 3-(trihydroxysilyl)-N-propyl-N, It is a vast improvement over commercially available aqueous solutions of N-dimethyloctadecylammonium chloride. 3-(Trihydroxysilyl)-N-propyl-N,N-dimethyloctadecylammonium chloride often contains significant amounts of methanol as a by-product of its synthesis.

[0257] These molecules are small enough in size that they can readily perfuse biofilms, even as oligomeric species, and can traverse the small channels of biofilms even in aqueous or glycerin solutions. Being as stable as possible, it provides increased penetration into the biofilm with the efficacy of removing the entire biofilm including surviving bacterial cells.

[0258] Efficacy is maintained after interaction with and killing of microorganisms. This is because the organosilane molecules are not consumed by such interactions and can remain lethal to active microorganisms. Furthermore, the killing mechanism of these compounds reduces the likelihood of developing resistance in the targeted organism compared to other topical infection treatments using antibiotics and antifungals.

[0259] Sulfonate-formed organosilane quaternary compounds have also been reported previously, but their application was dedicated to industrial and agricultural applications and not to medical applications as described above. The molecule appears to be toxic for medical uses, such as ophthalmic and otic treatments. These organosilanes have organic sulfates, which are both harmful and toxic to the eyes and ears (US Pat. No. 5,954,869).

[0260] Other organosilane quaternary compounds such as 3-(trimethoxysilyl)-N-propyl-N,N-dimethyloctadecyl ammonium chloride and related trialkoxysilanes are used to treat infections, including wounds. (U.S. Patent Nos. 4,865,844; 4,908,355; U.S. Patent Application Publication Nos. 2011 / 0293681; 2012 / 0052106; 2013 / 0231599; 2014 / 0100504; 0346193; 2017 / 0094974; and WO 2000 / 54587; WO 2004 / 004793). However, the compound hydrolyzes to release methanol, which can be toxic to organisms, both in the aqueous environment of biological systems and when aqueous compositions are formed, and in tissues. Absorption alone is as toxic as digestion (see Ind. Eng. Chem. 1931, 23, 931-936). The production of toxic methanol as a by-product severely limits or largely precludes their use in pharmaceutical and medical applications. Furthermore, stable forms of silane quaternary ammonium compounds are not known without additives that are considered unsuitable for medical applications.

[0261] In some embodiments, the quaternary ammonium compounds of the present invention are solid compounds that readily dissolve in water to form stable aqueous solutions. For example, a quaternary ammonium compound can be dissolved in saline, deionized water, or a buffer to form a visually clear aqueous solution. In some embodiments, the aqueous solution becomes turbid for at least 1, 2, 3, 4, 5, 6, 8, 12, 16, or more days. can be stored at room temperature. In another embodiment, the quaternary ammonium compound can be made more soluble by first using a lyophilizer to form a powder.

[0262] In another embodiment, the quaternary ammonium compounds of the present invention form a neutral or nearly neutral solution when dissolved in water. For example, the aqueous solution can have a pH of about 6.4, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, or 8.0.

[0263] In some embodiments, the above solution has a concentration of the quaternary ammonium compound of the present invention of at least 0.2%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.6%, 1.8%. %, or 2.0%.

[0264] Zwitterions of the invention In certain alternative embodiments, the quaternary ammonium compounds of the invention are zwitterionic. In these embodiments, X - may be absent and the quaternary amine is neutralized with an internal anion. One non-limiting example is the compound of Formula I below: [formation]

[0265] In other embodiments, the quaternary ammonium compounds of the invention are not zwitterionic. In this embodiment, the quaternary amine is X - is neutralized with For example, compounds of formula I can be: [formation]

[0266] In some embodiments, the zwitterionic quaternary ammonium compound is more soluble in aqueous media than its non-zwitterionic form. In yet another embodiment, the zwitterionic compound is more stable in aqueous solution than its non-zwitterionic form. In some embodiments, zwitterionic compounds are more soluble in aqueous media than their non-zwitterionic forms. In yet another embodiment, the zwitterionic compound is more stable in aqueous solution than its non-zwitterionic form. In certain embodiments, the sodium chloride (NaCl) salt can be replaced with another salt described herein.

[0267] In an alternative embodiment, the quaternary ammonium compound of Formula I is zwitterionic and X - ions do not exist. For example, in some embodiments, Formula I is [formation] and representative compounds of formula I are [formation] is.

[0268] In an alternative embodiment, the quaternary ammonium compound of Formula III is zwitterionic and X - ions do not exist. For example, in some embodiments, Formula III is [formation] and representative compounds of Formula III are: [formation] is.

[0269] In an alternative embodiment, the quaternary ammonium compound of Formula IV is zwitterionic and X - ions do not exist. For example, in some embodiments, Formula IV is [formation] and representative compounds of Formula IV are: [formation] is.

[0270] Representative compounds of the invention In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0271] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0272] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0273] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0274] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0275] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0276] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0277] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0278] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0279] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0280] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0281] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0282] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0283] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0284] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0285] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0286] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0287] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0288] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0289] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0290] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0291] In some embodiments, the quaternary ammonium compounds of the present invention are [formation] is.

[0292] Representative compounds of the invention In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] TIFF2022552017000089.tif220170TIFF2022552017000090.tif196170TIFF2022552017000091.tif223170TIFF2022552017000092.tif230170TIFF20225520170 00093.tif211170TIFF2022552017000094.tif79170.

[0293] In certain embodiments, the compounds of the invention are [formation] is selected from

[0294] In certain embodiments, the compounds of the invention are [formation] is selected from

[0295] In certain embodiments, the compounds of the invention are [formation] selected from TIFF2022552017000098.tif202170TIFF2022552017000099.tif132170 or in any of its alternative protonation states where possible at pH 6-8, additional B as appropriate to compensate for the change in charge + or X - have counter ions.

[0296] In certain embodiments, the compounds of the invention are [formation] selected from TIFF2022552017000101.tif184170TIFF2022552017000102.tif129170, or in any of its alternative protonation states where possible at pH 6-8, additional B as appropriate to compensate for the change in charge + or X - have counter ions.

[0297] In certain embodiments, the compounds of the invention are [formation] selected from TIFF2022552017000104.tif187170TIFF2022552017000105.tif123170, or in any of its alternative protonation states where possible at pH 6-8, and additional B as appropriate to compensate for the change in charge + or X - have counter ions.

[0298] In certain embodiments, the compounds of the invention are [formation] is selected from

[0299] In certain embodiments, the compounds of the invention are [formation] is selected from

[0300] In certain embodiments, the compounds of the invention are [formation] selected from TIFF2022552017000109.tif197170TIFF2022552017000110.tif174170 or in any of its alternative protonation states where possible at pH 6-8, additional B as appropriate to compensate for the change in charge + or X - have counter ions.

[0301] In certain embodiments, the compounds of the invention are [formation] is selected from

[0302] In certain embodiments, the compounds of the invention are [formation] selected from TIFF2022552017000113.tif192170TIFF2022552017000114.tif247170 or in any of its alternative protonation states where possible at pH 6-8, additional B as appropriate to compensate for the change in charge + or X - have counter ions.

[0303] In certain embodiments, the compounds of the invention are [formation] is selected from

[0304] In certain embodiments, the compounds of the invention are [formation] selected from TIFF2022552017000117.tif188170TIFF2022552017000118.tif131170, or in any of its alternative protonation states where possible at pH 6-8, additional B as appropriate to compensate for the change in charge + or X - have counter ions.

[0305] In certain embodiments, the compounds of the invention are [formation] is selected from

[0306] In certain embodiments, the compounds of the invention are [formation] is selected from

[0307] In certain embodiments, the compounds of the invention are [formation] is selected from or capable of being present at pH 6-8 is of one of its alternative protonation states, as appropriate to compensate for the change in charge. additional B. + or X - have counter ions.

[0308] In certain embodiments, the compounds of the invention are [formation] is selected from

[0309] In certain embodiments, the compounds of the invention are [formation] selected from or present at pH 6-8 where possible, in one of its alternative protonation states, as appropriate to compensate for the change in charge additional B. + or X - have counter ions.

[0310] In certain embodiments, the compounds of the invention are [formation] is selected from

[0311] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000134.tif182170TIFF2022552017000135.tif198170.

[0312] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000137.tif196170TIFF2022552017000138.tif131170.

[0313] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000140.tif228170TIFF2022552017000141.tif252170.

[0314] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000143.tif177170TIFF2022552017000144.tif254170.

[0315] In certain embodiments, the compounds of the invention are [formation] is selected from

[0316] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000147.tif216170.

[0317] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000149.tif225170.

[0318] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000151.tif221170.

[0319] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000153.tif224170.

[0320] In certain embodiments, the compounds of the invention are [formation] is selected from

[0321] In certain embodiments, the compounds of the invention are [formation] is selected from

[0322] In certain embodiments, the compounds of the invention are [formation] is selected from

[0323] In certain embodiments, the compounds of the invention are [formation] is selected from

[0324] In certain embodiments, the compounds of the invention are [formation] is selected from

[0325] In certain embodiments, the compounds of the invention are [formation] is selected from

[0326] In certain embodiments, the compounds of the invention are [formation] is selected from TIFF2022552017000161.tif229170TIFF2022552017000162.tif158170TIFF2022552017000163.tif159170, or in any of its alternative protonation states where it can exist at pH 6-8, as appropriate to compensate for the change in charge additional to B. + or X - have counter ions.

[0327] In certain embodiments, the compounds of the invention are [formation] is selected from TIFF2022552017000165.tif183170TIFF2022552017000166.tif183170TIFF2022552017000167.tif183170, or in any of its alternative protonation states where it can exist at pH 6-8, as appropriate to compensate for the change in charge additional to B. + or X - have counter ions.

[0328] In certain embodiments, the compounds of the invention are [formation] is selected from

[0329] In certain embodiments, the compounds of the invention are [formation] Selected from TIFF2022552017000170.tif185170TIFF2022552017000171.tif195170TIFF2022552017000172.tif159170.

[0330] In some embodiments, the present invention provides the following formula: [formation] (where all variables are as defined herein).

[0331] In certain embodiments of Formula I, R 2 , R 3 , and R 4 is independently [formation] (In the formula, R 8 , R 9 , X 1 , X 2 , and B +are as defined herein).

[0332] In certain embodiments, R 8 and R 9 are independently hydrogen, hydroxyl, C 1 ~C 8 alkyl, and C 1 ~C 8 selected from hydroxyalkyl;

[0333] In certain embodiments, X 1 is NH.

[0334] In certain embodiments, X 1 is NR 17 where R 17 is C 1 ~C 8 is hydroxyalkyl.

[0335] In certain embodiments, X 1 is CH 2 is.

[0336] In certain embodiments, X 2 is C 1 ~C 3 is alkyl.

[0337] In certain embodiments, X 2 is C 1 ~C 3 is hydroxyalkyl.

[0338] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0339] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0340] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0341] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0342] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0343] In certain embodiments of Formula I, [formation] is independently [formation] selected from TIFF2022552017000187.tif197170, where B + is optionally H + or B + is absent and this moiety is anionic.

[0344] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0345] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0346] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0347] In certain embodiments of Formula I, [formation] is independently [formation] is selected from, where B + is optionally H + or B + is absent and this moiety is anionic.

[0348] In certain embodiments of Formula I, [formation] is independently [formation] selected from TIFF2022552017000198.tif217170, where B + is optionally H + or B + is absent and this moiety is anionic.

[0349] In certain embodiments of Formula I, [formation] is independently [formation] selected from TIFF2022552017000201.tif208170TIFF2022552017000202.tif57170, where B + is optionally H + or B + is absent and this moiety is anionic.

[0350] In certain embodiments of Formula I, [formation] is independently [formation] selected from TIFF2022552017000205.tif227170TIFF2022552017000206.tif125170, where B + is optionally H + or B + is absent and this moiety is anionic.

[0351] In certain embodiments of Formula I, R 2 , R 3 , and R 4 is independently [formation] (In the formula, R 10 , R 11 , R 12 , R 13 , and X 3 are as defined herein).

[0352] In certain embodiments, R 10 and R 11 are independently hydrogen and C 1 ~C 8 selected from alkyl;

[0353] In certain embodiments, R 12 and R 13 are independently hydrogen, hydroxyl, C 1 ~C 8 Alkyl, COOH, and C 1 ~C 8 selected from hydroxyalkyl;

[0354] In certain embodiments, X 3 are independently hydroxyl, C 1 ~C 8 alkyl, and C 1 ~C 8 selected from hydroxyalkyl;

[0355] In certain embodiments of Formula I, [formation] teeth, [formation] Selected from TIFF2022552017000210.tif226170.

[0356] In certain embodiments of Formula I, [formation] teeth, [formation] Selected from TIFF2022552017000213.tif241170.

[0357] In certain embodiments of Formula I, [formation] teeth, [formation] Selected from TIFF2022552017000216.tif210170TIFF2022552017000217.tif202170.

[0358] In certain embodiments of Formula I, [formation] teeth, [formation] is selected from

[0359] In certain embodiments of Formula I, R 2 , R 3 , and R 4 is independently [formation] (In the formula, R 8 , R 9 , X 1 , and X 4 are as defined herein).

[0360] In certain embodiments, [formation] teeth, [formation] Selected from TIFF2022552017000223.tif206170TIFF2022552017000224.tif108170.

[0361] In certain embodiments, [formation] teeth, [formation] is selected from

[0362] In certain embodiments, [formation] teeth, [formation] is selected from

[0363] In certain embodiments, [formation] teeth, [formation] is selected from

[0364] In certain embodiments, [formation] teeth, [formation] is selected from

[0365] In certain embodiments, [formation] teeth, [formation] is selected from

[0366] In certain embodiments, [formation] teeth, [formation] is selected from

[0367] In certain embodiments, [formation] teeth, [formation] is selected from

[0368] In certain embodiments, [formation] teeth, [formation] is selected from

[0369] In certain embodiments, [formation] teeth, [formation] is selected from

[0370] In certain embodiments, [formation] teeth, [formation] is selected from

[0371] In certain embodiments, [formation] teeth, [formation] is selected from

[0372] In certain embodiments, [formation] teeth, [formation] is selected from

[0373] In certain embodiments, [formation] teeth, [formation] is selected from

[0374] In certain embodiments, R 8 and R 9 are independently hydrogen, hydroxyl, C 1 ~C 8 alkyl, and C 1 ~C 8 selected from hydroxyalkyl;

[0375] In certain embodiments, X 1 is NH.

[0376] In certain embodiments, X 1 is NR 17 where R 17 are each independently hydrogen, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl and aryl;

[0377] In certain embodiments, X 1 is CH 2 is.

[0378] In certain embodiments, X 4 is the NH 2 is.

[0379] In certain embodiments, X 4 is N(R 7 ) 2 where R 7 are each independently hydrogen, C 1 ~C 8 Alkyl, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1 ~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl and aryl;

[0380] In certain embodiments, X 4 is C 1 ~C 12 is an alkanoic acid.

[0381] In certain embodiments of Formula I, [formation] teeth, [formation] is selected from

[0382] In certain embodiments of Formula I, [formation] teeth, [formation] Selected from TIFF2022552017000255.tif34170.

[0383] In certain embodiments of Formula I, [formation] teeth, [formation] is selected from

[0384] In certain embodiments of Formula I, [formation] teeth, [formation] is selected from

[0385] In certain embodiments, the quaternary ammonium compound of Formula I is [formation] TIFF2022552017000261.tif163170TIFF2022552017000262.tif156170TIFF2022552017000263.tif226170TIFF2022552017000264.tif227170TIFF20225520170 00265.tif233170TIFF2022552017000266.tif225170TIFF2022552017000267.tif152170, where B + is optionally H + or B + is absent and this moiety is anionic.

[0386] In certain embodiments, the quaternary ammonium compound of Formula I is [formation] TIFF2022552017000269.tif191170TIFF2022552017000270.tif221170TIFF2022552017000271.tif163170TIFF2022552017000272.tif122170.

[0387] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] or a salt or pharmaceutically acceptable composition thereof.

[0388] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] or a salt or pharmaceutically acceptable composition thereof.

[0389] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] or a salt or pharmaceutically acceptable composition thereof.

[0390] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] or a salt or pharmaceutically acceptable composition thereof.

[0391] In another aspect of the invention, the quaternary ammonium compound of Formula I is [formation] or a salt or pharmaceutically acceptable composition thereof.

[0392] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] or a salt or pharmaceutically acceptable composition thereof.

[0393] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0394] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0395] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0396] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0397] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0398] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0399] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0400] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0401] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0402] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0403] In another aspect of the invention, the quaternary ammonium compound of formula I is [formation] is selected from

[0404] In some embodiments, the present invention provides the following formula: [formation] (In the formula, a, R 1 , R 14 , R 15 , R 16 , and X - is as defined herein) or a salt thereof or a pharmaceutically acceptable composition thereof.

[0405] In certain embodiments of Formula II, R 14 and R 15 are independently [formation] , R 2 , and R 17 is selected from

[0406] In certain embodiments of Formula II, R 14 and R 15 are independently [formation] is selected from

[0407] In certain embodiments of Formula II, R 14 and R 15 are each independently R 2 is selected from

[0408] In certain embodiments of Formula II, R 14 and R 15 are each independently R 17 is selected from

[0409] In certain embodiments, the quaternary ammonium compound of Formula II is [formation] TIFF2022552017000302.tif217170TIFF2022552017000303.tif178170TIFF2022552017000304.tif217170TIFF2022552017000305.tif201170TIFF20225520170 00306.tif254170, or a salt or pharmaceutically acceptable composition thereof.

[0410] In another aspect of the invention, the quaternary ammonium compound of Formula II is [formation] or a salt or pharmaceutically acceptable composition thereof.

[0411] In another aspect, the present invention provides a compound of the formula: [formation] (In the formula, a, p, q, y, R 1 , R 5 , R 6 , R 16 , and X - is as defined herein) or a salt thereof or a pharmaceutically acceptable composition thereof.

[0412] In certain embodiments of Formula III, R 5 is independently [formation] (In the formula, R 8 , R 9 , X 1 , X 2 , and B + are as defined herein).

[0413] In certain embodiments of Formula III, R 5 is independently [formation] (In the formula, R 10 , R 11 , R 12 , R 13 , and X 3 are as defined herein).

[0414] In certain embodiments of Formula III, R 5 is independently [formation] (In the formula, R 8 , R 9 , X 1 , and X 4 are as defined herein).

[0415] In certain embodiments of Formula III, R 5 independently, R 17 is selected from R 17 are each independently hydrogen, C 1 ~C 8 hydroxyalkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 1~C 8 haloalkyl, C 1 ~C 8 selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl and aryl;

[0416] In certain embodiments of Formula III or Formula IV, R 6 is independently selected from alkyl, aryl, cycloalkyl, and heterocyclyl, each of said alkyl, aryl, cycloalkyl, and heterocyclyl optionally being C 1 ~C 6 Alkyl, hydroxyl, halogen, NH 2 , NHR 7 , N(R 7 ) 2 , C(O)OH, C(O)R 7 , C(O)H, CH 2 OR 7 , C(O)OR 7 , CONH 2 , CONHR 7 , CON(R 7 ) 2 , and NO 2 has a substituent selected from

[0417] In certain embodiments of Formula III, R 5 is independently [formation] (In the formula, p and (R 6 ) y are as defined herein).

[0418] In certain embodiments of Formula III, [formation] teeth, [formation] is selected from

[0419] In certain embodiments of Formula III, [formation] teeth, [formation] Selected from TIFF2022552017000317.tif185170.

[0420] In certain embodiments of Formula III, R 5 are each independently C 1 ~C 12 is selected from alkanoic acids or salts thereof; 5 forms a bond with this alkanoic acid at any available carbon atom on the hydrocarbon chain to form a C-O bond.

[0421] For example, R 5 teeth, [formation] A bond can be formed in

[0422] In certain embodiments of Formula III, R 5 is C 1 ~C 12 an alkanoic acid, optionally a diacid, wherein R 5 forms a bond with this alkanoic acid at any available carbon atom on the hydrocarbon chain to form a C-O bond.

[0423] For example, if the alkanoic acid is a diacid, then R 5 teeth, [formation] A bond can be formed in

[0424] In certain embodiments of Formula III, R 5 is C 1 ~C 12 is an alkanoic acid, which optionally has one or more substituents on the hydrocarbon chain, the substituents being hydrogen, halogen, hydroxyl, N(R 7 ) 2 is selected from

[0425] For example, if the alkanoic acid has one or more substituents, then R 5 teeth, [formation] A bond can be formed in

[0426] In certain embodiments of Formula III, R 5 teeth, [formation] C selected from 1 ~C 12 is an alkanoic acid.

[0427] In certain embodiments of Formula III, R 5 teeth, [formation] C selected from 1 ~C 12 is an alkanoic acid.

[0428] In certain embodiments of Formula III, R 5 teeth, [formation] C selected from TIFF2022552017000324.tif201170TIFF2022552017000325.tif228170 1 ~C 12 is an alkanoic acid.

[0429] In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is two. In certain embodiments, y is three. In certain embodiments, y is four.

[0430] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is two. In certain embodiments, p is three. In certain embodiments, p is four.

[0431] In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is two. In certain embodiments, q is three. In certain embodiments, q is four.

[0432] In certain embodiments, a is 1. In certain embodiments, a is two. In certain embodiments, a is 3. In certain embodiments, a is 4. In certain embodiments, a is 5. In certain embodiments, a is 6. In certain embodiments, a is 7. In certain embodiments, a is eight.

[0433] In certain embodiments of Formula III, [formation] teeth, [formation] is selected from

[0434] In certain embodiments of Formula III, [formation] teeth, [formation] is selected from

[0435] In certain embodiments of Formula III, [formation] teeth, [formation] is selected from

[0436] In certain embodiments of Formula III, [formation] teeth, [formation] is selected from

[0437] In certain embodiments of Formula III, [formation] teeth, [formation] is selected from

[0438] In certain embodiments of Formula III, [formation] teeth, [formation] is selected from

[0439] In certain embodiments of Formula III, [formation] teeth, [formation] Selected from TIFF2022552017000340.tif98170.

[0440] In certain embodiments of Formula III, [formation] teeth, [formation] Selected from TIFF2022552017000343.tif213170TIFF2022552017000344.tif203170.

[0441] In certain embodiments of Formula III, [formation] teeth, [formation] Selected from TIFF2022552017000347.tif163170.

[0442] In certain embodiments of Formula III, [formation] teeth, [formation] Selected from TIFF2022552017000350.tif159170.

[0443] In certain embodiments of Formula IV, [formation] teeth, [formation] is selected from

[0444] In certain embodiments of Formula IV, [formation] teeth, [formation] is selected from

[0445] In certain embodiments of Formula IV, [formation] teeth, [formation] Selected from TIFF2022552017000357.tif226170.

[0446] In certain embodiments of Formula IV, [formation] teeth, [formation] is selected from

[0447] In certain embodiments of Formula IV, [formation] teeth, [formation] is selected from

[0448] In some embodiments of Formula IV, [formation] teeth, [formation] is selected from

[0449] In some embodiments of Formula IV, [formation] teeth, [formation] Selected from TIFF2022552017000366.tif36170.

[0450] In some embodiments of Formula IV, [formation] teeth, [formation] Selected from TIFF2022552017000369.tif205170TIFF2022552017000370.tif199170.

[0451] In some embodiments of Formula IV, [formation] teeth, [formation] Selected from TIFF2022552017000373.tif145170.

[0452] In some embodiments of Formula IV, [formation] teeth, [formation] Selected from TIFF2022552017000376.tif217170.

[0453] In another aspect of the invention, the quaternary ammonium compound of formula III is [formation] Selected from TIFF2022552017000378.tif101170.

[0454] In another aspect of the invention, the quaternary ammonium compound of formula III is [formation] is selected from

[0455] In another aspect of the invention, the quaternary ammonium compound of Formula IV is [formation] Selected from TIFF2022552017000381.tif192170.

[0456] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] Selected from TIFF2022552017000383.tif169170.

[0457] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0458] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0459] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0460] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0461] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] Selected from TIFF2022552017000389.tif194170.

[0462] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0463] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0464] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] Selected from TIFF2022552017000393.tif184170.

[0465] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0466] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0467] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0468] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0469] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0470] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0471] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0472] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] Selected from TIFF2022552017000402.tif61170.

[0473] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] Selected from TIFF2022552017000404.tif162170.

[0474] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0475] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0476] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0477] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0478] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] is selected from

[0479] In certain embodiments, the quaternary ammonium compounds of the present invention are [formation] Selected from TIFF2022552017000411.tif138170.

[0480] blend In certain embodiments, a mixture of quaternary ammonium compounds is provided, the mixture comprising: (1) 0.01% to 99.9% compounds of the invention; (2) 0.01% to 99.9% alkyl (C14, 50%, C12, 40%, C16, 10%) dimethylbenzylammonium chloride; and (3) 0.01% to 99.9% dioctyldimethylammonium chloride; or PVA).

[0481] In certain embodiments, a mixture of quaternary ammonium compounds is provided, the mixture comprising: (1) 0.01% to 99.9% of a compound of the invention; (2) 0.01% to 99.9% of another compound of the invention; (3) 0.01% to 99.9% alkyl (C14, 50%, C12, 40%, C16, 10%) dimethylbenzylammonium chloride; and (4) 0.01% to 99.9% dioctyldimethylammonium chloride; Including any desired solvent mixture, with or without a thickening agent (eg, guar gum or PVA).

[0482] In certain embodiments, a mixture of quaternary ammonium compounds is provided, the mixture comprising: (1) 0.01% to 99.9% of the compound of Formula I; (2) 0.01% to 99.9% of the compound of Formula XII; (3) 0.01%-99.9% alkyl (C14, 50%, C12, 40%, C16, 10%) dimethylbenzylammonium chloride; and (4) 0.01-99.9% dioctyldimethylammonium chloride; and any desired with or without a thickening agent (eg, guar gum or PVA).

[0483] In certain embodiments, a mixture of quaternary ammonium compounds is provided, the mixture comprising (1) 0.01% to 99.9% of a compound of the invention; and (2) 0.01% to 99.9% of a compound of the invention. another compound; and any desired solvent mixture, with or without a thickening agent (eg, guar gum or PVA).

[0484] In certain embodiments, a mixture of quaternary ammonium compounds is provided, the mixture comprising: (1) 0.01% to 99.9% of a compound of formula I; and (2) 0.01% to 99.9% of a another compound; and any desired solvent mixture, with or without a thickening agent (eg, guar gum or PVA).

[0485] In certain embodiments, a mixture of quaternary ammonium compounds is provided, the mixture comprising: (1) 0.01% to 99.9% of a compound of formula I; and (2) 0.01% to 99.9% of a compound of formula XII. compound; and any desired solvent mixture, with or without a thickening agent (eg, guar gum or PVA).

[0486] In certain embodiments, a mixture of quaternary ammonium compounds is provided comprising: (1) 0.01% to 99.9% of a compound of the invention; and (2) 0.01% to 99.9% alkyl (C14 , 50%, C12, 40%, C16, 10%) dimethylbenzylammonium chloride; and any desired solvent mixture, with or without a thickening agent (eg, guar gum or PVA).

[0487] In certain embodiments, a mixture of quaternary ammonium compounds is provided comprising: (1) 0.01% to 99.9% of a compound of the invention; and (2) 0.01% to 99.9% dodecyldimethylammonium chloride; and any desired solvent mixture, with or without a thickening agent (eg, guar gum or PVA).

[0488] In certain embodiments, a mixture of quaternary ammonium compounds is provided comprising: (1) 0.01% to 99.9% of a compound of the invention; and (2) 0.01% to 99.9% dioctyldimethylammonium chloride; and any desired solvent mixture, with or without a thickening agent (eg, guar gum or PVA).

[0489] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (1) has a concentration of about 5% to 99%.

[0490] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (1) has a concentration of about 10% to 99%.

[0491] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (1) has a concentration of about 20% to 99%.

[0492] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (1) is present at a concentration of about 30% to 99%.

[0493] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (1) has a concentration of about 5% to 90%.

[0494] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (1) is present at a concentration of about 10% to 80%.

[0495] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (1) has a concentration of about 20% to 70%.

[0496] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (1) is present at a concentration of about 30% to 60%.

[0497] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (1) is present at a concentration of about 40%-60%.

[0498] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (2) has a concentration of about 5% to 99%.

[0499] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (2) has a concentration of about 10% to 99%.

[0500] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (2) has a concentration of about 20% to 99%.

[0501] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (2) has a concentration of about 30% to 99%.

[0502] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (2) is present at a concentration of about 5% to 90%.

[0503] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (2) is present at a concentration of about 10% to 80%.

[0504] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (2) has a concentration of about 20% to 70%.

[0505] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (2) is present at a concentration of about 30%-60%.

[0506] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (2) is present at a concentration of about 40%-60%.

[0507] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (3) has a concentration of about 5% to 99%.

[0508] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (3) has a concentration of about 10% to 99%.

[0509] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (3) has a concentration of about 20% to 99%.

[0510] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (3) has a concentration of about 30% to 99%.

[0511] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (3) is present at a concentration of about 5% to 90%.

[0512] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (3) is present at a concentration of about 10% to 80%.

[0513] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (3) is present at a concentration of about 20% to 70%.

[0514] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (3) is present at a concentration of about 30%-60%.

[0515] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (3) is present at a concentration of about 40%-60%.

[0516] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (4) has a concentration of about 5% to 99%.

[0517] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (4) has a concentration of about 10% to 99%.

[0518] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (4) has a concentration of about 20% to 99%.

[0519] In certain embodiments, one of the above component mixtures is provided wherein the quaternary ammonium compound (4) has a concentration of about 30% to 99%.

[0520] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (4) is present at a concentration of about 5% to 90%.

[0521] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (4) is present at a concentration of about 10% to 80%.

[0522] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (4) is present at a concentration of about 20% to 70%.

[0523] In certain embodiments, one of the above component mixtures is provided in which the quaternary ammonium compound (4) is present at a concentration of about 30% to 60%.

[0524] In certain embodiments, one of the mixtures of the above components is provided in which the quaternary ammonium compound (4) is present at a concentration of about 40%-60%.

[0525] In certain embodiments, the concentration is the mass of compound (1), (2), (3), or (4) divided by the mass of compound (1), (2), (3), or (4). Calculated by dividing by the total mass. In other embodiments, the concentration is measured as a percentage in mol / L.

[0526] In certain embodiments, the above mixture is provided as a blend with another mixture above.

[0527] Non-limiting examples of solvents include water, ethanol, saline, DMSO, glycols (eg, propylene glycol).

[0528] Non-limiting examples of thickeners, humectants, and / or gelling agents include guar gum, PVA, PVP, starch, and xanthan gum.

[0529] Infection treatment The present invention includes methods of treating infections in a host using the quaternary ammonium compounds or products described herein or mixtures thereof.

[0530] In some embodiments, infections are treated directly with a solution (typically reconstituted from a sterile powder or solid) containing one or more quaternary ammonium compounds of the invention.

[0531] In some embodiments, infections are treated directly on the biological surface with a solution containing one or more quaternary ammonium compounds of the invention. Typical biological surfaces include oral areas such as teeth, gums, gingival sulcus, periodontal pockets, ear areas such as outer ear, middle ear (tympanic cavity), inner ear (labyrinth), female reproductive system (eg vagina, uterus). cervix, uterus, fallopian tubes), male reproductive system (e.g. penis, scrotum, testis, epididymis), anus, perineum, rectum, peritoneum, prostate, urinary tract, endothelium, conjunctiva, corneal tissue, Wounds include, but are not limited to, any surface of airways, lung tissue (e.g., bronchi and alveoli), heart valves, gastrointestinal tract, skin, scalp, nails, and wounds, particularly chronic wound surfaces. , which may be local or internal.

[0532] biofilm Biofilms can occur in many environments, including healthcare settings, equipment, and surfaces of medical devices, and, most importantly, the skin, ears, and surfaces of humans and animals. , wounds, and other in vivo local areas. These colonized microbial communities are very different from their corresponding planktonic communities. Estimates vary, but as many as 40% of bacterial genes may be up- or down-regulated in the planktonic-to-biofilm transition in order to acquire specialized functions (Davies et al. D.G., Parsek M.R., Pearson J.P., Iglewski B.H., Costerton J.W., Greenberg E.P. "The involvement of cell-to-cell signals in the development of a bacterial biofilm" Science.1998, 280, 295-298; and Hall-Stoodley L. , Costerton J.W., Stoodley P. "Bacterial biofilms: From the natural environment to infectious diseases" Nat. Rev. 2004, 2, 95-108). "What was once defined as the formation of microbial communities attached to surfaces has come to be recognized as a complex developmental process with a multifaceted and dynamic nature." (Kostakioti M., Hadjifrangiskou M., Hultgren, S. "Bacterial Biofilms: Development, Dispersal, and Therapeutic Strategies in the Dawn of the Postantibiotic Era" Cold Spring Harb Perspect Med 2013, 3:a010306. reference).

[0533] Up to 80% of human bacterial infections are associated with biofilms. Biofilm communities can cause "persistent infections that are resistant to conventional antimicrobial therapies" and are "a major cause of treatment failure today" (Roemling, U. Balsalobre, C. "Biofilm infections, their resilience to therapy and innovative treatment strategies." Journal of Internal Medicine, 2004, 272: 541-561). When microbes form biofilms in vivo, they can become resistant not only to antimicrobial agents, but also to the host's own immune defenses. Antibiotics designed to fight infections have traditionally been developed to kill planktonic bacteria, under the assumption that such drugs would kill the same bacteria in different forms. However, even the same bacteria in a biofilm state differ from those in a planktonic state because of a dramatic shift in gene expression. These changes in gene expression have emergent properties that cannot be predicted based on studies in planktonic cells alone. Bacteria protected within biofilms have up to 1000-fold higher antibiotic resistance than when bacteria are in planktonic form (Rasmussen TB, Givskov M. Int J Med Microbiol. 2006, 296(2-3):149 -161).

[0534] Clinically, biofilms are responsible for many common persistent and chronic infections in humans and animals because of their acquired and inherent resistance to antimicrobial agents and the selection of phenotypic variants. Such resistance tends to be multifactorial, and biofilms typically contain a mixture of fungal / bacterial species that may improve rejection of antimicrobial agents. (See Non-Patent Document 4 and Al-Fattani M.A and Douglas L.J. "Biofilm matrix of Candida albicans and Candida tripicalis: chemical composition and role in drug resistance" Journal of Medical Microbiology 2006; 55:999-1008).

[0535] Biofilms are often composed of multiple cell layers. The laminated nature of biofilms results in heterogeneous exposure of individual organisms to oxygen and nutrients, especially in deeper environments, which can lead to changes in metabolic activity. invite. Often these deep-lying organisms are known as "survivors" and are in quiescent phase. These quiescent cells are often fortified against chemical agents by their overlying cell layer and are therefore exposed to lesser amounts of treatment than those on the surface of the biofilm. For example, the efficacy of antibiotics often decreases with increasing depth of the biofilm, because most of the antibiotic is consumed by cells in the upper layers before diffusing into the lower layers, resulting in Indeed, insufficient concentrations are reached (Roemling and Balsalobre, 551). This phenomenon leads to incomplete removal of biofilms during many antimicrobial therapeutic regimens, resulting in the observable survival of resistant cells, thus creating a situation of chronic or persistent infection (Musk, Jr. D. and Hergenrother, P. "Chemical Countermeasures for the Control of Bacterial Biofilms: Effective Compounds and Promising Targets" Current Medicinal Chemistry 2006, 13, 2163-2177).

[0536] By genetically encoding information identifying the antibiotics encountered, the surviving cells enable new colonies in the future to recognize and resist such therapeutic regimens. This genetic information can be transferred and shared with other microorganisms in multiple ways, such as by electrical signaling, conjugation, mutation, and heterologous expression, thus providing a wide range of available drugs. "Antibiotic resistance" exponentially spreads, leading to the development of "hyperresistant" strains of pathogenic organisms (Davies, J and Davies, D. "Origins and Evolution of Antibiotic Resistance" Microbiology and Molecular Biology Reviews 2010, 417 -433; and Humphries, J., Xiong, L., Liu, J., Prindle, A., Yuan, F., Arjes, H.A., Tsimring, L. and Gurol, S. "Species-Independent Attraction to Biofilms through Electrical Signaling" Cell 2017, 168, 200-209).

[0537] The formation and maintenance of mature biofilms is closely associated with the production of extracellular matrix. Multiple layers of cells and EPS can constitute complex and dense structures in which it is difficult for biocides to penetrate and reach the inner layers, thus hindering the effectiveness of biocides. (see Bridier, et. al. "Resistance of bacterial biofilms to disinfectants: a review" Biofouling 2011, Vol. 27). Since biocides are often chemically highly reactive molecules, the presence of organic matter, such as proteins, nucleic acids, or carbohydrates, can greatly impair the effectiveness of biocides, and antimicrobial agents and biofilm components may also contribute to the limited penetration of antimicrobials into biofilms.

[0538] "More than 5 million central venous catheters are installed in the United States each year, and biofilm infections occur in more than 50% of these catheters. There are approximately 100,000 deaths and $6.5 billion in overspending annually in the United States alone. is” (ibid.). Biofilms are also a major problem associated with implant devices. "Fungal biofilms are often resistant to known antifungal agents" (Id.). "Removal of some of these devices... can be costly, in some cases can be dangerous to the patient, and administration of high doses of antifungals can be... renal and may lead to further complications, including liver damage.Such treatment is often not even possible, as many critically ill patients cannot tolerate such treatment, and such Patients are left with few options available, highlighting the need to find better therapeutic and diagnostic therapies to combat these biofilms." Gulati, M. and Nobile, C., "Candida albicans biofilms: development, regulation, and molecular mechanisms." Microbes Infect 2016, 18(5), 310-321; Doi: 10.101 / j.mocomf.2016.01.002). In certain embodiments, compounds described herein are useful for treating, preventing, or removing biofilms.

[0539] The most common ocular infections include ocular redness, bacterial or viral conjunctivitis (pink eyes), corneal ulcers, keratitis, bacterial, fungal, and herpetic (herpal) infectious keratitis, endophthalmitis ( endophthalmitic), and blepharitis (eyelid infection). Conjunctivitis is the most common eye infection and viral conjunctivitis is the most common form. The most common causes of bacterial conjunctivitis are Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus (Antibiotics versus placebo for acute bacterial conjunctivitis. Sheikh A, Hurwitz B., Cochrane Database Syst Rev. 2006). Apr 19; (2): CD001211;). Both viral and bacterial conjunctivitis present with ocular redness and are highly contagious (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC6003010 / ). Blepharitis is inflammation of the eyelids. Blepharitis is a common cause of sore, red eyelids, and stiff eyelashes. The eyelid margin can become infected with bacterial or fungal infections, the accumulation of which forms biofilms. The parasitic eyelash mite, called Demodex, feeds on biofilms, which leads to overgrowth of mites that exacerbate eyelid margin inflammation (https: / / www.allaboutvision.com / conditions / bleparitis. htm, https: / / www.reviewofoptometry.com / article / ro1117-could-eyelids-be-the-key-to-ded).

[0540] Bacterial infection is the most common cause of infectious keratitis. Common bacteria include S. aureus, coagulase-negative Staphylococcus, S. pneumoniae, and Pseudomonas aeruginosa (Sharma A, Taniguchi J. Review: Emerging strategies for antimicrobial drug delivery to the ocular surface: Implications for infectious keratitis. Ocul Surf 2017, 15, 670-9.; Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea 2008, 27, 22-7). P. aeruginosa is the most common organism associated with bacterial keratitis among contact lens wearers. Acanthamoeba is suspected if the patient swims or goes to spas while wearing contact lenses (Stapleton F, Dart JK, Seal DV, Matheson M. Epidemiology of Pseudomonas aeruginosa keratitis in contact lens wearers. Epidemiol Infect 1995). , 114, 395-402).

[0541] Dry eye syndrome, or dry eye disease (DED), is one of the most common ocular conditions worldwide. Dry eye is often accompanied by inflammation of the eyelid margins, but this inflammation may be given relatively little attention as a cause rather than a consequence of dry eye. Blepharitis is often treated with an ointment, often erythromycin, which appears to help. It has been suggested that there are four stages of dry eye syndrome. Stage 1 involves the eyelash follicle, where the biofilm can establish its home. Stage 2 involves both eyelash follicles and meibomian glands and can explain trivial versus non-trivial meibomian gland dysfunction (MGD). This is because the biofilm blocks the meibomian gland opening (combination of biofilm with defective or modified meibum). It will take longer to reach stage 2. Stage 3 involves hair follicles, meibomian glands, and Krause and Wolfring accessory glands. The distance, ductal narrowness, and constant tear flow serve to protect these glands for decades, making them among the last glands to be affected by biofilm formation. It's becoming Stage 4 occurs when the structural integrity of the eyelid is ultimately destroyed due to chronic inflammation, which is clinically characterized by, for example, eyelid laxity, floppy eyelid syndrome, eyelid ectropion, and entropion of the eyelid (Rynerson JM, Perry HD. DEBS-a unification theory for dry eye and blepharitis. Clin Ophthalmol. 2016, 10, 2455-67; ​​Baudouin C. Ocular surface and external filtration surgery). 2012, 50, 64-78; Baudouin C, Messmer EM, Aragona P, et al. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol. 2016, 100(3)300-6).

[0542] Ear infections can occur in the external ear canal (otitis externa), the inner ear (interna otitis), or the middle ear canal (otitis media). Most ear infections occur in the middle ear, causing fluid retention, swelling, and inflammation when bacteria or viruses grow. Ear infections can become chronic, which can generally be due to biofilm accumulation. Recent clinical trials have provided evidence that almost all chronic OM cases are associated with bacterial biofilms behind the tympanic membrane (eardrum) and in the middle ear. Biofilms are typically very thin and cannot be seen using an ordinary otoscope. Otitis media (OM) is the most common childhood disease in the United States, with three-quarters of children under the age of three having at least one OM. Although most cases are chronic infections, long-term or permanent damage to the ear can still occur. Acute otitis media can resolve after a week or two without treatment, but may require treatment with antibiotics. Approximately 50% of antibiotic prescriptions for children under 3 years of age are issued for ear infections. However, in chronic OM, antibiotics may no longer help and surgery is usually required to place a tympanic ventilation tube in the middle ear tympanic membrane. (https: / / biophotonics.illinois.edu / sites / default / files / BOE-LCI_Biofilms_0.pdf).

[0543] Vulvovaginal candidiasis occurs when Candida species invade the superficial layers of the mucosal lining of the vagina and cause an inflammatory response. The primary inflammatory cells are typically polymorphonuclear cells and macrophages. Patients may experience discharge (which is typically thick and sticky or accompanied by excoriation), "external" dysuria, vaginal itching, vaginal burning, dyspareunia, or swelling. may present.

[0544] Periodontal or gingival disease is a pathological inflammatory condition of the gums and bone support (periodontal tissue) that surrounds the teeth. The two most common periodontal diseases are gingivitis, an inflammation of the gums at the gums, and periodontitis, an inflammation that affects the bone and tissue of the teeth.

[0545] Biofilms formed by pathogenic fungi have received increasing attention in recent years, and several species of filamentous fungi, yeasts, and dimorphic fungi have been described as capable of developing into communities. Biofilms are colonized microbial communities that are strongly attached to surfaces and to each other and protected by a polymeric extracellular matrix (ECM) composed primarily of polysaccharides. The cells in this case exhibit enhanced resistance and different phenotypes compared to planktonic or free cells, which are associated with persistence of infection (Costa-Orlandi et al., "Fungal Biofilms and Polymicrobial Diseases", J. Fungi, 2017, 3, 22; doi:10.3390 / jof3020022).

[0546] Candida species, including the novel opportunistic pathogen Candida dubliniensis, are now the emerging force of major pathogens of nosocomial infections. Many such occurrences of infections associated with Candida biofilm formation include those occurring in devices such as intravascular indwelling catheters. Fungal biofilm-associated infections are often refractory to conventional therapy because of antimicrobial resistance.

[0547] Biofilm-associated Candida species exhibit uniform resistance to a wide range of currently available conventional antifungal agents, implying a need for antimicrobial agents that specifically target biofilm-associated infections. are doing. A novel class of antifungal agents, amphotericin lipid formulations and echinocandins, has demonstrated unique antifungal activity against resistant Candida biofilms and represents a breakthrough in the treatment of life-threatening invasive systemic mycoses. offer. The use of effective drugs in combating biofilm-associated infections could lead to major advances in the treatment of fungal implant infections (Jabra-Rizk et al., "Fungal biofilm and Drug resistance." (2004). Fungal Biofilms and Drug Resistance, Emerging infectious diseases, 2004, 10, 14-9; 10.3201 / eid1001.030119).

[0548] Pathogenic fungi can also adhere to non-living surfaces such as prostheses and catheters, and yeast in particular take advantage of this situation to gain access to the blood circulation and reach the patient's internal organs. . This is alarming because disseminated fungal infections have a high mortality rate (Verstrepen K.J., Klis F.M. Flocculation, adhesion and biofilm formation in yeasts. Mol. Microbiol. 2006, 60, 5- 15; doi: 10.1111 / j.1365-2958.2006.05072.x).

[0549] Candida albicans, the best-studied model of biofilm formation, exhibits discrete stages of development similar to those of bacterial biofilms. Paracoccidioides brasiliensis is a dimorphic fungus responsible for paracoccidioidomycosis, a systemic mycosis endemic to Central and South America. Sardi et al. (Sardi Jde C., Pitangui Nde S., Voltan A.R., Braz J.D., Machado M.P., Fusco Almeida A.M., Mendes Giannini M.J. In vitro Paracoccidioides brasiliensis biofilm and gene expression of adhesins and hydrolytic enzymes. Virulence. 2015, 6 , 642-651. doi: 10.1080 / 21505594.2015.1031437.). Histoplasma capsulatum biofilms were first described by Pitangui et al. This fungus is also characterized by thermodimorphism and is the cause of histoplasmosis. Histoplasmosis is a respiratory and systemic mycosis whose expression is dependent on the survival and replication of yeast in alveolar macrophages (Pitangui N.S., Sardi J.C., Silva J.F., Benaducci T., Moraes da Silva R.A., RODRIGUEZ-ARELLANES G., TAYLOR M.L., Mendes-Giannini M.J., FUSCO-ALMEIDA A.M. Adhesion of Histoplasma Capsulatum To Pneumoches and Biofi LM Formation on an abiotic surface. Biofouling. 2012, 28, 711-718. Doi: 10.1080 / 08927014.2012. 703659).

[0550] Dermatophytes are fungi that invade keratinized tissue and cause dermatophytosis, which is one of the most common cutaneous mycoses in humans and animals (Weitzman I., Summerbell R.C. The dermatophytes. Clin. Microbiol. Rev. 1995, 8, 240-259. doi: 10.1016 / S0733-8635(05)70320-X). Among the dermatophytopathies, onychomycosis is often associated with relapses and long-term treatment, and treatment may be ineffective. Considering this situation and the hypothesis of Burkhart et al., who stated that biofilm formation by dermatophytes could explain dermatophyte balls, Costa-Orlandi et al. , confirmed in vitro biofilm formation by Trichophyton rubrum and T. mentagrophytes (Burkhart C.N., Burkhart C.G., Gupta A.K. Dermatophytoma: Recalcitrance to treatment because of existence of fungal biofilm. 2002, 47, 629-631. doi: 10.1067 / mjd.2002.124699; Costa-Orlandi C.B., Sardi J.C., Santos C.T., Fusco-Almeida A.M., Mendes-Giannini M.J. and T. mentagrophytes biofilms. Biofouling. 2014, 30, 719-727. doi: 10.1080 / 08927014.2014.919282).

[0551] Candida auris is an emerging yeast that causes healthcare-associated infections. It can be misidentified by tests and is often resistant to antifungal drugs. An explosive spread of C. auris infections in healthcare facilities has been reported in New York City, New York, USA (Adams et al., Candida auris in Healthcare Facilities, New York, USA, 2013-2017, Emerg Infect Dis. 2018, 24(10), 1816-1824. https: / / dx.doi.org / 10.3201 / eid2410.180649). In another embodiment, an infection is treated by applying a dressing comprising one or more quaternary ammonium compounds of the present invention as an antimicrobial composition to the site of infection, the dressing comprising a quaternary ammonium compound of the present invention. One or more quaternary ammonium compounds are released at the site of infection. Infectious diseases may involve the presence of bacteria, fungi, viruses, amoebas, or combinations of these infectious species.

[0552] Topical application also includes treatment of the oral cavity, including teeth and gums. Gingivitis occurs in both chronic and acute forms. Acute gingivitis is usually associated with certain infections, microbes, or trauma. Chronic inflammation of the gum tissue surrounding teeth is associated with bacterial biofilms (plaque) covering the teeth and gums (https: / / www.dentalhealth.ie / dentalhealth / causes / Periodontaldisease.html). The organosilicon quaternary ammonium compounds of the present invention are useful as oral health care agents, e.g. can be used to These compounds can also be used to treat and prevent infections or infectious diseases that can occur in the oral cavity, such as gingivitis and periodontitis. The organosilicon quaternary ammonium compounds of the present invention can also be incorporated as ingredients in oral health care agents (eg, toothpaste) to prevent caries (cavities) and gingivitis.

[0553] Topical applications also include oral / lip care, oral ulcers, and treatment of cold sores. Herpes simplex is contagious and strict hygiene measures must be adopted if an individual becomes infected. Primary oral infections are caused by herpes simplex virus (HSV), the causative virus of herpes labialis. After primary oral infection, HSV may remain inactive and activate only later in the more common herpes labialis, or "herpes simplex." Triggers for reactivation are known and include sunlight, trauma, fatigue, stress, and menstruation (https: / / www.dentalhealth.ie / dentalhealth / causes / coldsoles.html). The most common form of oral ulcers is called small aphthous ulcers. One to five small ulcers (less than 1 mm in diameter) usually appear on the inside of the lips or cheeks, on the floor of the mouth or tongue. Ulcers tend to concentrate toward the front of the oral cavity. Other more serious causes of oral ulcers include herpes infections (https: / / www.dentalhealth.ie / dentalhealth / causes / mouthulcers.html).

[0554] In some embodiments, treating an infection comprises placing a dressing comprising an antimicrobial composition as described herein into or over the infected site.

[0555] In another embodiment, treating an infection comprises placing an antimicrobial composition containing one or more quaternary ammonium compounds of the invention at the site of infection. The length of time to administer the quaternary ammonium compound, or composition, is such that the antimicrobial treatment remains effective or the infection resolves. Treatment may be applied sequentially, with sequential application after an appropriate timeframe, or alternating with another infection treatment after an appropriate timeframe. The quaternary ammonium compounds described herein can be administered to the infected site of the host at appropriate intervals as determined by the healthcare provider.

[0556] In some embodiments, a quaternary ammonium compound described herein is left at the site of infection for 1 day or less. In other embodiments, the quaternary ammonium compounds described herein are left at the site of infection for one week or more.

[0557] An effective amount of an antimicrobial composition as described herein, in combination or alternation with another active pharmaceutical agent, or prior, concurrent, or subsequent use of another active pharmaceutical agent The antimicrobial compositions described herein inhibit the progression of disorders (e.g., infectious diseases) caused by the presence of infectious organisms in or on the host; cause regression of disorders due to the presence of sexual organisms; cause healing of disorders due to the presence of infectious organisms in or on the host; or near, in, or on the host. is used in an amount sufficient to inhibit or prevent the development of disorders due to the presence of infectious organisms in the body. Treatment was once daily (q.d.), twice daily (b.i.d.), three times daily (t.i.d.), four times daily (q.i.d.), once every two days (Q2d), as appropriate. It can be administered once every 3 days (Q3d) or using any dosing schedule that provides treatment for infections as described herein.

[0558] In some embodiments, a method of treating and / or preventing an infection comprises placing a dressing saturated with an antimicrobial composition over the wound and / or the site of infection. The dressing may be directly saturated with the antimicrobial composition prior to placement on the wound and / or infected site, ie, it may be pre-saturated and manufactured and packaged. In other embodiments, a method of treating and / or preventing an infection comprises placing a dressing over a wound and / or infected site, followed by subsequent saturating the dressing with an antimicrobial composition. The antimicrobial composition may be added by dropper, syringe, or other suitable means after placement of the dressing.

[0559] In some embodiments, one or more quaternary ammonium compounds or pharmaceutical compositions as described herein treat medical disorders mediated by the presence of bacteria, such as bacterial infections. used to treat or prevent

[0560] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat disorders caused by pathogenic bacteria, typically infections.

[0561] In some embodiments, a method comprising administering to a subject an effective amount of a quaternary ammonium compound or composition thereof described herein for treating an infection caused by a bacterium. is provided.

[0562] In some embodiments, one or more quaternary ammonium compounds of the invention can be used to treat disorders, typically infections, caused by Gram-positive bacteria.

[0563] In some embodiments, administering an effective amount of a quaternary ammonium compound or composition thereof as described herein to treat an infection caused by Gram-positive bacteria. A method is provided.

[0564] Non-limiting examples of Gram-positive bacteria that may be treated with the quaternary ammonium compounds of the present invention either alone or in combination with another therapeutic agent include: Actinomyces ( Actinomyces species, including Actinomyces israelii, Actinomyces naeslundii, Actinomyces viscosus, Actinomyces odontolyticus and Actinomyces pyogenes; Bacillus species, including Bacillus anthracis, Bacillus cereus, and Bacillus subtilis; Clostridium species, including Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium sordellii, and Clostridium tetani Corynebacterium species, including Corynebacterium diphtheriae, Corynebacterium jeikeium, Corynebacterium minutissimum , Corynebacterium mucifaciens, Corynebacterium pseudotuberculosis, Corynebacterium striatum, Corynebacterium tenuis, and Corynebacterium alcelans Enterococcus species, including Enterococcus casseliflavus, Enterococcus faecalis, Enterococcus faecium, Enterococcus raffinosus, and Enterococcus hirae ); Leuconostoc species, including Leuconostoc pseudomesenteroides; Micrococcus species, such as Micrococcus luteus, etc. Nocardia spp, including Nocardia asteroides; Propionibacterium spp, including Propionibacterium acnes; Staphylococcus spp. This includes Staphylococcus aureus, Staphylococcus capitis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus lugdunensis (Staphylococcus lugdunensis), Staphylococcus pasteuri, and Staphylococcus saprophyticus; and Streptococcus species, including Streptococcus agalactiae, Streptococcus agalactiae. Streptococcus anginosus, Streptococcus bovis, Streptococcus dysgalactiae, Streptococcus mitis, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pi Ogenes( Streptococcus pyogenes, Streptococcus sanguinis, Streptococcus suis, and Streptococcus viridans.

[0565] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat disorders, typically infections, caused by Gram-negative bacteria.

[0566] In some embodiments, a method comprising administering an effective amount of a quaternary ammonium compound or composition thereof described herein to treat an infection caused by Gram-negative bacteria is provided.

[0567] Non-limiting examples of Gram-negative bacteria that may be treated with the quaternary ammonium compounds of the present invention either alone or in combination with another therapeutic agent include: Acinetobacter species, including Acinetobacter baumannii and Acinetobacter iwoffii; Aeromonas species, including Aeromonas veronii biovar sobria (formerly Aeromonas veronii biovar sobria); Aeromonas sobria, Aeromonas caviae, and Aeromonas hydrophila; Alcaligenes / Achromobacter species, including Alcaligenes faecalis faecalis and Alcaligenes xylosoxidans; Bacteroides species, including Bacteroides fragilis; Bartonella species, including Bartonella bacilliformis; ), Bartonella Clarridgeiae, Bartonella Elizabethae, Bartonella Henselae (Bartonella Henselae), Bartonella Henselae. La Koehlerae), Bartonalla Naantalienis, Bartonella Quintana ), Bartonella rochalimae, Bartonella vinsonii, and Bartonella washoensis; Bordetella species, including Bordetella bronchispetica, Bordetella partis (Borrelia pertussis), and Bordetella parapertussis; Borrelia species, including Borrelia afzelii, Borrelia burgdorferi, Borrelia crocidulae ( Borrelia crocidurae, Borrelia duttoni, Borrelia garinii, Borrelia hermsii, Borrelia hispanica, Borrelia miyamotoi, Borrelia parkeri ), Borrelia persica, Borrelia recurrentis, Borrelia turicatae, and Borrelia venezuelensis; Brevundimonas species, including includes Brevundimonas diminuta and Brevundimonas vesicularis; Brucella species, including Brucella abortus, Brucella canis, Brucella Brucella melitensis, and Brucella suis; Burkholderia species, including Burkholderia cepacia, Burkholderia mallei, and Burkholderia pseudomallei; Campylobacter species, including Campylobacter jejuni, Campylobacter coli, Campylobacter upsaliensis, Campylobacter upsaliensis; Campylobacter lari, and Campylobacter coli; Chlamydia / Chlamidophila species, including Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydophila pecorum ), and Chlamydia trachomatis; Citrobacter species, including Citrobacter amalonaticus, Citrobacter freundii, Citrobacter koseri; ), and Citrobacter diversus; Coxiella burnetti; Ehrlichia species, including Ehrlichia canis and Ehrlichia chaffeensis. Enterobacter species, including Enterobacter aerogenes and Enterobacter cloacae; Escherichia species, including Escherichia coli; Francisella (Francisella) species, including Francisella novicida, Francisella philomiragia, and Francisella tularensis; Haemophilus species, including Haemophilus influenzae and Helicobacter species, including Helicobacter pylori; Klebsiella species, including Klebsiella granulomatis; including Klebsiella oxytoca, and Klebsiella pneumoniae; Leclercia adecarboxylata; Legionella species, including Legionella pneumophila Leptospira species, including Leptospira interrogans, Leptospira noguchii, Leptospira santarosai, and Leptospira weilii; Listeria ( Listeria spp, including Listeria monocytogenes; Moraxella spp, including Moraxella catarrhalis, Moraxella lacunata, and Moraxella bovis. Moraxella bovis; Moraxella bovoculi; Morganella species, including Morganella morganii; Mycoplasma species, including Mycoplasma amphoriforme ( Mycoplasma amphoriforme, Mycoplasma buccale, Mycoplasma faucium, Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma lipophilum ( Mycoplasma lipophilum, Mycoplasma orale, Mycoplasma penetrans, Mycoplasma pirum, Mycoplasma pneumoniae, Mycoplasma primatum, Mycoplasma salivarium ), and Mycoplasma spermatophilum; Neisseria species, including Neisseria meningitidis and Neisseria gonorrhoeae;Orientia species, including Orientia tsutsugamushi and Orientia chuto; Pantoea species, including Pantoea agglomerans Paracoccus species, including Paracoccus yeei; Prevotella species, including Prevotella intermedia and Prevotella melaninogenica; Proteus species, including Proteus mirabilis, Proteus penneri, and Proteus vulgaris; Providencia species, including Providencia rettgeri Pseudomonas species, including Pseudomonas aeruginosa, Pseudomonas oryzihabitans, Pseudomonas plecoglossidica, and Pseudomonas stutzeri. (Pseudomonas stutzeri); Ralstonia species, including Ralstonia pickettii and Ralstonia insidiosa; Rickettsia species, including Rickettsia africae ( Rickettsia africae, Rickettsia akari, Rickettsia australis, Rickettsia conorii, Rickettsia felis, Rickettsia japonica, Rickettsia prowazekii, Rickettsia rickettsia, Rickettsia sibirica, and Rickettsia typhi; Roseomonas species, including Roseomonas gilardii Salmonella species, including Salmonella bongori, Salmonella enterica, Salmonella paratyphi, Salmonella typhi, and Salmonella typhimurium; typhimurium); Serratia species, including Serratia marcescens, Serratia liquefaciens, Serratia rubidaea, and Serratia odoriferae. Shigella species, including Shigella dysenteriae and Shigella sonnei; Sphingomonas species, including Sphingomonas mucosissima and Stenotrophomas species, including Stenotrophomas maltophilia; Treponema species, including Treponema carateum ( Ureaplasma species, including Ureaplasma urealyticum. Vibrio species, including Vibrio cholera, Vibrio parahaemolyticus, and Vibrio vulnificus; and Yersinia species, including includes Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis. ;

[0568] In some embodiments, the quaternary ammonium compounds of the present invention can be used to treat disorders, typically infections, caused by mycobacteria.

[0569] In some embodiments, administering an effective amount of a quaternary ammonium compound or composition thereof as described herein to treat an infection caused by Mycobacterium. A method is provided.

[0570] Non-limiting examples of mycobacteria that may be treated with the quaternary ammonium compounds of the present invention, either alone or in combination with another therapeutic agent, include: Mycobacterium abscessus. (Mycobacterium abcessus), Mycobacterium africanum, Mycobacterium agri, Mycobacterium aichiense, Mycobacterium alvei, Mycobacterium alvei Mycobacterium arabiense, Mycobacterium aromaticivorans, Mycobacterium arosiense, Mycobacterium arupense, Mycobacterium aquaticum, Mycobacterium aquaticum Bacterium asiaticum, Mycobacterium aubagnese, Mycobacterium aurum, Mycobacterium austroafricanum, Mycobacterium avium ( Mycobacterium avium, Mycobacterium avium paratuberculosis, Mycobacterium avium silvaticum, Mycobacterium avium hominussuis, Mycobacterium avium subsp. Mycobacterium bacteremicum, Mycobacterium barrassiae, Mycobacterium boenickei, Mycobacterium bohemicum, Mycobacterium bolletii, Mycobacterium Bacterium botniense, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brisbanense, Mycobacterium brumae, Mycobacterium Bacterium canariasense, Mycobacterium canettii, Mycobacterium caprae, Mycobacterium chimaera, Mycobacterium chelonae, Mycobacterium chitae, Mycobacterium chubuense, Mycobacterium columbiense, Mycobacterium conceptionense, Mycobacterium confluence (Mycobacterium confluentis), Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium cosmeticum, Mycobacterium diernhoferi , Mycobacterium doricum, Mycobacterium duvalii, Mycobacterium elephantis, Mycobacterium fallax, Mycobacterium falcinogenes farcinogenes), Mycobacterium flavescens, Mycobacterium florentinum, Mycobacterium fortuitum, Mycobacterium frederikbergense, Mycobacterium Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gilvum, Mycobacterium gordonae, Mycobacterium Bacterium haemophilum, Mycobacterium hassiacum, Mycobacterium heidelbergense, Mycobacterium heckshornense, Mycobacterium hiberniae (Mycobacterium hiberniae), Mycobacterium hodleri, Mycobacterium holsaticum, Mycobacterium houstonense, Mycobacterium icosiumassilensis, Mycobacterium Mycobacterium immunogenum, Mycobacterium indicus pranii, Mycobacterium intacellulare, Mycobacterium intracellulare, Mycobacterium interjectum (Mycobacterium interjectum), Mycobacterium intermedium, Mycobacterium iranicum, Mycobacterium kansasii, Mycobacterium komossense, Mycobacterium komossense Mycobacterium kubicae, Mycobacterium lentiflavum, Mycobacterium leprae, Mycobacterium lepraemurium, Mycobacterium lepromatosis, Mycobacterium liflandii, Mycobacterium llatzerense, Mycobacterium madagascariense, Mycobacterium mageritense, Mycobacterium marmoens malmoense), Mycobacterium marinum, Mycobacterium massiliense, Mycobacterium massilipolynesiensis, Mycobacterium microti, Mycobacterium Mycobacterium monacense, Mycobacterium montfiorense, Mycobacterium morokaense, Mycobacterium mucogenicum, Mycobacterium mungi, Mycobacterium murale, Mycobacterium nebraskense, Mycobacterium neoaurum, Mycobacterium neworleansense, Mycobacterium nonchromogenicum (Mycobacterium nonchromogenicum), Mycobacterium obuense, Mycobacterium orygis, Mycobacterium palustre, Mycobacteriumparascofulaceum, Mycobacterium parafortuitum, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium phocaicum, Mycobacterium phlei Mycobacterium pinnipedii, Mycobacterium porcinum, Mycobacterium pseudoshottsii, Mycobacterium psychotolerans, Mycobacterium pulveris, mycobacterium Bacterium pyrenivorans, Mycobacterium saskatchewanense, Mycobacterium sediminis, Mycobacterium senegalense, Mycobacterium septicum ), Mycobacterium shimoidei, Mycobacterium shottsii, Mycobacterium simiae, Mycobacterium smegmatis, Mycobacterium sphagni ( Mycobacterium sphagni), Mycobacterium stephanolepidis, Mycobacterium suricattae, Mycobacterium szulgai, Mycobacterium talmoniae, Mycobacterium Mycobacterium terrae, Mycobacterium thermoresistibile, Mycobacterium triplex, Mycobacterium triviale, Mycobacterium tuberculosis ), Mycobacterium tusciae, Mycobacterium ulcerans, Mycobacterium vaccae, Mycobacterium vanbaalenii, Mycobacterium xenopi ), and Mycobacterium yongonense.

[0571] Non-limiting examples of bacterial-mediated disorders that may be treated with the quaternary ammonium compounds of the invention, either alone or in combination with another therapeutic agent, include: Actinomycosis , anaplasmosis, anthrax, bacterial angiomatosis, actinomycetoma, bacterial conjunctivitis, bacterial pneumonia, bacterial vaginosis, bacterial endocarditis, bartonellosis, botulism, boutenneuse fever, brucella disease, Bejel, brucellosis spondylitis, bubonic plague, Buruli ulcer, Barnsdale ulcer, shigellosis, campylobacteriosis, carrion disease, cat scratch disease, cellulitis, chancroid, chlamydia, chlamydial conjunctivitis, clostridial myonecrosis , cholera, Clostridium difficile colitis, diphtheria, Daintree ulcer, donavanosis, dysentery, erhlichiosis, typhus, fried rice syndrome, five-day fever, floppy baby syndrome, Far Eastern scarlet fever Far East scarlet-like fever, gas gangrene, glanders, gonorrhea, inguinal granuloma, human necrotizing bacilliosis, necrotizing fasciitis, hemolytic uremic syndrome, human Ewingie gerlichiosis, human monocyte Ehrlichiosis, human granulocytic anaplasmosis, infant botulism, spring fever, Kawasaki disease, Kumusi ulcer, inguinal lymphogranulomatosis, Lemière's syndrome, Legionnaires' disease, leprosy, leptospirosis, listeriosis, Lyme disease, inguinal lymphogranulomatosis, Malta fever, Mediterranean fever, myonecrosis, mycoburuli ulcer, mucocutaneous lymph node syndrome, meliodosis, meningococcal disease, rash fever, mycoplasma pneumonia, mycetoma, neonatal Conjunctivitis, nocardiosis, Oroya fever, neonatal ophthalmia, avian disease, Pontiac fever, hepatic periosis, pneumonic plague, postanginal shock including sepsis, pasteurellosis, pelvic inflammatory disease, whooping cough, plague, pneumococcal infection pneumonia, psittacosis, psittacosis, pseudotuberculosis, Q fever, quintan fever, rabbit fever, relapsing fever, rickettsialpox, Rocky Mountain spotted fever, umbilical-bite fever, Reiter's syndrome, rheumatic fever, salmonella scarlet fever, sepsis, septic plague, Sarl's ulcer, shigellosis, chancroid, syphilis, streptobacillus fever, tsutsugamushi disease, Taiwanese acute respiratory pathogen, trench fever, trachoma, tuberculosis, tularemia, typhoid fever, typhus, Tetanus, toxic shock syndrome, undulating fever, ulcus molle, Vibrio parahaemolyticus enteritis, Whitmore's disease, ambulatory pneumonia, Waterhouse-Friedrichsen syndrome, yersinoma, and yersinia.

[0572] In some embodiments, one or more quaternary ammonium compounds or pharmaceutical compositions thereof as described herein treat medical disorders mediated by the presence of fungi, such as fungal infections. or used prophylactically.

[0573] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat disorders caused by pathogenic fungi, typically infections.

[0574] In some embodiments, a subject is administered an effective amount of a quaternary ammonium compound or composition thereof as described herein to treat an infection caused by a fungus. A method is provided comprising:

[0575] Non-limiting examples of fungi that may be treated with the quaternary ammonium compounds of the present invention either alone or in combination with another therapeutic agent include: Absidia species, Alterania species, including Alterania alternate; Aspergillus species, including Aspergillus clavatus. , Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus sydowii, Aspergillus terreus, Aspergillus versicolor, and Aspergillus vercaria ( Aureobasidium species, including Aureobasidium pullans; Batrachochytrium species, including Batrachochytrium dendrobatidis (Aspergillus verrucaria); Blastomyces species, including Blastomyces dermatitidis; Candida species, including Candida albicans. , Candida auris, Candida dubliniensis, Candida glabrata, Candida parapsilosis, Candida rugosa, and Candida tropicalis; Chaetomium species, which includes Chaetomium globsum; Cladosporium species, which includes Cladosporium cladosporioides; Coccidioides species , which includes Coccidioides immitis and Coccidioides posadasii; Cryptococcus species, including Cryptococcus albidus, Cryptococcus gattii, Cryptococcus gattii; including Cryptococcus laurentii, Cryptococcus neoformans, and Cryptococcus uniguttulatus; Cunninghamella species; Curvularia species, including Curvularia brachyspora, Curvularia Includes Curvularia clavata, Curvularia geniculata, Curvularia lunata, Curvularia pallescens, Curvularia senegalensis, and Curvularia verruculosa Dreschslera species, including Dreschlera australiensis; Epidermophyton species, including Epidermophyton floccosum; Fonsecaea species, including includes Fonsecaea compacta and Fonsecaea pedrosoi; Fusarium species, including Fusarium solani, Fusarium oxysporum, and Fusarium chlamydosporum; ); Geotrichum species, including Geotrichum capitatum, Geotrichum candidum, and Geotrichum clavatum; Gliomastix species; This includes Gliomastix cerealis; Gloeophyllum species, which includes Gloeophyllum trabeum; Histoplasma species, which includes Histoplasma Capsulatum and Histoplasma capsulatum var. faciminosum; Malassezia species, including Malassezia furfur and Malassezia globosa; Microsporum species; Monilia species, including Monilia grisea; Mucor species, including Mucor indicus; Paracoccidioides species, including includes Paracoccidioides brasiliensis; Penicillium spp.; Piedraia spp., which includes Piedraia hortae and Piedraia quintanilhae; Phialophora spp. Phoma species, including Phoma fimeti; Pithomyces species, including Pithomyces chartarum ); Pneumocystis spp., including Pneumocystis carinii and Pneumocystis jirovecii; Poria spp., including Poria placenta; Rhizopus species, including Rhizopus microspores, Rhizopus oryzae, and Rhizopus stolonifer; Scolecobasidium species; This includes Scolecobasidium humicola; Sporothrix species, including Sporothrix brasiliensis, Sporothrix globosa, and and Trichoderma species, including Trichoderma viride; and Trichophyton species, including Trichosporon beigelii, Trichophyton concentricum, Trichophyton interdigitale, Trichophyton mentagrophytes, Trichophyton rubrum, and Trichophyton tonsurans be

[0576] Non-limiting examples of fungal-mediated disorders that may be treated with the quaternary ammonium compounds of the invention, either alone or in combination with another therapeutic agent, include: Invasive Aspergillus. candidiasis, black gizzard, blastomycosis, oropharyngeal candidiasis, vulvovaginal candidiasis, melanoblastomycosis, chytrid fungus, coccidioidomycosis, cryptococcosis, dermatomycosis, fusariosus, Geotrichosis, histoplasmosis, mucormycosis, mycetoma, paracoccidioidomycosis, pneumocystis pneumonia, sporotrichosis, tinea pedis, tinea capitis, tinea corporis, tinea cruris, tinea manum, tinea manum, Tinea unguium, tinea versicolor, white sand, and zygomycosis.

[0577] In some embodiments, the quaternary ammonium compounds of the present invention can be used to treat disorders caused by viruses, typically infections.

[0578] In some embodiments, a method comprising administering an effective amount of a quaternary ammonium compound as described herein or a composition thereof to treat an infection caused by a virus is provided.

[0579] Non-limiting examples of viruses that may be treated with the quaternary ammonium compounds of the invention, either alone or in combination with another therapeutic agent, include: adeno-associated virus, astrovirus. , BK polyomavirus, cosavirus A, coxsackievirus, echovirus, Epstein-Barr virus, GB virus C, human adenovirus, human coronavirus, human cytomegalovirus, human herpesvirus (1, 2, 6, 7, and 8), human papillomavirus (1, 2, 16, and 18), human parainfluenza virus, human parvovirus, human respiratory syncytial virus, human rhinovirus, human SARS coronavirus, influenza virus (A, B, and C ), molluscum contagiosum virus, norovirus, rotavirus (A, B, and C), rubella virus, SARS coronavirus 2, vaccinia virus, and varicella zoster virus.

[0580] Non-limiting examples of viral mediated disorders that may be treated with the quaternary ammonium compounds of the invention either alone or in combination with another therapeutic agent include: influenza, the common cold , respiratory syncytial virus infection, adenovirus infection, parainfluenza virus infection, severe acute respiratory syndrome (SARS), norovirus infection, rotavirus infection, astrovirus infection, measles, rubella, varicella / shingles Herpes, rosea, smallpox, fifth disease, human papillomavirus (HPV), warts including genital warts, oral herpes, genital herpes, herpes labialis, herpes simplex virus keratitis, and molluscum contagiosum.

[0581] In some embodiments, one or more quaternary ammonium compounds or pharmaceutical compositions thereof as described herein treat medical disorders mediated by the presence of amoebas, such as amoebic infections. or used prophylactically.

[0582] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat disorders caused by pathogenic amebas, typically infections.

[0583] In some embodiments, a subject is administered an effective amount of a quaternary ammonium compound as described herein or a composition thereof to treat an infection caused by an ameba. A method is provided comprising:

[0584] Non-limiting examples of amoebas that may be treated with the quaternary ammonium compounds of the present invention either alone or in combination with another therapeutic agent include: Acanthamoeba species; Balamuthia spp, including Balamuthia mandrillaris; Dientamoeba spp, including Dientamoeba fragilis; Endolimax spp, including includes Endolimax nana; Entamoeba species, including Entamoeba Bangladeshi, Entamoeba coli, Entamoeba dispar; , Entamoeba gingivalis, Entamoeba hartmanni, Entamoeba histolytica, Entamoeba moshkovskii, and Entamoeba polecki; Iodamoeba species, including Iodamoeba butschlii; Naegleria species, including Naegleria fowleri; and Sappinia species, including include Sappinia diploidea and Sappinia pedata.

[0585] Non-limiting examples of amoeba-mediated disorders that may be treated with the quaternary ammonium compounds of the invention, either alone or in combination with another therapeutic agent, include: amebiasis, Amoebic dysentery, amoebic liver abscess, cutaneous amoebiasis, amoebic brain abscess, amebiasis cutis, acanthamoeba keratitis, cutaneous acanthamoebiasis, granulomatous amebic encephalitis, balamthia amoebiasis Encephalitis, and Sappinia-amebic encephalitis.

[0586] In some embodiments, the infection is Acinetobacter spp., Aspergillus spp., Burkholderia cepacia complex, Campylobacter spp., Candida spp., Clostridium difficile, Coccidioides spp., Cryptococcus spp., Enterobacteriaceae, Enterococcus species, Helicobacter pylori, Mycobacterium tuberculosis complex, Neisseria gonorrhoeae, Neisseria meningitidis, nontuberculous mycobacterial species, Pseudomonas species, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae , Streptococcus pyogenes, and Vibrio cholerae.

[0587] In certain alternative embodiments, the infection is Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pyogenes, Candida albicans, Candida auris, Cladosporium herbalum, Aspergillus niger, Proteus mirabilis, Klebsiella Caused by Pneumoniae, Acinetobacter baumannii, Enterobacter spp., or Fusarium spp.

[0588] In some embodiments, the quaternary ammonium compounds of the present invention are used to treat inflammatory disorders caused by the presence of infectious organisms such as bacteria, fungi, viruses, or amoebas as described herein. can be used to treat

[0589] Non-limiting examples of such inflammatory disorders include: adenoid pharyngitis, appendicitis, arteritis, ascending cholangitis, balanitis, blepharitis, bronchitis, bursitis, cellulitis. , cerebral vasculitis, cervicitis, conjunctival edema, cholecystitis, chondritis, choroioamnionitis, colitis, conjunctivitis, constrictive pericarditis, cryptitis, dacryodenitis, dermatitis, diabetic ulcer , duodenal lymphocytosis, encephalitis, endocarditis, endometritis, endotheliitis, enteritis, enteritis, eosinophilic fasciitis, epididymitis, esophagitis, folliculitis, gastritis, gingiva inflammation, glomerulonephritis, glossitis, hepatitis, infectious arthritis, ileitis, intertrigo, keratitis, keratoconjunctivitis, labyrithitis, lymphadenitis, mastitis, mastoiditis, myocarditis, myocardium Pericarditis, myositis, necrotizing fasciitis, nephritis, ophthalmitis, oophoritis, ophthalmitis, orchitis, osteitis, osteomyelitis, pancreatitis, paraproctitis, mumps, heart Meningitis, perichonditis, perifolliculitis, periodontitis, peritonitis, pharyngitis, phlebitis, pleuritis, interstitial pneumonia, pulmonitis, proctitis, prostatitis, pulpitis, pyelonephritis, suppurative Myositis, retinal vasculitis, rheumatic fever, rhinitis, scleritis, salpingitis, sialadenitis, sinusitis, stomatitis, synovitis, sepsis, tenosynovitis, thyroiditis, tonsillitis, tularemia, urethritis, uvea inflammation, vaginitis, vasculitis, and vulvitus.

[0590] In some embodiments, the quaternary ammonium compounds of the invention are used to treat skin infections in a host, eg, a human. Infections may be due to the presence of bacteria, fungi, amoebas, or viruses as described herein.

[0591] In some embodiments, a host, e.g., a human, is administered an effective amount of a quaternary ammonium compound as described herein or a composition thereof to treat a skin infection. A method is provided comprising:

[0592] In another embodiment, the method is used to treat skin infections in another mammal, such as a cat, dog, cow, pig, or horse.

[0593] Examples of bacterial skin infections that may be treated with the quaternary ammonium compounds of the present invention include, but are not limited to: acne vulgaris, African tick bite; American tick bite. (Rickettsia parkeri infection); bacterial angiomatosis; Bejel (endemic syphilis); blastomycosis-like pyoderma (proliferative pyoderma); bubonic plague; bullous impetigo; Campylobacter jejuni; cat scratch disease (cat-scratch fever, English-Wear infection); ), inoculation lymphoreticulosis, subacute localized lymphadenitis); cellulitis; chancre; Chronic undermining burrowing ulcers (Melenian gangrene); Condyloma flatus; Cutaneous actinomycosis; Dermatitis gangrenosum (cutaneous gangrene); typhus (louse-borne typhus); erysipelas (sacred fire, St. Anthony's Fire); Rosenbach's erysipelas; erythema cricoid; Flying squirrel typhus; folliculitis; Fournier's gangrene (fournier's gangrene of the penis and scrotum); furunculosis; gas gangrene (clostridial myonecrosis, myonecrosis); malleus); gonococcal sepsis (arthritic dermatosis syndrome, disseminated gonococcal infection); gonorrhoea (crap); Gram-negative folliculitis; venereal inguinal granuloma, venereal granuloma, venereal genital inguinal granuloma, lupoid-type inguinal ulceration, tortuous inguinal ulceration, vulvar ulceration granuloma, ulceration sclerosing granuloma); green nail syndrome; nosocomial furunculosis; hot tub folliculitis (Pseudomonas aeruginosa folliculitis); human granulocytotropic anaplasmosis; human monocytotropic ehrlichiosis; Japanese spotted fever; leptospirosis (Fort Bragg fever, tibialis anterior fever, Weil's disease); listeriosis; Tumor (climate bubo, Durand-Nicola-Favre disease, inguinal lymphogranuloma, poradenitis inguinale, strumous bubo); malakoplakia (malacoplakia)); Mediterranean spotted fever (Button fever); melioidosis (Whitmore disease); Necrotizing fasciitis (flesh-eating bacteria syndrome); neonatal toxic shock-like eruption; gangrenous stomatitis neonatal; North Asian tick typhus; neonatal ophthalmia; perianal cellulitis (perineal dermatitis, streptococcal anal disease); apical abscess; pinta; punctate keratolysis (keratolysis plantare sulcatum, keratoma plantare sulcatum); plague; primary gonococcal Dermatitis; Pseudomonas pyoderma; Pseudomonas hot-foot syndrome; Paronychia suppurativa; Myositis suppurativa; Q fever; (Recurrent toxin-mediated perineal erythema); nasal scleroma; Rocky Mountain spotted fever; scarlet fever; trigonosum; superficial pustular folliculitis (Bockhardt's impetigo, superficial folliculitis); acne vulgaris (barber eruption, shingles); syphilis eruption; syphilis (Syphilis (lues)); tick-borne lymphadenopathy; toxic shock syndrome (streptococcal toxic shock syndrome, streptococcal toxin shock-like syndrome, toxic streptococcal syndrome); trench fever (five-day fever, quintan fever, urban trench fever); tropical ulcers (Aden ulcer, jungle rot, Malabar ulcer, tropical phagedena); Peruvian verruca; and yaws (bouba, framboesie, parangi, pian).

[0594] Examples of mycobacterial skin infections that may be treated with the quaternary ammonium compounds of the present invention include, but are not limited to: aquarium granuloma (fish tank granuloma, swimming pool granuloma) border group leprosy; borderline group leprosy; borderline tuberculosis-type leprosy; leprosy-type leprosy; leprosy (leprosy); lichen adenopathy (lichenoid cutaneous tuberculosis); lupus vulgaris (lupus tuberculosis); acuta generalisata), disseminated cutaneous tuberculosis (tuberculosis cutis disseminata); gangrenous papular eruption; primary inoculated tuberculosis (early cutaneous change group, early tubercular change group, tuberculous chancre); cutaneous disease (soft skin tuberculosis) mucocutaneous junction tuberculosis (acute tubercular ulcer, orificial tuberculosis); cutaneous wart tuberculosis (lupus scar, lethal wart, cutaneous wart tuberculosis); tuberculous cellulitis; tuberculous gumma (metastatic tuberculous abscess, metastatic tuberculous ulcer); and tuberculoid leprosy.

[0595] Examples of fungal skin infections that may be treated with the quaternary ammonium compounds of the present invention include, but are not limited to: African histoplasmosis; alternariasis; antibiotic candidiasis ( Candida auris, Candida intertrigo, Candida onychomycosis, Candida paronychia, Candida vulvovaginitis, Candida eruption; mycoses (melanomycosis, cladosporiasis, Fonseca's disease, Pedroso's disease, pheosporotrichosis, verrucous dermatitis); chronic mucocutaneous candidiasis; coccidioidomycosis (California disease, desert rheumatism, San Joaquin Valley fever, valley fever); congenital cutaneous candidiasis; cryptococcosis; ringworm; diaper candidiasis; fungal folliculitis (Mayocchi granuloma); fusarium disease; geotrichosis; infantile gluteal granuloma; endothelium); achromic mycelium; kerion; loboiosis (keloid blastomycosis, lacaziosis, lobo disease); mucormycosis; blastomycosis, Gilchrist's disease); onychomycosis (dermatophytic onychomycosis, tinea of ​​the nail, tinea unguium); oral candidiasis (thrush); external otomycosis; perianal candidiasis; cheilitis); pheohyphomycosis; gizzard (trichosporosis); pityrosporum folliculitis; primary cutaneous aspergillosis; primary pulmonary histoplasmosis; progressive disseminated histoplasmosis; proximal subungual onychomycosis; rhinosporidiosis; ); sporotrichosis (rose gardener's disease); systemic candidiasis; Herpes tonsurans, tinea of ​​the scalp, tinea of ​​the scalp, tinea of ​​the scalp, tinea tonsurans); tinea corporis (tinea, ringworm, tinea vellus); tinea pruritus, tinea pruritus, Jim's pruritus, jockey's pruritus, tinea groin); facial tinea; Tinea imbricate (tokelau); tinea nigra palmaris et plantaris); tinea pedis (athlete's foot, tinea pedis); dermatomycosis furfuracea, pityriasis versicolor, tinea flava ); white gizzard; white superficial onychomycosis; and zygomycosis (algal mycosis).

[0596] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat ocular infections in a host, eg, a human. Ocular infections that may be treated with the quaternary ammonium compounds of the present invention include, but are not limited to: conjunctivitis, uveitis, hordeolum, blepharitis, chalazion, corneal ulcers and Infections, dacryodenitis, scleritis, keratitis, and iritis. In some embodiments, a method comprising administering to a subject, e.g., a human, an effective amount of a quaternary ammonium compound or composition thereof described herein to treat an ocular infection. is provided. In another embodiment, the method is used to treat ocular infections in another mammal, such as a cat, dog, cow, pig, or horse.

[0597] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat keratitis in a host, eg, a human. Keratitis can be caused by multiple infectious organisms, such organisms include: bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa; fungi such as Fusarium, Candida. genera, Aspergillus, and Curvularia species, and the like; viruses, such as herpes simplex virus and herpes zoster virus; and amoebas, such as Acanthamoeba species, and the like, or combinations thereof. In some embodiments, the quaternary ammonium compounds of the invention are used to treat bacterial keratitis in a host, eg, a human.

[0598] In another embodiment, the quaternary ammonium compounds of this invention are used to treat fungal keratitis in a host, eg, a human. In another embodiment, the quaternary ammonium compounds of the invention are used to treat viral keratitis in a host, eg, a human. In another embodiment, the quaternary ammonium compounds of the invention are used to treat Acanthamoeba keratitis in a host, eg, a human. In another embodiment, the method is used to treat keratitis in another mammal, such as a cat, dog, cow, pig, or horse.

[0599] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat conjunctivitis in a host, eg, a human. Conjunctivitis can be caused by multiple infectious organisms, including bacteria such as Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, and Pseudomonas aeruginosa. and viruses such as adenoviruses and enteroviruses. In some embodiments, the quaternary ammonium compounds of the invention are used to treat bacterial conjunctivitis in a host, eg, a human. In some embodiments, the quaternary ammonium compounds of the invention are used to treat viral conjunctivitis in a host, eg, a human. In another embodiment, the method is used to treat conjunctivitis in another mammal, such as a cat, dog, cow, pig, or horse.

[0600] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat ear infections in a host, eg, a human. Ear infections can be present in the outer ear and / or ear canal (otitis externa), the middle ear (otitis media), or the inner ear (otitis labyrinth). In some embodiments, a method is provided comprising administering to a subject an effective amount of a quaternary ammonium compound or composition thereof described herein for treating an ear infection. . In another embodiment, the method is used to treat ear infections in another animal, such as a cat, dog, cow, pig, or horse.

[0601] In some embodiments, the method of treatment involves applying a dressing comprising an effective amount of a quaternary ammonium compound of the invention, either alone or as a pharmaceutical composition, to the infected site of the host in need of treatment. including doing The dressing is preferably shaped to fit within the space provided by the ear canal. The dressing may be malleable, allowing the dressing to be compressed and shaped to fit within the ear canal, or the dressing may be rigid and rigid. well, which ensures that it sits against the wall of the ear canal to ensure proper contact and transfer of the antimicrobial composition.

[0602] In some embodiments, the dressing is placed in the ear canal only for one day or less. In other embodiments, the dressing is placed in the ear canal for one week or longer.

[0603] In some embodiments, a method of treating an infection in the ear canal of a host in need of treatment of the infection comprises applying a dressing to the ear canal of the host, followed by saturating the dressing with an antimicrobial composition. include. This method would allow for sequential or continuous application of the antimicrobial composition while the dressing remains in place.

[0604] In some embodiments, the dressing is composed of a soluble material that must be placed in the ear canal prior to being saturated with the antimicrobial composition. In another embodiment, the dressing is composed of a polymeric foam that expands upon subsequent wetting with an antimicrobial composition.

[0605] In some embodiments, methods of treating or preventing infections in chronic wounds are provided, comprising the steps of treating or preventing an infection in a chronic wound, comprising a quaternary ammonium compound of the invention, alone or in an antimicrobial composition, in an effective amount thereof. Such methods include administering to chronic wounds of a host in need thereof, eg, humans. Types of chronic wounds include venous ulcers, diabetic ulcers, and decubitus ulcers.

[0606] In some embodiments, methods of treating or preventing infections in chronic wounds are provided, comprising one or more quaternary ammonium compounds of the invention, alone or in a composition. This includes applying a dressing to the infected site of the host in need of such method.

[0607] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat fungal nail infections, ie, onychomycosis, in a host, eg, a human. A formulation for treating nail infections must be able to penetrate deep into the nail bed.

[0608] In such embodiments, the antimicrobial composition is formulated with a solvent that is capable of penetrating the host's nail bed, such as dimethylsulfoxide.

[0609] In some embodiments, a method is provided comprising administering to a subject an effective amount of a quaternary ammonium compound or composition thereof described herein for treating a fungal nail infection. be done.

[0610] In some embodiments, the quaternary ammonium compounds of the invention can be used to treat fungal vaginal infections, ie, vulvovaginal candidiasis, in a host, eg, a human.

[0611] In some embodiments, antimicrobial compositions are formulated as pessaries.

[0612] In some embodiments, a method is provided comprising administering to a subject an effective amount of a quaternary ammonium compound or composition thereof described herein for treating a fungal vaginal infection. be.

[0613] Methods for treating biofilms on abiotic surfaces The present invention includes methods of treating biofilms on non-living surfaces with the quaternary ammonium compounds or products described herein or mixtures thereof.

[0614] In some embodiments, non-living surfaces are treated directly with a solution (typically reconstituted from sterile powders or solids) containing one or more quaternary ammonium compounds of the invention.

[0615] In some embodiments, non-living surfaces are treated directly with a solution containing one or more quaternary ammonium compounds of the invention to remove and / or prevent the recurrence of bacterial biofilms. be.

[0616] In some embodiments, non-living surfaces are directly treated with a solution containing one or more quaternary ammonium compounds of the invention to remove and / or prevent the recurrence of fungal biofilms. be.

[0617] In some embodiments, non-living surfaces are treated directly with a solution containing one or more quaternary ammonium compounds of the invention to remove viral contamination and / or prevent its recurrence. In some embodiments, non-living surfaces are treated directly with a solution containing one or more quaternary ammonium compounds of the invention to prevent transmission of SARS coronavirus 2 from the treated surface to the host. be done.

[0618] Abiotic surfaces may harbor both enteric and respiratory human pathogenic viruses or bacteria. Multi-contact non-living surfaces can become points of transmission for bacterial, fungal, or viral contamination. Biofilms can exist on non-living surfaces. Viral contamination can exist on non-living surfaces. Abiotic surfaces are not particularly limited and include any surface on which microorganisms may grow or any such surface that may be exposed to microbial or viral contact or contamination. Examples of non-living surfaces include, but are not limited to, hospitals, surgical centers, doctor's offices, imaging centers, dental facilities, nursing homes, nursing homes, stadium locker rooms, mass transit vehicles (e.g., airplanes, trains, buses, and commercial vehicles). ), airports, railway stations, bus stops, public restrooms, food or beverage processing facilities, manufacturing facilities, schools, dormitories, furniture, tables, desks, walls, stairwells, elevators, machine surfaces, surfaces exposed to water, e.g. Surfaces such as those found in spas, hot tubs, saunas, bathtubs, or any surface exposed to the outside environment. Medical or surgical instruments or devices represent a special class of surfaces with potential for biofilm formation. This class can include all kinds of lines, such as catheters (e.g. central venous catheters and urinary catheters), prosthetics, e.g. heart valves, artificial joints, dentures, crowns, teeth. Caps, and soft tissue implants (eg, breast, hip, and lip implants) are included. All kinds of implantable medical devices are included (eg stents, intrauterine devices, pacemakers, intubation tubes, braces or prostheses, lines or catheters). An "indwelling" medical device may include a device in which any portion of the device is contained within the body, i.e., the device may be fully or partially indwelling. good.

[0619] The surface can be made of any material. Non-limiting examples include metals such as aluminum, copper, nickel-plated, gold-plated, steel, stainless steel, chromium, titanium, iron, alloys, and the like. Additional non-limiting examples of surfaces include plastics, e.g. , polyethylene terephthalate, etc.), and polyamides (eg, nylon), or combinations thereof. Other examples include acetal copolymers, polyphenylsulfones, polysulfones, polythermide, polycarbonates, polyvinylidene fluoride, poly(methyl methacrylate), and poly(tetrafluoroethylene). The surface can also be brick, glass, formica, tile, ceramic, porcelain, wood, vinyl, linoleum, or carpet, or combinations thereof.

[0620] Powder formulations for use in the invention In some embodiments, one or more active quaternary ammonium compounds of the invention can be provided as a powder formulation. Powder formulations may be prepared by removing any residual solvent, for example, by sublimation or boiling. In one embodiment, lyophilization is used to create powders for formulation. This is because the product integrity is typically maintained because the temperatures used in the process are low. In addition, freeze-dried solids can be reconstituted even more quickly and easily due to the presence of microscopic pores created by processing. The high vacuum used during freeze-drying ensures thorough removal of any undesired volatile components such as methanol, ethanol, or other volatile organic substances. In some embodiments, powder formulations of the quaternary ammonium compounds and products described herein contain about 5%, about 4%, about 3%, about 2%, about Contains less than 1%, about 0.5%, or about 0.01%. Lyophilization methods for solids, particularly sensitive materials, used in pharmaceutical applications are known in the art. Freeze-drying can be performed using any commercially available equipment, such as shelf / cabinet, contact, radiant, or microwave-assisted freeze-dryers.

[0621] A typical freeze-drying procedure consists of four steps. In the first step (pretreatment), the active quaternary ammonium compound is dissolved in a suitable solvent and admixed accordingly if necessary to improve stability, preserve appearance, or improve subsequent processing. Excipients are optionally added. Additionally, the solution of active quaternary ammonium compound can be suitably concentrated to aid in freezing and subsequent sublimation processes. In addition, each component can be individually flash frozen initially to ensure that a free-flowing solid forms upon completion of lyophilization.

[0622] In the second step (freezing), a solution of the active quaternary ammonium compound is frozen in a container below the triple point of the solution to ensure that sublimation rather than melting occurs. Optionally, the material can be subjected to cycling up and down in temperature in a process called annealing. If the quaternary ammonium compound to be lyophilized is an amorphous solid, this compound may not have a triple point, but instead has a critical point. Amorphous solids must be maintained below the critical point throughout the freeze-drying process to prevent re-melting or disintegration of the solid during subsequent drying steps. For sensitive materials, the freezing process is often expedited by lowering the material temperature to about -50°C to -80°C. This prevents the formation of giant solvent crystals that can reduce the structural integrity of the freeze-dried material and lead to structural defects.

[0623] In the third step (primary drying), the vessel pressure is reduced (typically in the range of a few millibars) and minimal heat is applied to the material so that the solvent sublimates. Pressure is typically controlled by application of a partial vacuum. A small amount of heat can be applied to facilitate sublimation of the solvent molecules. Due to the low air density within the container, this heat is typically applied via conduction or radiation.

[0624] In the fourth step (secondary drying), the temperature is raised above the primary drying stage in order to remove any residual antifreeze molecules. A temperature increase is necessary to destroy any physicochemical interactions that may have formed between the solvent molecules and the frozen material. Additionally, the pressure is typically lower than in the primary drying step to facilitate desorption.

[0625] Upon completion of the freeze-drying process, the vacuum is typically released with an inert gas, such as nitrogen, and a suitable container is sealed. Typical containers include sealed ampoules containing sealed glass that are broken open at the time of desired use. The active ingredient can then be reconstituted with a suitable carrier at the time of use, such as those described herein, eg sterile water or glycerin.

[0626] antibacterial composition The active quaternary ammonium compounds described herein can be administered to a host in need thereof as the pure chemical, but more typically as described herein or combinations thereof in an amount effective for a host, typically a human, in need of such treatment.

[0627] In some embodiments, the disclosure includes an effective amount of a quaternary ammonium compound together with at least one pharmaceutically acceptable carrier for any of the uses described herein. , provides an antimicrobial composition. A pharmaceutical composition may contain a quaternary ammonium compound as the only active agent.

[0628] In an alternative embodiment, a quaternary ammonium compound and at least one additional active agent. In a typical formulation, selected quaternary ammonium compounds of the present invention are provided in sterile powder or solid form to be reconstituted at the time of use.

[0629] An active quaternary ammonium compound as described herein, or the present invention when used in combination or alternation with another active agent, or prior, concurrent, or subsequent use of another active agent An effective amount of an active quaternary ammonium compound as described herein (a) inhibits progression of an infection described herein; (b) (c) cause cure of an infection described herein; or used in an amount sufficient to inhibit or prevent the development of an infection described herein It is possible. Thus, an effective amount of an active quaternary ammonium compound or composition described herein is one that provides a sufficient amount of the active agent when administered to a patient to provide clinical benefit. become.

[0630] The precise amount of active quaternary ammonium compound or antimicrobial composition described herein to be delivered to a host in need, typically a human, is determined to achieve the desired clinical benefit. , will be determined by the healthcare provider.

[0631] In certain embodiments, the antimicrobial composition contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active quaternary ammonium compound in unit dosage form. , and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent.

[0632] For example, at least about 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg of the active quaternary ammonium compound. or 16 Dosage form containing 00mg There is In some embodiments, the dosage form comprises at least about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600 mg of the active quaternary ammonium compound. The dosage form is optionally administered, for example, once daily (q.d.), twice daily (b.i.d.), three times daily (t.i.d.), four times daily (q.i.d.), once every two days (Q2d. ), once every three days (Q3d), or any dosing schedule that provides treatment for the disorders described herein.

[0633] The antimicrobial composition can include, for example, the active quaternary ammonium compound and the additional active agent in molar ratios to achieve the desired result. For example, the pharmaceutical composition has a molar ratio of at least about 0.5:1, at least about 1:1, at least about 2:1, at least about 3:1, or from about 1.5:1 to about 4:1 (additional active agent: Active Compounds) can include additional active agents in combination with the active quaternary ammonium compounds described herein.

[0634] The quaternary ammonium compounds disclosed herein or used as described herein can be administered topically, via sprays, creams, gels, foams, suppositories, via implants, including ocular implants. , transdermally, in dermatological formulations, or as eye drops, in unit dosage formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the quaternary ammonium compound may be administered via an immediate or controlled release manner, e.g., as a solution, suspension, or other formulation, via an ophthalmic device, or topically, if desired. For example, it can be administered as a solution or suspension provided as eye drops.

[0635] Antimicrobial compositions may be in any pharmaceutically useful form, such as aerosols, creams, gels, foams, microparticles, nanoparticles, injectable or infusion solutions, transdermal patches, subcutaneous patches, suppositories, dry powders, It can be formulated in a medical device as a parenteral formulation, a dermatological formulation, or as an eye drop or suspension. Some dosage forms are subdivided into suitably sized unit doses containing appropriate amounts of the active ingredient, eg, an effective amount to achieve the desired purpose.

[0636] Compositions suitable for administration as contemplated herein and methods of making such compositions are known in the art. Examples of known techniques include, for example, US Pat. Nos. 5,723,269 and 9,060,938, which are incorporated herein by reference.

[0637] The antimicrobial compositions contemplated herein may optionally contain a carrier. Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. A carrier can be inert or possess pharmaceutical benefits of its own. The amount of carrier used in conjunction with the quaternary ammonium compound is that amount sufficient to provide a practical amount of material per unit dose of compound for administration.

[0638] Classes of carriers include binders, buffers, colorants, diluents, disintegrants, emulsifiers, fillers, flavors, glidants, lubricants, pH modifiers, preservatives, stabilizers (e.g. xanthan gum, polyvinyl pyrrolidone (PVP), guar gum, polyvinyl alcohol (PVA), etc.), surfactants, solubilizers, tableting agents, thickeners (e.g., xanthan gum, polyvinylpyrrolidone (PVP), guar gum, polyvinyl alcohol (PVA), etc.) , gelling agents, and wetting agents (eg, urea, etc.).

[0639] Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and as a diluent in others. Examples of pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, dicalcium phosphate, and starch. Examples of surfactants include sodium lauryl sulfate and polysorbate 80.

[0640] Examples of drug-complexing or solubilizing agents include polyethylene glycol, caffeine, xanthene, gentisic acid, and cylodextrins.

[0641] Examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, colloidal silicon dioxide, and croscarmellose sodium. Examples of binders include methylcellulose, microcrystalline cellulose, starch, and gums such as guar gum and tragacanth.

[0642] Examples of lubricants include magnesium stearate and calcium stearate.

[0643] Examples of pH adjusters include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, etc.; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, triphosphate; Buffers include sodium, sodium hydroxide, calcium hydroxide, aluminum hydroxide, etc., and generally mixtures of acids and salts of such acids. Optional other active agents that do not substantially interfere with the activity of the quaternary ammonium compounds of the present invention can also be included in the pharmaceutical composition.

[0644] Non-limiting examples of aqueous solutions that can be used for the carrier include distilled water, saline, plasma, bone marrow aspirate, buffers such as Hank's Balanced Salt Solution (HBSS), HEPES (4-(2-hydroxyethyl)-1 -piperazine ethanesulfonic acid), Ringer's buffer, ProVisc™, diluted ProVisc™, ProVisc™ diluted in PBS, Krebs' buffer, Dulbecco's PBS, normal PBS, sodium hyaluronate solution, simulated body fluid, concentrated Examples include plasma platelets, tissue culture media, aqueous solutions containing organic solvents, and mixtures thereof. In all cases, the solution can be sterilized in any suitable manner known to those skilled in the art.

[0645] In certain examples, the antimicrobial composition contains a polymeric material. The polymeric material should be biocompatible so that it can be administered to a patient without undesirable effects. Polymers are well known in the art and are the subject of extensive literature and patents. In certain embodiments, the polymer is present in an effective amount to provide the desired viscosity and wettability as required for the desired application, eg, in treating infected wounds. The specific amount of polymer used will depend on a number of factors, such factors being, by way of example and not limitation, the specific chemical composition of the polymer used, the molecular weight of the specific polymer used. , the viscosity of the antimicrobial composition desired, and the level of water retention and release desired for a particular polymer.

[0646] In certain embodiments, the antimicrobial compositions are used in polymeric materials for medical, personal, or industrial use. Examples of medical applications include wound healing materials, medical devices, suitable protective equipment, artificial cartilage, biomaterials, catheters, other implantable and non-implantable devices (e.g. surgical sponges, and packaging), medical orthopedic or dental patches or devices, ophthalmic solutions or suspensions, short-term wound packings, direct patches to ocular tissue, hydrophilic coatings for catheters, leads, etc. agents, vascular embolizing agents, etc., but are not limited to these.

[0647] In certain embodiments, the antimicrobial compositions are used to control medical device infections, including polymeric materials for medical devices, pacemakers, contact lenses, dentures, prosthetics, heart valves, and joints. biomaterials, implantable devices, non-implantable devices, wound healing materials, personal protective materials such as gloves, face masks, surgical / hospital gowns, clothing, sheets, woven or non-woven materials, sponges; Medical devices such as orthopedic or dental appliances, eye drops or suspensions, ocular inserts, ocular films, selective ocular delivery, short-term wound sealants, direct patches to ocular tissue, catheters , hydrophilic coating agents for lead wires and the like, and vascular embolization agents.

[0648] In certain embodiments, the polymeric material is a polymer, a thermoplastic polymer, a thermoset polymer, a biodegradable polymer, a modified polymer, a crosslinked polymer, a controlled delivery polymer, Hydrogels, hydrocolloids, liquid-forming polymers, gel-forming polymers, silicone-based polymeric materials, film-forming polymers, polymeric adhesives, controlled-delivery polymeric copolymers, medical polymers, copolymers, or Including mixtures thereof and the like.

[0649] In certain embodiments, the silane quaternary ammonium compounds and polymeric materials described herein are at least 1:1000:1000:1; 1:500:500:1, 1:300:300 :1, 1:250:250:1;1:200:200:1;1:150:150:1;1:100:100:1;1:75:75:1;1:50:50:1 ;1:40:40:1;1:30:30:1,1:25:25:1;1:20:20:1;2:25:15:1;1:10:10:1;1 : 5:5:1; 1:3:3:1; 1:2:2:1; or in a 1:1 ratio.

[0650] In certain embodiments, the composition of silane quaternary ammonium compound and polymeric material forms a solid, stable composition.

[0651] In certain embodiments, the composition forms a clear stable solution. In certain embodiments, the composition is stable for at least one month. In certain embodiments, the composition is stable for at least two months. In certain embodiments, the composition is stable for at least 3 months.

[0652] In certain embodiments, the silane quaternary ammonium compounds described herein are mixed with the polymers described herein to form flexible films. In certain embodiments, the films are present at various thickness levels suitable for specific applications described herein.

[0653] In certain embodiments, the silane quaternary ammonium compounds described herein are incorporated into polyvinyl alcohol. In certain embodiments, the resulting products are used in medical applications and devices such as soft contact lenses, eye drops, embolizing particles, tissue adhesion barriers, and as artificial cartilage and menisci. In certain embodiments, the resulting product is a medical device implant material for cartilage replacement surgery. In certain embodiments, the resulting products are transiently used as short-term wound sealants, direct patches to ocular tissue, catheters, hydrophilic coatings for leads, or vascular embolization agents. See, for example, Baker, M., et al., "A review of polyvinyl alcohol and it uses in cartilage and orthopedic applications", Wiley Online Library. DOI: 10.1002 / jbm.b.32694 (2012), which is incorporated herein by reference. form part of the book.

[0654] In certain embodiments, the polymer is polyvinyl alcohol hydrogel. In certain embodiments, polyvinyl alcohol hydrogen is useful for drug delivery systems. In certain embodiments, drug delivery systems include ocular inserts, ophthalmic films, nanoparticles, microspheres, floating microspheres, mucoadhesives, selective drug delivery agents, or the like. In certain embodiments, the drug delivery system is an ocular insert, ophthalmic film, microspheres, floating microspheres, or selective drug delivery.

[0655] Polyvinyl alcohol hydrogels are biocompatible and toxicologically safe polymers used as matrices for sustained release hydrogel drug delivery systems in solid, liquid, and semisolid configurations. Polyvinyl alcohol hydrogels have excellent mucoadhesive-like physical properties and swell, making them suitable for a variety of drug delivery applications. See, for example, Gajra, Balaram & Pandya et al., "Poly vinyl alcohol Hydrogel and its Pharmaceutical and Biomedical Applications: A Review", International Journal of Pharmaceutical Research, 2011, 4. 20-26, which is incorporated herein by reference. Form part of the specification.

[0656] In some examples, the antimicrobial composition contains a hydrogel. Hydrogels must be biocompatible so that they can be administered to patients without undesirable effects. Hydrogels are known in the art and are the subject of extensive literature and patents. The hydrogel is present in an effective amount to provide the desired viscosity and wettability as required for the desired application, eg, in treating infected wounds. The specific amount of hydrogel used will depend on a number of factors, including, by way of example and not limitation, the specific chemical composition of the hydrogel used, the molecular weight of the specific hydrogel used, the antimicrobial desired. Viscosity of the composition, as well as the level of water retention and release desired for a particular hydrogel.

[0657] In some embodiments, hydrogels control the release rate of one or more quaternary ammonium compounds of the invention. In some embodiments, hydrogels are biodegradable. Examples of useful hydrogel carriers include poly(vinyl alcohol), sodium polyacrylate, poly(acrylamide), poly(N-vinyl-2-pyrrolidone), poly(N-isopropylacrylamide), cross-linked carboxymethylcellulose, cross-linked polyethylene glycol. , poly(lactic acid), hyaluronic acid, sodium alginate, agarose, starch, chitosan, methylcellulose, polyethylene oxide, amorphous hydrogels, crosslinked polymer gels with high water content, copolymers thereof, derivatives thereof, mixtures thereof etc., but not limited to these.

[0658] In some examples, the antimicrobial composition contains a hydrocolloid. In some embodiments, hydrocolloids can interact with the site of infection by forming a gel. Hydrocolloids can be present to provide a combination of moisture and absorbency where deemed necessary. As hydrocolloids, natural gums such as gum arabic, gati gum, karaya gum, tragacanth gum, guar gum, locust bean gum, acacia gum, etc.; Microbial gums such as dextran gum and xanthan gum, pectin, gelatin, casein, collagen, polyvinylpyrrolidone, low methoxyl pectin, propylene glycol alginate, carboxymethyl locust bean gum, carboxymethyl guar gum, and oxidized, acetylated, carboxylated, esterified modified, methylated, aminated, etherified, sulfated, borated, or phosphorylated; absorbent colloidal materials with polyurethane-coated elastomers; .

[0659] In certain embodiments, the antimicrobial composition for administration further comprises a quaternary ammonium compound as described herein, optionally phosphoglyceride; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC) Dioleylphosphatidylethanolamine (DOPE);Dioleyloxypropyltriethylammonium (DOTMA);Dioleoylphosphatidylcholine;Cholesterol;Cholesterol ester;Diacylglycerol;Diacylglycerol succinate;Diphosphatidylglycerol (DPPG);Hexanedecanol ( hexanedecanol); fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surfactant fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid monoglycerides; fatty acid diglycerides; Sorbitan Monolaurate (Span™ 20); Polysorbate 20 (Tween™ 20); Polysorbate 60 (Tween™ 60); Polysorbate 65 (Tween™ 65); 80 (Tween(TM) 80); polysorbate 85 (Tween(TM) 85); polyoxyethylene monostearate; surfactin; poloxomer; sorbitan fatty acid esters such as sorbitan trioleate; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (kephalin); cardiolipin; phosphatidic acid; cerebroside; dicetyl phosphate; stearates; isopropyl myristate; tyloxapol; poly(ethylene glycol) 5000-phosphatidylethanolamine; poly(ethylene glycol) 400-monostearate; phospholipids; synthetic and / or natural detergents with high surfactant properties; deoxycholate; cyclodextrins; chaotropic salts; ion pairing agents; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose, xylose, arabinose, glucuronic acid glucoronic acid, galactoronic acid, mannuronic acid, glucosamine, galatosamine and neuramic acid; pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC) , methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxyethyl starch, carrageenan, glycon, amylose, chitosan, N,O-carboxymethylchitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan (glucommannan), pustulan, heparin, hyaluronic acid, curdlan and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol, pluronic polymers, polyethylene, polycarbonates (e.g. poly(1,3-dioxane-2) -on)), polyanhydrides (e.g. poly(sebacic anhydride)), polypropylfumarate, polyamides (e.g. polycaprolactam), polyacetals, polyethers, polyesters (e.g. polylactide, polyglycolide, polylactide-co - glycolide, polycaprolactone, polyhydroxy acids (e.g. poly((β-hydroxyalkanoates))), poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, Polystyrene and polyamines, polylysine, polylysine-PEG copolymer and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol, vitamin E TPGS (as d-α-tocopheryl polyethylene glycol 1000 succinate ), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), polyethylene Contains one or more of glycol (PEG), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS).

[0660] In some embodiments, the antimicrobial composition can include polymers for controlled delivery of the compounds described, such polymers including pluronic polymers, polyesters (e.g., polylactic acid, poly(lactic acid- Co-glycolic acid, polyethylene terephthalate (PET), glycol-modified polyethylene terephthalate (PETG), polybutylene terephthalate (PBT), polycyclohexylene dimethylene terephthalate (PCT), polycyclohexylene dimethylene terephthalate glycol (PCTG), acid modification Polycyclohexylene dimethylene terephthalate (PCTA), polytrimethylene terephthalate (PTT), woven and non-woven polyethylene terephthalate (PET), spunbond, spunlace, embossed polyethylene terephthalate, LDPE non-woven polyethylene terephthalate, glyco-modified polyethylene terephthalate ( PETG), or another type of polyester that may contain monomers or comonomers with other carboxylic acid or alcohol functional groups), polycaprolactone, polyvalerolactone, poly(1,3-dioxane-2-one )); polyanhydrides (eg, poly(sebacic anhydride)); polyethers (eg, polyethylene glycol); polyurethanes; polymethacrylates;

[0661] In some embodiments, the polymer can be modified with polyethylene glycol (PEG), with carbohydrates, and / or with acyclic polyacetals derived from polysaccharides. See, eg, Papisov, 2001, ACS Symposium Series, 786:301, which is incorporated herein by reference.

[0662] In certain embodiments, the additional polymer is a polyolefin (including cyclic polyolefins), including polypropylene and polyethylene; polyvinyl chloride; polystyrene; polyvinylidene chloride; polystyrene; polyvinylidene chloride; polyvinyl chloride; polylactic acid; or combinations of one or more of these.

[0663] In some embodiments, the antimicrobial composition contains a biodegradable polymer. Biodegradable polymers must be biocompatible so that they can be administered to patients without undesirable effects. Biodegradable polymers are known in the art and are the subject of extensive literature and patents. The biodegradable polymer or combination of polymers can be selected to provide the desired properties for the chosen application, including the proper mix of hydrophobic and hydrophilic qualities, half-life and degradation. These include, but are not limited to, speed, compatibility with one or more quaternary ammonium compounds of the invention to be delivered, and appropriate behavior at the site of application.

[0664] In some embodiments, the biodegradable polymer gels in the presence of an aqueous solution, such as that present in a wound or infection site.

[0665] In some embodiments, the biodegradable polymeric carrier provides for release of one or more quaternary ammonium compounds of the invention to the site of infection at a desired rate. Examples of useful biodegradable polymers include poly(lactic acid), polyglycolic acid, poly(D,L-lactide-co-glycolide), poly(D,L-lactic acid), polyesters, poly(caprolactone), poly (3-hydroxybutyrate), poly(s-caproic acid), poly(p-dioxanone), poly(propylene fumarate), poly(ether (orther) ester), polyol / diketone acetal, poly(sebacic anhydride) ), poly(maleic anhydride), poly(carboxybis-carboxyphenoxyphosphazene), poly[bis(p-carboxyphenoxy)methane], poly(amino acid), or copolymers thereof, but these include Not limited.

[0666] Optional active ingredients can be included in the antimicrobial composition that do not substantially interfere with the activity of the one or more quaternary ammonium compounds of the invention used in the invention. In certain embodiments, two or more carrier components can be combined if deemed necessary for a particular application.

[0667] In some embodiments, the antimicrobial composition further comprises one or more additional additives such as urea and / or DMSO. These quaternary ammonium compounds assist, if deemed necessary, in tissue healing or symptomatic amelioration at the site of infection to enhance the effectiveness of the desired antimicrobial composition in penetrating the site of infection being treated. or to extend the effective shelf life of the antimicrobial composition either alone or in combination with other active agents.

[0668] In some embodiments, the antimicrobial composition further comprises a surfactant. Addition of surfactants disrupts the complex hydrophobic / hydrophilic interactions between biofilm layers, thereby allowing one or more quaternary ammonium compounds of the present invention to subsurface biofilms present at the site of infection. It can help facilitate compound penetration and is added when one or more of the quaternary ammonium compounds of the invention alone has been shown to be insufficient for this purpose. . The selected surfactant additive can be selected to provide desired properties to the antimicrobial composition, for example, the surfactant and one of the present invention in a suitable carrier. These include the stability of the quaternary ammonium compounds, the desired level of biofilm penetration, and the level of reactivity with other components in the composition. Appropriate surfactants could be selected by one skilled in the art. In some embodiments, surfactants can facilitate leaching of one or more quaternary ammonium compounds of the present invention from the carrier of choice.

[0669] In some embodiments, surfactants can facilitate leaching of one or more quaternary ammonium compounds of the invention from either formulated microparticles or polymerizable nanoparticles. Examples of suitable surfactants include octenidine dihydrochloride, cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium chloride (DODAB), cocamidopropyl hydroxysultaine (CAHS), cocamidopropyl betaine (CAPB), cocamide MEA, sodium oxychlorosene, and combinations thereof.

[0670] In some embodiments, the antimicrobial composition further comprises a buffering agent. Some of the other candidate additives to antimicrobial compositions (eg, urea and / or DMSO) may require a very narrow pH range in order to function optimally. Buffers can be provided at appropriate concentrations to maintain the optimum pH range. Buffers optimized for particular desired uses will be known to those skilled in the art. Examples of suitable buffers include, but are not limited to, citrates, sulfonates, carbonates, acetates, borates, gluconates, phosphates, or combinations thereof.

[0671] In some embodiments, the antimicrobial composition further comprises suitable enzymes. Addition of enzymes either by breaking down extracellular polymeric substances (EPS) or inhibiting intercellular communication that is sent through ion channels in the form of electrical signals to coordinate cellular behavior. , can help break down established biofilms. In some embodiments, the enzyme may be a proteolytic enzyme. Proteolytic enzymes may be able to act on some of the polymeric material present in the EPS, thereby improving penetration of the antimicrobial composition. Examples of proteolytic enzymes include, but are not limited to, collagenase, cellulase, keratinase, papain, bromelain, trypsin, thermolysin, and combinations thereof.

[0672] In some embodiments, the antimicrobial composition further comprises a suitable tissue growth promoter. In some applications, the biofilm-induced infection being treated is within a wound. Inclusion of a suitable tissue growth promoter may help promote tissue regrowth within an existing wound during the time of infection treatment with a dressing. Examples of suitable tissue growth promoters include endothelial cell growth factor (ECGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), nerve growth factor (NGF), platelet-derived Including, but not limited to, growth factors (PDGF), transforming growth factors (TGF), or combinations thereof.

[0673] In some embodiments, the antimicrobial composition further comprises a preservative. Although the one or more quaternary ammonium compounds of the present invention are antimicrobial in nature, additional preservatives can optionally be included depending on the shelf life desired for the antimicrobial composition. Examples of suitable preservatives include, but are not limited to, methylparaben, propylparaben, benzyl alcohol, benzalkonium chloride, sorbic acid, phenol, phenylethyl alcohol, BHA, BHT, or combinations thereof.

[0674] In some embodiments, the antimicrobial composition further comprises an antioxidant. Antioxidants may be required to stabilize any other additives present in the antimicrobial composition from aerial oxidation over a suitable shelf life. Examples of suitable antioxidants include, but are not limited to, ascorbic acid, BHA, BHT, sodium bisulfite, vitamin E, sodium metabisulfite, propyl gallate, or combinations thereof.

[0675] In some embodiments, the antimicrobial composition further comprises an astringent. It may be desirable to add an astringent to the antimicrobial composition to cause contraction of the infected surface tissue, thereby facilitating penetration of the antimicrobial composition into the infected space. Examples of suitable astringents include zinc oxide, ferric oxide, zinc sulfate, silver nitrate, potassium permanganate, aluminum chloride, aluminum acetate, formaldehyde, blow's solution, benzoin tincture, or combinations thereof. is not limited to

[0676] Antimicrobial compositions suitable for topical application to the skin preferably take the form of ointments, creams, lotions, foams, pastes, gels, sprays, aerosols or oils. Carriers that can be used include petroleum jelly, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more of these.

[0677] Antimicrobial compositions suitable for transdermal administration can be provided as discrete patches that are configured to maintain intimate contact with the epidermis of the recipient for extended periods of time. Antimicrobial compositions suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3 (6):318 (1986)), which typically uses active quaternary It takes the form of an optionally buffered aqueous solution of the ammonium compound. In some embodiments, a microneedle patch or device is provided for delivering drugs across or into living tissue, particularly skin. Microneedle patches or devices allow drugs to be delivered across or into skin or other tissue barriers at clinically relevant rates, with minimal damage, pain, or irritation to tissue. or not at all.

[0678] Many methods and devices for ocular drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications (incorporated herein in full by reference): US Pat. Examples are US Pat. No. 8,192,408 entitled "Ocular trocar assembly" (Psivida Us, Inc.); US Pat. No. 7,585,517 entitled "Transcleral delivery" (Macusight, Inc.); U.S. Pat. Nos. 5,710,182 entitled "Ophthalmic compositions" and U.S. Pat. US Patent No. 8,663,639 entitled "Formulations and methods for vascular permeability-related diseases or conditions"; US Patent No. 8,486,960 entitled "Formulations and methods for vascular permeability-related diseases or conditions"; U.S. Pat. Nos. 8,367,097 and 8,927,005 entitled "Liquid formulations for treatment of diseases or conditions"; U.S. Patent No. 7,455,855 (Santen Pharmaceutical Co., Ltd.) entitled "Delivery System Using the Same"; International Publication No. "Conformable Therapeutic Shield For Vision and Pain"; 2011 / 050365 and WO 2009 / 145842 entitled "Therapeutic Device for Pain Management and Vision" (Forsight Labs, LLC); WO 2014 / 160884 entitled "Ophthalmic Implant for Delivering Therapeutic Substances"; U.S. Pat. No. 8,399,006, U.S. Pat. No. 8,277,830, U.S. Pat. No. 8,795,712, U.S. Pat. No. 8,808,727, U.S. Pat. WO 2014 / 152959 and U.S. Patent Application Publication entitled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant". No. 20140276482, U.S. Pat. Nos. 8,905,963 and 9,033,911 entitled "Injector apparatus and method for drug delivery", "Formulations and methods for increasing or reducing mucus ( WO 2015 / 057554 entitled "Formulations and Methods for Increasing or Reducing Mucus"; U.S. Patent Nos. 8,715,712 and 8,939,948 entitled "Ocular insert apparatus and methods"; WO 2013 / 116061 entitled "Insertion and Removal Methods and Apparatus for Therapeutic Devices", "Ophthalmic System for Sustained Release of Drugs to the Eye". WO2014 / 066775 entitled "Sustained Release of Drug to the Eye", WO2015 / 085234 and WO2012 / 019176 entitled "Implantable Therapeutic Device" WO 2012 / 065006 entitled "Methods and Apparatus to determine Porous Structures for Drug Delivery", entitled "Anterior Segment Drug Delivery". International Publication No. WO 2010 / 141729 entitled "Corneal Denervation for Treatment of Ocular Pain", International Publication No. WO 2011 / 050327 entitled "Corneal Denervation for Treatment of Ocular Pain"; WO2013 / 022801 entitled "Small Molecule Delivery with Implantable Therapeutic Device", WO2012 entitled "Subconjunctival Implant for Posterior Segment Drug Delivery". / 019047, WO2012 / 068549 entitled "Therapeutic Agent Formulations for Implanted Devices", WO2012 / 068549 entitled "Combined Delivery Methods and Apparatus" WO 2013 / 040426 entitled "Ocular Insert Apparatus and Methods", WO 2012 / 019139, "Injector Apparatus and Method for Drug Delivery" WO 2012 / 019136 entitled "Fluid Exchange Apparatus and Methods", WO 2013 / 040247 (ForSight Vision 4, Inc.).

[0679] Additional non-limiting examples of methods of delivering active quaternary ammonium compounds are described in WO 2015 entitled "Intracameral Implant for Treatment of an Ocular Condition". / 085251 (Envisia Therapeutics, Inc.); WO 2013 / 082111 entitled "Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses", "Degradable compounds and methods of their use, especially with particle replication in non-wetting molds". International Publication No. WO 2009 / 132265 entitled "Interventional drug delivery system and associated methods". 2010 / 099321, WO 2008 / 100304 entitled "Polymer particle composite having high fidelity order, size, and shape particles", "Nanoparticles WO 2007 / 024323 (Liquidia Technologies, Inc. and University of North Carolina at Chapel Hill) entitled Nanoparticle fabrication methods, systems, and materials; WO 2010 / 009087 (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" and "For Intracellular Delivery and Release of Cargo WO 2009 / 132206 entitled "Compositions and Methods for Intracellular Delivery and Release of Cargo"; WO 2009 / 132206 entitled "Nano-particles for cosmetic applications"; 2007 / 133808, WO2007 / 056561 entitled "Medical device, materials, and methods", WO2007 / 056561 entitled "Method for producing patterned materials"; WO 2010 / 065748, WO 2007 / 081876 entitled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.).

[0680] Additional non-limiting examples of ocular drug delivery methods and devices include, for example, WO 2011, entitled "Sustained delivery of therapeutic agents to an eye compartment." / 106702 and U.S. Patent No. 8,889,193; Patent No. 8,962,577, WO2013 / 138346 entitled "Non-Linear Multiblock Copolymer-Drug Conjugates for the Delivery of Active Agents" and U.S. Patents Application Publication No. 2013 / 0272994, WO 2005 / 072710 entitled "Drug and Gene Carrier Particles that Rapidly Move Through Mucus Barriers" and U.S. Patent No. 8,957,034 WO 2008 / 030557, entitled "Compositions and Methods for Enhancing Transport Through Mucous," U.S. Patent Application Publication No. 2010 / 0215580, U.S. Patent Application Publication No. 2013 / 0164343, WO 2012 / 061703 entitled "Compositions and Methods Relating to Reduced Mucoadhesion", U.S. Patent Application Publication No. 2012 / 0121718 and U.S. Patent Application Publication No. 2013 / 0236556, WO 2012 / 039979 entitled "Rapid Diffusion of Large Polymeric Nanoparticles in the Mammalian Brain" and US Patent Application Publication No. 2013 / 0183244 WO 2012 / 109363 entitled "Mucus Penetrating Gene Carriers" and U.S. Patent Application Publication No. 2013 / 0323313, "Nanoparticles that improve mucosal penetration or reduce inflammation WO 2013 / 090804 and U.S. Patent Application Publication No. 2014 / 0329913 entitled "Nanoparticle formulations with enhanced mucosal penetration". Publication No. 2013 / 110028, WO 2013 / 166498 entitled "Lipid-based drug carriers for rapid penetration through mucus linings" and US patent application Publication No. 2015 / 0086484 (Johns Hopkins University); U.S. Patent Application Publication No. 2013 / 0323179 (Johns Hopkins University and Kala Pharmaceuticals, Inc.) entitled Nanocrystals, Compositions, And Methods that Aid Particle Transport in Mucus; WO 2015 / 066444 entitled Compositions and methods for ophthalmic and / or other applications, "Pharmaceutical nanoparticles showing improved mucosal transport. WO 2014 / 020210 and WO 2013 / 166408 (Kala Pharmaceuticals, Inc.) entitled "mucosal transport"; "Ophthalmic injection device including dosage control device". U.S. Patent No. 9,022,970, entitled "Ophthalmic compositions comprising pbo-peo-pbo block copolymers," International Publication No. WO 2011 / 153349, entitled "Stabilized ophthalmic WO 2011 / 140203 entitled "Stabilized ophthalmic galactomannan formulations", WO 2011 / 068955 entitled "Ophthalmic emulsions", "Injectable aqueous ophthalmic compositions and their WO 2011 / 037908 entitled Injectable aqueous ophthalmic composition and method of use therefor, Pharmaceutical Formulation for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye. U.S. Patent Application Publication No. 2007 / 0149593, entitled "Of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye"; U.S. Patent Application, entitled "Water insoluble polymer matrix for drug delivery." No. 8,632,809 (Alcon, Inc.).

[0681] In another aspect, ophthalmic formulations are provided, the formulations comprising one or more quaternary ammonium compounds described herein in an ophthalmically suitable carrier. A suitable carrier should keep the quaternary ammonium compound from being toxic or irritating to the eye and prevent unwanted side effects or damage to the eye. Examples of ingredients unsuitable for use in ophthalmic formulations include corrosive agents such as strongly alkaline or strongly acidic substances, e.g. urea or ammonia, strong surfactants, and substances with known ocular toxicity, e.g. Hydrogen oxide etc. are mentioned.

[0682] In another aspect, formulations for the treatment of onychomycosis are also provided, wherein the formulations contain one or more quaternary ammonium compounds described herein to penetrate and activate the nail bed. Contained in a carrier capable of delivering a quaternary ammonium compound. One representative example of a carrier that can penetrate the nail bed is dimethylsulfoxide.

[0683] Additional non-limiting examples of drug delivery devices and methods include, for example, Delivery of an active drug to the posterior part of the eye by subconjunctival or periocular delivery of a prodrug. U.S. Patent Application Publication No. 20050009910 entitled "eye via subconjunctival or periocular delivery of a prodrug"; U.S. Patent No. 20130071349 entitled "Biodegradable polymers for lowering intraocular pressure"; U.S. Patent No. 8,481,069 entitled "Tyrosine kinase microspheres"; U.S. Patent No. 8,465,778 entitled "Method of making tyrosine kinase microspheres"; U.S. Pat. No. 8,409,607, entitled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods," entitled "Biodegradable intravitreal tyrosine kinase implants." US Patent No. 8,512,738 and US Patent No. 2014 / 0031408, US Patent No. 2014 / 0294986 entitled "Microsphere Drug Delivery System for Sustained Intraocular Release", "Therapeutic U.S. Patent No. 8,911,768 entitled "Methods For Treating Retinopathy With Extended Therapeutic Effect" (Allergan, Inc.); U.S. Pat. No. 6,495,164 (Alkermes Controlled Therapeutics, Inc.) entitled "Preparation of injectable suspensions having improved injectability"; International Publication entitled "Biodegradable Microcapsules Containing Filling Material"; WO 2014 / 047439 (Akina, Inc.); WO 2010 / 132664 entitled "Compositions And Methods For Drug Delivery" (Baxter International Inc. Baxter Healthcare SA); U.S. Patent Application Publication No. 20120052041 (The Brigham and Women's Hospital, Inc.) entitled "Polymeric nanoparticles with enhanced drugloading and methods of use thereof"; US Patent Application Publication No. 20140178475; US Patent Application Publication No. 20140248358; Published Application No. 20140249158 (BIND Therapeutics, Inc.); U.S. Patent No. 5,869,103 (Danbiosyst UK Ltd.) entitled "Polymer microparticles for drug delivery"; U.S. Patent No. 8628801 (University of Navarra) entitled "Pegylated Nanoparticles"; U.S. Patent Application Publication No. 2014 / 0107025 (Jade Therapeutics, LLC) entitled "Ocular drug delivery system"; U.S. Patent entitled "Agent delivery system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof." No. 6,287,588, U.S. Patent entitled "Bioactive agent delivery system comprised of microparticles within a biodegradable to improve release profiles." 6,589,549 (Macromed, Inc.); U.S. Patent No. 6,007,845 and U.S. Patent entitled "Nanoparticles and microparticles of non-linear hydrophilic / hydrophobic multiblock copolymers"; 5,578,325 (Massachusetts Institute of Technology); U.S. Patent Application Publication No. 20040234611, entitled "Ophthalmic depot formulations for periocular or subconjunctival administration"; No. 20080305172, U.S. Patent Application Publication Nos. 20120269894 and U.S. Patent Application Publication No. 20130122064 (Novartis Ag); U.S. Patent No. 6,413,539 entitled "Block polymer" (Poly-Med, Inc.); US Patent Application Publication No. 20070071756 (Peyman) entitled "Delivery of an agent to ameliorate inflammation"; "Methods and compositions for improved delivery of bioactive molecules"; US Patent No. 6,706,289 (PR Pharmaceuticals, Inc.) entitled "for enhanced delivery of bioactive molecules"; and US Patent No. 8,663,674 entitled "Microparticle containing matrices for drug delivery." (Surmodics).

[0684] dressing material, etc. In some embodiments, an antimicrobial composition containing one or more quaternary ammonium compounds of the invention is dispersed in a suitable dressing. The dressing chosen should be capable of releasing the desired antimicrobial composition over a period of time depending on the desired application. The dressing can be moistened by saturating it with the antimicrobial composition prior to placement on the infected site, even though it may become more moist due to exudate at the infected site. Alternatively, the dressing may be placed on the wound and / or infected site and subsequently saturated with the antimicrobial composition, for example by dispensing the antimicrobial composition via a dropper or syringe or other suitable means. can be done.

[0685] In another embodiment, an infection is treated by applying a dressing comprising one or more quaternary ammonium compounds of the present invention as an antimicrobial composition to the site of infection, the dressing comprising a quaternary ammonium compound of the present invention. One or more quaternary ammonium compounds are released at the site of infection. Infectious diseases may involve the presence of bacteria, fungi, viruses, amoebas, or combinations of these infectious species.

[0686] In some embodiments, treating an infection comprises placing a dressing comprising an antimicrobial composition as described herein into or over the infected site.

[0687] In certain embodiments, one or more quaternary ammonium compounds of the present invention are gram-positive, gram-negative, Mycobacterium, fungal species, or viral species described herein. It can be used to treat the underlying disorder, typically an infection.

[0688] In certain embodiments, for treating infections caused by Gram-positive, Gram-negative, Mycobacterium, fungal or viral species described herein, A method is provided comprising administering an effective amount of a quaternary ammonium compound or composition thereof as described in .

[0689] In a further embodiment, a dry powder formulation containing a quaternary ammonium compound of the invention is impregnated into a dressing, which dry powder formulation subsequently interacts with exudate or other bodily fluids at the site of infection. Wetting with action. A dressing can be placed in or over an infected site involving biofilm. The dressing may adhere to the wound and / or site of infection to provide proper localization, or it may not adhere to the site of infection to prevent unwanted tissue damage upon removal. The dressing may be rigid, allowing it to be held in place during treatment, or malleable, allowing placement and attachment in the desired location. In some cases.

[0690] Additionally, the dressing may contain additional additives (eg, urea and / or DMSO) to ensure that a moist environment is maintained at the infected site. Dressings must be composed of hypoallergenic and non-toxic materials in order to be acceptable for application to a living host. In some embodiments, the dressing will absorb the antimicrobial composition and will subsequently release the antimicrobial composition once placed at the site of the biofilm-involved infection.

[0691] In certain embodiments, the dressing is low enough to allow the antimicrobial composition to be incorporated therein, yet high enough to provide sufficient structural integrity. It has a bulk density that is The dressing must be porous to provide sufficient insertion of the antimicrobial composition into the material so that there is sufficient space for the antimicrobial composition to flow to the treatment site. Allow to be wetted. The level of porosity of the dressing must be high enough to allow sufficient wetting with the antimicrobial composition, yet still allow the dressing to have sufficient material strength. must.

[0692] In certain embodiments, the dressing is made from a flexible polymeric material that provides sufficient porosity for the desired application while still providing structural integrity. In certain embodiments, two or more dressing components can be combined into a composite material if deemed necessary for a particular application. In some cases, two or more components can be present in layers. In other cases, two or more components are impregnated or intercalated with each other. A combination of dressing components may be necessary for structural integrity to ensure placement, positioning, and functionalization at the infected site.

[0693] In some embodiments, the dressing comprises polymeric foam, eg, conformable foam. The polymeric foam can allow release of the desired antimicrobial composition either by diffusion, ionic interactions, or by degradation of the material composition of the dressing.

[0694] In some embodiments, the polymeric foam can absorb exudates that may result from infections involving the presence of biofilms. In some embodiments, the polymeric foam is biodegradable or non-degradable, depending on its intended use within a patient.

[0695] Examples of materials suitable for forming polymeric foams include cellulose and cellulose derivatives, microcrystalline cellulose, calcium alginate, polyacrylic acid, polyethylene glycol, polypropylene glycol, divinyl glycol, polyethylene oxide, polypropylene oxide, carboxymethylcellulose, hydroxyethylcellulose, polylactide, polyglycolide, polymethacrylic acid, poly-γ-benzyl-L-glutamic acid, polypropylene fumarate, poly-ε-caprolactone, poly-butylene terephthalate, polyvinyl alcohol, polyvinyl ether, poly-1-vinyl-2-pyrrolidinone, 2,5-dimethyl-1,5-hexadiene, divinylbenzene, polystyrene-divinylbenzene, polyanhydrides such as polybis(p-carboxy-phenoxy)propane-co-sebacic acid, polyhydroxyalkanoates such as Examples include, but are not limited to, alkyl-substituted silica gels formed from reagents such as poly-β-hydroxybutyrate or poly-β-butyrolactone, and reagents such as tetraethylorthosilicate and dimethyldiethoxysilane. In a preferred embodiment, the polymeric foam is composed of polyurethane.

[0696] In another embodiment, the polymeric foam is composed of cellulose. In yet another embodiment, the polymeric foam is composed of calcium alginate.

[0697] In some embodiments, the dressing comprises a fabric composition. The fabric composition may be composed of fibers, which include natural fibers, synthetic fibers, cellulose, woven or non-woven materials, gauze materials, or mixtures thereof. Examples of acceptable fibers include, but are not limited to, cotton, polyester, wool, silk, and rayon. The fabric composition can have varying levels of absorbency depending on the desired use. The fabric composition can be further coated with a suitable polymer composition to affect absorption and dispersion of active quaternary ammonium compounds or additional additives (eg, urea and / or DMSO).

[0698] In some embodiments, the dressing further comprises a polymeric film. A polymeric film may be desirable to ensure proper sealing by the dressing to maintain moisture at the treatment site. In a preferred embodiment, the polymeric film includes an adhesive surface and a non-adhesive surface that adhere to the edges of the infected site to provide a seal. In some embodiments, the polymer film is composed of polyurethane.

[0699] In certain embodiments, the dressing is self-adhesive.

[0700] In some embodiments, the dressing further comprises a collagen matrix. A collagen matrix can be included in applications where it may be deemed desirable, such as providing a template in wound healing. Collagen matrices can exist as gels, pads, pastes, or sheets. Collagen matrices can be derived from bovine, porcine, equine, or poultry sources. Collagen matrices can be composed of type I, II, III, IV, or V collagen.

[0701] In some embodiments, the collagen matrix can interact with the site of infection caused by the biofilm by forming a gel. Additional macromolecular structures such as hyaluronic acid or hyaluronan, fibronectin, laminin, proteoglycans, and mixtures thereof can be incorporated into the collagen matrix. In some embodiments, the collagen matrix is ​​chemically crosslinked.

[0702] In some embodiments, the dressing is composed of a soluble material. A dressing composed of a soluble material may allow the dressing to be placed over a wound and / or infected site without having to be retrieved upon completion of treatment. In certain embodiments, the dressing is a polymeric material, including thermoplastic polymers, thermoset polymers, biodegradable polymers, modified polymers, crosslinked polymers, controlled delivery polymer, hydrogel, hydrocolloid, liquid-forming polymer, gel-forming polymer, silicone-based polymer material, film-forming polymer, polymeric adhesive, controlled delivery polymer, copolymer, medical polymer, or mixtures thereof; including fabric materials, non-adhesive dressing materials, or hydrofibers.

[0703] In certain embodiments, the dressing is hydrofiber. Hydrofiber is a soft, sterile, nonwoven pad or ribbon dressing composed of sodium carboxymethylcellulose that is incorporated into a unitary fleece form in a needle bonding process. This conformable material is capable of absorbing large amounts of wound fluid, such as exudate containing bacteria. This is then transformed into a soft gel that creates a moist environment to assist the body's healing process. The gel also aids in removing non-viable tissue from the wound (autolytic debridement) without damaging the newly formed tissue. Hydrofibers are neither hydrocolloids nor alginates, but a separate class that incorporates the benefits of both (Thomas S. Sodium Carboxymethylcellulose Primary Wound Dressing, Aquacel. Available accessed 22 October, 2010).

[0704] In certain embodiments, non-stick dressing materials include non-stick fabric materials such as non-stick gauze, petroleum impregnated gauze, petroleum blend impregnated gauze, oil emulsion dressings, and the like.

[0705] In certain embodiments, the dressing comprises polymer gels (gel-forming polymers), silicones, or copolymers thereof, optionally with additional ingredients for use in topical applications. A polymer gel may be desirable to ensure proper sealing by the dressing to maintain moisture at the treatment site. In a preferred embodiment, the polymeric film includes an adhesive surface and a non-adhesive surface that adhere to the edges of the infected site to provide a seal.

[0706] In some embodiments, the polymer film is composed of polyurethane. In certain embodiments, the polymer gel comprises a biodegradable polymer.

[0707] In certain embodiments, the polymer film has a glue-like consistency.

[0708] In certain embodiments, the dressing comprises a compound described herein, polymer gel, silicone or copolymer thereof, and a pharmaceutically acceptable carrier.

[0709] In certain embodiments, the dressing further comprises a polymer, which can form a variety of shapes, sizes, and thicknesses suitable for particular applications.

[0710] In certain embodiments, the polymer is a silicone-based or silicone gel, or a silicone-based polymer.

[0711] In certain embodiments, the polymer is a hydrogel, hydrocolloid, or organogel.

[0712] In certain embodiments, the polymer is a polymeric biomaterial.

[0713] In certain embodiments, the polymer is guar gum.

[0714] In one particular embodiment, the polymer is polyvinyl alcohol.

[0715] In certain embodiments, the polymer is a hydrogel or crosslinked hydrogel.

[0716] In certain embodiments, the polymer is a hydrocolloid.

[0717] In certain embodiments, the dressing is in gel, film, foam, liquid, or hydrocolloid form.

[0718] In one particular embodiment, the polymer is polyvinyl alcohol and the polymer is a soluble polyvinyl alcohol film.

[0719] In certain embodiments, the soluble polyvinyl alcohol film comprises the silane quaternary compounds described herein for the treatment of infections described herein.

[0720] In certain embodiments, the soluble polyvinyl alcohol film comprises the silane quaternary compounds described herein for the treatment of eye infections.

[0721] In certain embodiments, the soluble polyvinyl film is in the form of eye drops or suspensions.

[0722] In certain embodiments, the soluble polyvinyl film is used to coat medical devices such as catheters and leads, as well as covers for medical device infection control, such as pacemakers, contact lenses, and the like. , dentures, prostheses, heart valves, or joints.

[0723] In certain embodiments, soluble polyvinyl films are used to treat biofilms, which are bacterial or fungal. Fungal biofilms on implantable medical devices are highly resistant to drugs and the host immune system and have the potential to disseminate disseminated bloodstream infections. Non-Patent Document 9.

[0724] In certain embodiments, the gel, film, or hydrocolloid forms a clear stable solution. In certain embodiments, the gel, film, or hydrocolloid is stable for at least one month. In certain embodiments, the gel, film, or hydrocolloid is stable for at least two months. In certain embodiments, the gel, film, or hydrocolloid is stable for at least 3 months. In certain embodiments, the gel, film, or hydrocolloid is stable for at least 4 months. In certain embodiments, the gel, film, or hydrocolloid is stable for at least 5 months. In certain embodiments, the gel, film, or hydrocolloid is stable for at least 6 months.

[0725] Examples of polymer gels include polyvinyl alcohol, polyvinyl acetate, sodium polyacrylate, acrylic acid polymers, agarose, galactoarabinane, polyacrylic acid, polyvinyl chloride, guar gum, xanthan gum, polyacrylonitrile, polyurethane, poly(lactide). -co-glycolide) (PLGA), polyethylene glycol (PEG), polyethylene glycol / dopa, polycaprolactone (PCL), poly(vinylpyrrolidone), poly(ethylene glycol), poly(methyl methacrylate), poly(N-isopropyl) Acrylamide, polyaniline (PANI), polypyrrole (PPy), polythiophene (PTh), poly(3,4-ethylenedioxythiophene) (PEDOT), polyesters, sulfated polysaccharides (e.g. heparin sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate), proplast or alloplastic, glucan, dextran, or derivatives or copolymers thereof, but are not limited thereto.

[0726] Examples of polymer gels include silk sericin, spider silk protein, keratin, hyaluronic acid, pectin, homoglycan, pallulan, yeast, cellulose, chitin, modified skin substitutes (single or multiple layers), bio-modified skin substitutes. (single-layer or multi-layer), tissue-engineered skin substitute, dermis substitute (e.g., Transcyte, Dermagraft, Composite graft, Orcel, Apligraf, etc.), epidermis substitute, cultured epidermal autograft (e.g., Epicel, etc.), or acellular Xenografts (e.g., EZ-Derm, Integra, AlloDerm, Derma Martix, etc.), including but not limited to (Mir et al., "Synthetic polymeric biomaterial for wound healing: a review", Prog Biomater., 2018). , 1-21; doi: 10.1007 / s40204-018-0083-4; Murray et al., "Development and use of biomaterials as wound healing therapies", Burns & Trauma, 2019, 7(2), DOI: https: / / doi.org / 10.1186 / s41038-018-0139-7).

[0727] In certain embodiments, the dressing is used to cover a wound, ie, as a wound care patch, to cover an infection, or to cover exposed skin. For example, wounds include infections, burns, exposed skin, open wounds, skin lacerations, abrasions, punctures, lacerations, crusts, surgical wounds, abscesses, skin lacerations, skin ulcers or lesions, damaged tissue, bites, fluids. It can be due to associated skin injuries, foot ulcers, necrosis, non-healing wounds, compromised skin grafts or flaps, acute wounds, chronic wounds, trauma, and other skin exposure-related injuries.

[0728] Examples include fiber mats, gauze (cotton, thread, natural or synthetic fibers, non-woven fabrics, blends thereof, etc.), cotton balls, tulle fabrics, plasters (liquid plasters), adhesives, tissue adhesives, bio-adhesives, tapes, They include, but are not limited to, sheets, labels, backings, rolls of films and sheets, tear-apart sheets, rolls, fabric materials described herein, and the like.

[0729] In certain applications, the dressing comprises a composite material, where the substrate comprises polyethylene or polypropylene (which can be spunbonded, spunlaced, or embossed), or combinations thereof. Substrates include, for example, paper, textiles (including pharmaceutical grade textiles and coated textiles, such as vinyl-coated textiles), vinyls (including embossed vinyls), polypropylenes (including oriented polypropylenes such as MOPP and BOPP), polyesters. Urethanes, polyethylenes (including LDPE, LLDPE, MDPE, HMWPE, and HDPE, which are more commonly polyolefins), acrylonitrile butadiene styrene, polycarbonates, polyvinyl chloride, cellophane, cellulose, cellulose acetate, block copolymers Composed films, block copolymers such as styrene-isoprene, butadiene, or thylene-butylene / styrene (SIS, SBS, or SEBS), polyurethanes, ethylene copolymers such as ethylene vinyl acetate. (including embossed ethylene vinyl acetate), ethylene / propylene copolymer elastomer or ethylene / propylene / diene terpolymer, etc., nylon, crepe fabric, flatback, foil, rayon, polyvinyl derivative, polyamide, cuprammonium cellulose, wool , silk, jute, hemp, cotton, flax, sisal hemp, ramie, polystyrene, polyurethane, polyvinylidene chloride, saponified ethylene-vinyl acetate copolymer, linoleum, acrylic, natural rubber, recycled rubber, synthetic rubber, thermoplastic resin film, Biodegradable resins such as polylactic acid and polyhydroxyalkanoates, polyamides, polyimides, papers, foils, metal-containing films such as copper films, other resin films, polylactic acid films, other thin films, or these One or more materials such as combinations can be included. Other substrates can include textile materials such as one or more woven or nonwoven layers, such as polyester nonwovens having reinforcing mesh therein, or combinations thereof. One example is the fabric manufactured by DuPont E.I. de Nemours & Co., Inc. under the trademark Sontara™.

[0730] In certain embodiments, the dressing comprises a composite substrate, which is a pharmaceutical grade textile material, a polyethylene film material, a vinyl material, an ethylene vinyl acetate material, a polyurethane material, a polyester urethane material, a polyester material. (including polyethylene terephthalate materials, glycol-modified polyethylene terephthalate (PETG) materials, spunlace polyethylene terephthalate materials, spunlace polyethylene terephthalate nonwoven materials, embossed nonwoven polyethylene terephthalate materials, LDPE polyethylene terephthalate nonwoven materials), or coated fabric materials such as vinyl Including coating fabric...

Claims

1. The following formula: 【Chemistry 1】 (In the formula, a is 1, 2, 3, 4, 5, 6, 7, or 8; y is 0, 1, 2, 3, or 4; p and q are each independently selected from 1, 2, 3, and 4; R １ are each independently C ６ ~C ２２ Alkyl (and C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (It is possible that ６ ~C ２２ Alkenyl (and C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ ), and C ６ ~C ２２ Alkanoyl (and C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (which can be R ２ , R ３ , and R ４ are each independently 【Chemistry 2】 or C ２ ~C １０ Alkanoic acid (which is C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , or C １０ or a salt thereof, and in some embodiments, R ２ , R ３ , and R ４ are all alkanoic acids, R ５ are each independently R ２ , R １７ , and C ２ ~C １０ Alkanoic acid (which is C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , or C １０ wherein the acid is optionally a diacid or a salt thereof; R ６ is independently selected from hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl, each of said alkyl, aryl, cycloalkyl, and heterocyclyl optionally being selected from C １ ~C ６ Alkyl, hydroxyl, halogen, N(R ７ ) ２ , COOR ７ , C(O)R ７ , C.H. ２ OR ７ , CON(R ７ ) ２ , and NO ２ and having a substituent selected from R ７ are each independently hydrogen, C １ ~C ８ Alkyl, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl, and aryl; R ８ , R ９ , R １０ , R １１ , R １２ , and R １３ are each independently hydrogen, halogen, hydroxyl, N(R ７ ) ２ , C.H. ２ OR ７ , CON(R ７ ) ２ , COOR ７ , C(O)R ７ , C １ ~C ８ Alkyl, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ selected from alkanoyl, heterocyclyl, heteroaryl, and aryl; X １ are each independently NR １７ , C.H. ２ , CHOH, and C(O); X ２ are each independently C １ ~C ３ Alkyl, and C １ ~C ３ hydroxyalkyl; X ３ are each independently hydroxyl, NO ２ , N(R ７ ) ２ , C.H. ２ OR ７ , CON(R ７ ) ２ , COOR ７ , C(O)R ７ , C １ ~C ８ Alkyl, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ selected from alkanoyl, heterocyclyl, heteroaryl, and aryl; X ４ are each independently X ３ is selected from R １４ and R １５ are each independently 【Transformation 3】 , R ２ , and R １７ is selected from R １６ are each independently C １ ~C ４ Alkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, and C １ ~C ４ haloalkyl; R １７ are each independently hydrogen, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl, and aryl; X － is an anion, B ＋ is a cation), or a pharmaceutically acceptable salt or composition thereof.

2. 2. The quaternary ammonium compound of claim 1, wherein the anion is selected from the group consisting of chloride, fluoride, iodide, bromide, hydroxide, chlorite, chlorate, hydroxide, formate, acetate, lactate, benzoate, and salicylate.

3. 10. The quaternary ammonium compound of claim 1, wherein the quaternary ammonium compound has a negatively charged substituent.

4. 4. The quaternary ammonium compound of claim 3, wherein the negatively charged substituent is neutralized with a pharmaceutically acceptable cation.

5. 5. The quaternary ammonium compound of claim 4, wherein the cation is selected from potassium, sodium, and calcium cations.

6. 10. The quaternary ammonium compound of claim 1, wherein the pharmaceutically acceptable composition comprises at least 50% by molar of the quaternary ammonium compound relative to other quaternary ammonium compounds in the composition.

7. 10. The quaternary ammonium compound of claim 1, wherein the compound is a zwitterion.

8. R ２ , R ３ , and R ４ is C １ ~C １２ 2. The quaternary ammonium compound of claim 1 which is an alkanoic acid.

9. R ２ , R ３ , and R ４ teeth, 【Chemistry 4】 2. The quaternary ammonium compound of claim 1, selected from the group consisting of:

10. R ２ , R ３ , and R ４ teeth, 【Transformation 5】 2. The compound of claim 1 selected from the group consisting of:

11. R ５ teeth, 【Transformation 6】 2. The quaternary ammonium compound of claim 1, selected from the group consisting of:

12. R ５ is hydrogen, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, and C １ ~C ８ 2. The quaternary ammonium compound of claim 1, selected from the group consisting of haloalkyl.

13. X １ The compound according to any one of claims 9 to 11, wherein is NH.

14. X １ is NR １７ wherein R １７ is C １ ~C ８ The quaternary ammonium compound according to any one of claims 9 to 11, which is hydroxyalkyl.

15. X ２ is C １ ~C ３ 12. The quaternary ammonium compound of claim 9 or 11, which is alkyl.

16. X ２ is C １ ~C ３ 12. The quaternary ammonium compound of claim 9 or 11, which is hydroxyalkyl.

17. X ３ is hydroxyl, N(R ７ ) ２ , C.H. ２ OR ７ , COOR ７ , C １ ~C ８ Alkyl, and C １ ~C ８ 12. The quaternary ammonium compound according to claim 10 or 11, selected from hydroxyalkyl.

18. X ４ is N(R ７ ) ２ , C １ ~C ８ Alkyl, C １ ~C ８ Hydroxyalkyl, and C １ ~C １２ 12. The quaternary ammonium compound according to claim 10 or 11, selected from the group consisting of alkanoic acids.

19. below: 【Transformation 7】 【change】 【change】 【change】 【change】 8. The quaternary ammonium compound of claim 7 selected from the group consisting of:

20. below: 【Transformation 8】 2. The quaternary ammonium compound of claim 1, selected from the group consisting of:

21. 20. The quaternary ammonium compound of claim 19, which exists as a monocation or a dication.

22. The quaternary ammonium compound according to any one of claims 1 to 21, which is a powder or solid.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, and optionally a pharmaceutically acceptable carrier.

24. 24. The pharmaceutical composition of claim 23, suitable for topical delivery.

25. 25. The pharmaceutical composition of any one of claims 22 to 24, in a form selected from the group consisting of a liquid, a cream, a gel, a spray, a foam, a wipe, a powder, a paste, and a solid.

26. 26. A method of treating a topical infection in a host, said treatment comprising administering to a host in need thereof an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutical composition according to any one of claims 22 to 25.

27. 26. A method of treating a host having an infection selected from the group consisting of an eye infection, an ear infection, a skin infection, and a nail infection, said treating comprising administering to said host an effective amount of a compound of any one of claims 1 to 21 or a pharmaceutical composition of any one of claims 22 to 25.

28. 28. The method of claim 26 or 27, wherein the infection is caused by a bacterial infection, a fungal infection, an amoebic infection, or a viral infection, or a combination thereof.

29. 28. The method of claim 26 or 27, wherein the infection is caused by Staphylococcus aureus, Pseudomonas aeruginosa, Fusarium spp., Aspergillus spp., Candida albicans, Candida auris, Curvularia spp., Haemophilus influenzae, or Acanthamoeba keratitis, or a combination thereof.

30. 30. The method of any one of claims 26 to 29, wherein the infection is an eye infection.

31. 30. The method of any one of claims 26 to 29, wherein the infection is an ear infection, and the infection is in the outer ear (otitis externa), middle ear (otitis media), or inner ear (otitis interna).

32. 30. The method of any one of claims 26 to 29, wherein the infection is a nail infection.

33. The method of any one of claims 26 to 29, wherein the infection is a chronic wound.

34. The method of any one of claims 26 to 29, wherein the infection causes periodontal disease.

35. 31. The method of claim 30, wherein the eye infection is selected from the group consisting of bacterial or viral conjunctivitis (pink eye), corneal ulcer, keratitis, bacterial, fungal, or herpes infection keratitis, endophthalmitis, and blepharitis.

36. 22. A method of treating a dermatological disorder in a host in need thereof, comprising administering to said host an effective amount of a compound according to any one of claims 1 to 21.

37. 37. The method of claim 36, wherein the dermatological disorder is selected from the group consisting of acne vulgaris, cystic acne, eczema, folliculitis, and skin infections.

38. 38. The method of claim 37, wherein the dermatological disorder is acne vulgaris.

39. 38. The method of claim 37, wherein the dermatological disorder is selected from the group consisting of eczema, eczema herpeticum, eczema vaccinatum, and eczema coxsackiei.

40. 38. The method of claim 37, wherein the dermatological disorder is cystic acne.

41. 38. The method of claim 37, wherein the dermatological disorder is a skin infection.

42. 42. The method of any one of claims 36 to 41, wherein the dermatological disorder is caused by a pathogen selected from the group consisting of gram-positive bacteria, gram-negative bacteria, fungi, and viruses.

43. 42. The method of any one of claims 36 to 41, wherein the dermatological disorder is caused by a pathogen selected from the group consisting of staphylococcal bacteria such as Propionibacterium acnes, Staphylococcus epidermidis, Staphylococcus aureus, or streptococcal bacteria.

44. 43. The method of claim 42, wherein the virus is selected from the group consisting of herpes simplex virus and molluscum contagiosum virus.

45. 37. The method of claim 36, wherein the dermatological disorder is a skin infection caused by Staphylococcus aureus.

46. The method of any one of claims 26 to 45, wherein the host is a human.

47. The method of any one of claims 26 to 45, wherein the host is a mammal.

48. 46. ​​The method of any one of claims 26 to 45, wherein the host is a dog, cat, rabbit, horse, pig, or cow.

49. 22. An antibacterial composition for treating an infection in a host in need thereof, comprising an effective amount of a compound of any one of claims 1 to 21 in combination with one or more of glycerol, glycerol-propylene oxide copolymer, solketal, glycidol, or epichlorohydrin, optionally with the addition of another pharmaceutically acceptable excipient.

50. 50. The antimicrobial composition of claim 49, wherein the infection is an eye infection.

51. 50. The antimicrobial composition of claim 49, wherein the infection is an ear infection selected from the group consisting of an outer ear (otitis externa) infection, a middle ear (otitis media) infection, or an inner ear (otitis interna) infection.

52. 50. The antimicrobial composition of claim 49, wherein the infection is a nail infection.

53. 50. The antimicrobial composition of claim 49, wherein the infection is a chronic wound.

54. 50. The antimicrobial composition of claim 49, wherein the infection causes periodontal disease.

55. 51. The antimicrobial composition of claim 50, wherein the eye infection is selected from the group consisting of bacterial or viral conjunctivitis (pink eye), corneal ulcer, keratitis, bacterial, fungal, or herpes infection keratitis, endophthalmitis, or blepharitis.

56. 50. The antimicrobial composition of claim 49, wherein the infection causes a dermatological disorder.

57. 57. The antimicrobial composition of claim 56, wherein the dermatological disorder is selected from the group consisting of acne vulgaris, cystic acne, eczema, folliculitis, and skin infections.

58. 58. The antimicrobial composition of claim 57, wherein the dermatological disorder is acne vulgaris.

59. 57. The antimicrobial composition of claim 56, wherein the dermatological disorder is selected from the group consisting of eczema, eczema herpeticum, eczema vaccinatum, or eczema coxsackiei.

60. 58. The antimicrobial composition of claim 57, wherein the dermatological disorder is cystic acne.

61. 58. The antimicrobial composition of claim 57, wherein the dermatological disorder is a skin infection.

62. 57. The antimicrobial composition of claim 56, wherein the dermatological disorder is a chronic wound.

63. 63. The antimicrobial composition of any one of claims 56 to 62, wherein the dermatological disorder is caused by a gram-positive bacterium, a gram-negative bacterium, a fungus, or a virus, or a combination thereof.

64. 63. The antimicrobial composition of any one of claims 56 to 62, wherein the dermatological disorder is caused by a staphylococcal bacterium such as Propionibacterium acnes, Staphylococcus epidermidis, Staphylococcus aureus, or a streptococcal bacterium, or a combination thereof.

65. 64. The antimicrobial composition of claim 63, wherein the virus comprises herpes simplex virus or molluscum contagiosum virus.

66. 62. The antimicrobial composition of claim 61, wherein the skin infection is caused by Staphylococcus aureus.

67. 50. The antimicrobial composition of claim 49, wherein the infection is due to biofilm formation.

68. 68. The antimicrobial composition of any one of claims 49 to 67, in the form of a spray, cream, gel, foam, dry powder, wipe, paste, solid, transdermal patch, skin solution, subcutaneous patch, eye drops, or suspension.

69. The antimicrobial composition of any one of claims 49 to 68, wherein the antimicrobial composition is added to a polymeric material.

70. 70. The antimicrobial composition of claim 69, wherein the polymeric material is selected from the group consisting of thermoplastic polymers, thermosetting polymers, biodegradable polymers, modified polymers, cross-linked polymers, controlled delivery polymers, hydrogels, hydrocolloids, liquid-forming polymers, gel-forming polymers, silicone-based polymeric materials, film-forming polymers, polymeric adhesives, copolymers, and medical grade polymers, and mixtures thereof.

71. 71. The antimicrobial composition of claim 70, wherein the polymer is a hydrogel.

72. 71. The antimicrobial composition of claim 70, wherein the polymer is a gel-forming polymer.

73. 71. The antimicrobial composition of claim 70, wherein the polymer is a film-forming polymer.

74. 71. The antimicrobial composition of claim 70, wherein the polymer is a hydrocolloid.

75. 71. The antimicrobial composition of claim 70, wherein the polymer is a silicone-based polymer material.

76. 71. The antimicrobial composition of claim 70, wherein the polymer is an adhesive.

77. 77. The antimicrobial composition of any one of claims 70 to 76, wherein the polymer is a modified polymer, a copolymer, or a mixture thereof.

78. 78. The antimicrobial composition of any one of claims 70 to 77, wherein the polymer is a biodegradable polymer.

79. 79. The antimicrobial composition of any one of claims 70 to 78, wherein the polymer is a soluble polymer.

80. 80. The antimicrobial composition of any one of claims 70 to 79, comprising one or more additional additives.

81. 81. The antimicrobial composition of claim 80, wherein the additional additives comprise a surfactant, a buffer, an enzyme, a tissue growth promoter, a preservative, an antioxidant, an astringent, a topical carrier, or a pharmaceutically acceptable carrier.

82. 22. The compound of any one of claims 1 to 21, applied to a surface selected from the group consisting of medical devices, medical device coatings, pacemakers, contact lenses, dentures, prosthetics, heart valves, and cardiac interfaces; biomaterials, implantable devices, non-implantable devices, wound healing materials, personal protective materials, gloves, face masks, surgical or hospital gowns, apparel, sheets, sponges, woven or non-woven materials, ocular inserts, ophthalmic films, short-term wound packings, catheter hydrophilic coatings, catheter leads, and vascular embolic agents.

83. 100. A method of treating an infection in a host, comprising: a) applying a dressing comprising the antimicrobial composition of any one of claims 49 or 69-81 to an infected site in the host, wherein the dressing releases one or more compounds of claims 1-21 to the infected site; and b) covering the wound, infection, or exposed skin with the dressing.

84. 84. The method of claim 83, wherein the dressing is in the form of a spray, cream, gel, foam, film, dry powder, wipe, paste, solid, suspension, solution, or solid material.

85. 85. The method of claim 83 or 84, wherein the dressing comprises a material selected from the group consisting of thermoplastic polymers, thermosetting polymers, biodegradable polymers, modified polymers, crosslinked polymers, controlled delivery polymers, hydrogels, hydrocolloids, liquid-forming polymers, gel-forming polymers, silicone-based polymeric materials, film-forming polymers, polymeric adhesives, copolymers, polymeric materials including medical grade polymers, fabric materials, non-adherent dressing materials, and hydrofibers, or combinations thereof.

86. 86. The method of claim 85, wherein the dressing is a film-forming polymer.

87. 86. The method of claim 85, wherein the dressing is a polymeric adhesive.

88. 86. The method of claim 85, wherein the dressing is a gel-forming polymer.

89. 86. The method of claim 85, wherein the dressing is a silicone-based polymer or material.

90. 86. The method of claim 85, wherein the dressing is a hydrogel.

91. 86. The method of claim 85, wherein the dressing is a hydrocolloid.

92. A method according to any one of claims 83 to 91, wherein the dressing is a modified polymer, copolymer or mixture thereof.

93. A method according to any one of claims 83 to 92, wherein the dressing is a biodegradable polymer.

94. A method according to any one of claims 83 to 93, wherein the dressing is a dissolvable polymer.

95. 95. The method of any one of claims 83 to 94, comprising one or more additional additives comprising a penetration enhancer, tissue adhesive, anti-adhesive agent, or plasticizer.

96. A method according to any one of claims 83 to 95, wherein the dressing comprises a composite material.

97. 84. The method of claim 83, wherein the dressing is a fabric material.

98. 98. The method of claim 97, wherein the fabric material comprises natural fibers, synthetic fibers, cellulosic, woven or nonwoven materials, or mixtures thereof.

99. 84. The method of claim 83, wherein the infection is caused by a gram-positive bacterium, a gram-negative bacterium, a fungus, a virus, an amoeba, or a combination of infectious species thereof, or by biofilm formation.

100. 84. The method of claim 83, wherein the infection is a chronic wound.

101. 84. The method of claim 83, wherein the infection is caused by biofilm formation.

102. 84. The method of claim 83, wherein the dressing is useful for covering a wound or exposed skin.

103. 103. The method of claim 102, wherein the wound is or is caused by an infection, a burn, exposed skin, an open wound, a skin laceration, an abrasion, a puncture, an abruption, a scab, a surgical wound, an abscess, a skin tear, a skin ulcer or lesion, damaged tissue, a bite, a moisture-related skin injury, a foot ulcer, necrosis, a compromised skin graft or flap, an acute wound, a chronic wound, trauma, diabetes, a pressure ulcer, a venous ulcer, an arterial wound, a neuropathic ulcer, a diabetic ulcer, a leg ulcer, a skin tear, a moisture-related skin injury (MASD), and other skin exposure-related injuries.

104. A compound of the formula: 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 (In the formula, a is 1, 2, 3, 4, 5, 6, 7, or 8; y is 0, 1, 2, 3, or 4; p and q are each independently selected from 1, 2, 3, and 4; R １ are each independently C ６ ~C ２２ Alkyl (and C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (It is possible that ６ ~C ２２ Alkenyl (and C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ ), and C ６ ~C ２２ Alkanoyl (and C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (which can be Each R ２１ are independently １ ~C ２２ Alkyl (and C １ , C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (It is possible that ２ ~C ２２ Alkenyl (and C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (It is possible that ２ ~C ２２ Alkanoyl (and C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ and -alkyl-aryl, R ２１ is optionally substituted with 1, 2, or 3 substituents, the substituents being independently selected from the group consisting of: １ ~C ６ Alkyl, halogen, and 【Chemistry 10】 is selected from R ２２ , R ２３ , and R ２４ are each independently 【Chemistry 11】 is selected from R ２５ are each independently R ２２ , R １７ , and C ２ ~C １０ Alkanoic acid (which is C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ , or C １０ wherein the acid is optionally a diacid or a salt thereof; R ３１ is C ６ ~C ２２ Alkyl (and C ６ , C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (It is possible that ６ ~C ２２ Alkenyl (and C ６ , C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (It is possible that ６ ~C ２２ Alkynyl (and C ６ , C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ ), and C ６ ~C ２２ Alkenylalkynyl (and C ６ , C ７ , C ８ , C ９ , C １０ , C １１ , C １２ , C １３ , C １４ , C １５ , C １６ , C １７ , C １８ , C １９ , C ２０ , C ２１ , or C ２２ (which can be Each R ３２ are independently hydrogen, 【Chemistry 12】 is selected from R ３３ are each independently hydroxyl, hydrogen, C １ ~C ６ alkyl, and halogen; R ３４ and R ３５ are each independently 【Chemistry 13】 , R ２２ , and R １７ is selected from Each R ３６ are independently hydrogen, 【Chemistry 14】 is selected from X １ are each independently NR １７ , C.H. ２ , CHOH, and C(O); X ２ are each independently C １ ~C ３ Alkyl, and C １ ~C ３ hydroxyalkyl; X ３ are each independently hydroxyl, NO ２ , N(R ７ ) ２ , C.H. ２ OR ７ , CON(R ７ ) ２ , COOR ７ , C(O)R ７ , C １ ~C １２ Alkanoic acid, C １ ~C ８ Alkyl, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ selected from alkanoyl, heterocyclyl, heteroaryl, and aryl; X ４ are each independently X ３ is selected from X ５ is selected from heterocycle, cycloalkyl, alkyl, aryl, heteroaryl, alkenyl, haloalkyl, and alkynyl; R ６ is independently selected from hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl, each of said alkyl, aryl, cycloalkyl, and heterocyclyl optionally being selected from C １ ~C ６ Alkyl, hydroxyl, chloro, bromo, iodo, fluoro, N(R ７ ) ２ , COOR ７ , C(O)R ７ , C.H. ２ OR ７ , CON(R ７ ) ２ , and NO ２ and having a substituent selected from R ７ are each independently hydrogen, C １ ~C ８ Alkyl, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl, and aryl; R ８ , R ９ , R １０ , R １１ , R １２ , and R １３ are each independently hydrogen, halogen, hydroxyl, N(R ７ ) ２ , C.H. ２ OR ７ , CON(R ７ ) ２ , COOR ７ , C(O)R ７ , C １ ~C ８ Alkyl, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ selected from alkanoyl, heterocyclyl, heteroaryl, and aryl; R １７ are each independently hydrogen, C １ ~C ８ Hydroxyalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ selected from alkanoyl, heterocyclyl, heteroaryl, heterocycloalkyl, and aryl; X － is an anion, for example, chloride, fluoride, iodide, bromide, hydroxide, chlorite, chlorate, formate, acetate, lactate, benzoate, or salicylate; and B ＋ is a cation, for example, ammonium, potassium, or sodium, o is 1 or 2; n is independently selected from 0, 1, and 2; each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22; Q is -CR １０４ R １０４ - and R １０１ and R １０２ are both hydrogen or In an alternative embodiment, R １０１ and R １０２ are each independently selected from hydrogen and ethyl; R １０３ are each independently 【Chemistry 15】 is selected from Each R １０４ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, and haloalkyl; R １０５ is hydrogen or -CH ２ CH ２ OH, R １０６ are each independently hydrogen, hydroxy, and C １ ~C ６ alkoxy; R １０７ and R １０８ are each independently C １ ~C ６ alkyl, R Ａ teeth, 【Chemistry 16】 and Each A is independently 【Chemistry 17】 is selected from p' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; q', r, and s are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X is [Chemistry 18] is selected from M is selected from hydrogen, sodium, potassium, cesium, or lithium; t is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each Z is independently 【Chemistry 19】 is selected from Each L is independently 【Chemistry 20】 is selected from R １２４ and R １２５ are each independently hydrogen, ethyl, 【Chemistry 21】 is selected from T is a monovalent capping group, which can optionally be derived from a curing agent; The hardening agent can be any pharmaceutically acceptable compound; X － is an anion, and X － However, for anions with two or more negative charges, the charge stoichiometry must be neutralized by other cations).

105. Compounds formed by reacting a quaternary ammonium compound of formula A with one or more compounds of formula B, C, D, E, F, G, H, J, K, L, or M: 【Chemistry 22】 (In the formula, Q is -CR １０４ R １０４ - and X is 【Chemistry 23】 is selected from M is selected from hydrogen, sodium, potassium, cesium, or lithium; each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22; n is independently selected from 0, 1, and 2; o is 1 or 2; R １０４ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, and haloalkyl; R １０６ are each independently hydrogen, hydroxy, and C １ ~C ６ alkoxy; R １０７ and R １０８ are each independently C １ ~C ６ alkyl, Each R １０９ are each independently selected from halo, hydroxyl, and alkoxy; X － is an anion, and X － However, for anions with two or more negative charges, the charge stoichiometry must be neutralized by other cations).

106. 106. A pharmaceutical composition comprising a compound of claim 104 or 105, and optionally a pharmaceutically acceptable carrier.

107. 107. A compound of claim 104 or 105 or a pharmaceutical composition of claim 106 for use in treating an infection in a host, wherein the infection is of the eye, ear, skin, or nail.

108. A method for treating a localized infection in a host in need thereof, said treatment comprising administering to said host in need thereof an effective amount of a compound of claim 104 or 105.

109. A method for manufacturing a medicament for therapeutic use in treating a topical infection, said treatment comprising administering to a host in need of said treatment an effective amount of a compound of claim 104 or 105.

110. 106. A method of treating a dermatological disorder in a host, said treatment comprising administering to a host in need of said treatment an effective amount of a compound of claim 104 or 105.

111. A method for the manufacture of a medicament for the therapeutic treatment of a dermatological disorder, said treatment comprising administering to a host in need of said treatment an effective amount of a compound of claim 104 or 105.

112. 106. An antibacterial composition for treating an infection in a host in need thereof, comprising an effective amount of a compound of claim 104 or 105 in combination with one or more of glycerol, glycerol-propylene oxide copolymer, solketal, glycidol, or epichlorohydrin, optionally with the addition of another pharmaceutically acceptable excipient.

113. A method of treating an infection in a host in need thereof, comprising: a) applying a dressing comprising the antimicrobial composition of claim 112 to the site of infection, wherein the dressing releases one or more compounds of claim 104 or 105 to the site of infection in the host; and b) covering the wound, infection, or exposed skin with the dressing.

114. 106. Use of a product formed by reacting a compound of claim 104 or 105 with one or more compounds selected from glycerol, glycerol-propylene oxide copolymer, solketal, glycidol, or epichlorohydrin in the manufacture of a medicament for the treatment of a bacterial, fungal, or viral infection, or a combination thereof.

115. 106. A method of disinfecting a surface, comprising applying to said surface a compound according to any one of claims 1 to 21, 104 or 105, or a mixture thereof.

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