Compositions and uses of locally applied synthetic cationic and hydrophobic amino acid block copolymers, for prevention and treatment of bacterial and fungal infections

Abstract

Antimicrobial pharmaceutical compositions that contain synthetic cationic and hydrophobic amino acid block copolymer antimicrobials, and methods of using them to prevent and / or treat colonisation, overgrowth, or infection by bacteria, fungi, or a combination thereof. Exemplary pharmaceutical composition include a synthethic cationic and hydrophobic amino acid block copolymer comprising of lysine and leucine.

Description

AMIC.006WO PATENT COMPOSITIONS AND USES OF LOCALLY APPLIED SYNTHETIC CATIONIC AMINO ACID POLYMERS FOR PREVENTION AND TREATMENT OF BACTERIAL AND FUNGAL INFECTIONS INCORPORATION BY REFERENCE TO PRIORITY APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 694,463, filed September 13, 2024, which is hereby incorporated herein by reference in its entirety. BACKGROUND Field

[0002] This disclosure relates to antimicrobial pharmaceutical compositions that contain cationic antimicrobials and methods of using them to prevent and / or colonization, overgrowth, or infection by bacteria, fungi, or both. Description

[0003] A wide variety of cationic antimicrobials are known for their ability to bind to and disrupt microbial membranes, including certain antibiotics, bisbiguanides, polymer biguanides, quaternary ammonium compounds, natural antimicrobial peptides, and synthetic cationic polypeptides. A number of publications disclose biological properties of synthetic peptides, including WO 2016 / 044683, US 2015 / 0225458 and U.S. Patent Nos. 7,847,059; 8,088,888; 8,350,003; and 8,470,769.

[0004] US Patent No. 9,017,730 describes synthetic cationic copolypeptides containing varying ratios of cationic amino acid recurring units (such as lysine (K)) and hydrophobic amino acid units (such as leucine (L), isoleucine (l), valine (V), phenylalanine (F) or alanine (A)). US Patent No.9,017,730 indicates that poly(L-hydrophilic amino acid-HCl)55- block-poly(hydrophobic amino acid)20, X55(rac-Y)20(for X= K or RH; Y= racemic L, racemic L / F, or enantiopure L), at very low concentration (100 ^g / ml), achieved maximum observable (5-log) reduction of yeast counts for Candida albicans (ATCC 10231). US Patent No. 9,017,730 indicates that selected copolypeptides were also shown to be quite effective against a variety of bacteria, including S. aureus, P. aeruginosa, and E. coli O157:H7, as well as other food-borne pathogens, and even against certain endospore forms of microbes. US Patent No.9,017,730 indicates that certain microbial organisms (e.g., P. acnes) may be less sensitive to certain copolypeptides than other microorganisms (e.g., S. aureus). US Patent No. 9,017,730 indicates that certain solution phase copolypeptides demonstrated antiviral activity against Influenza A virus, with RH / K (partially guanylated lysine) diblock copolypeptide being particularly active.

[0005] U.S. Patent No.9,446,090 describes synthetic cationic polypeptide(s) along with mutually water-miscible mixtures that contain such a polypeptide and a second pharmaceutically acceptable polymer. Specific examples describe antimicrobial activity against certain bacteria using particular mixtures of synthetic cationic polypeptide(s) with second polymers such as polyethylene glycol (PEG), hydroxyethylcellulose (HEC), and Poloxamer 407.

[0006] U.S. Patent No. 11,285,189 describes the development of cationic antimicrobial pharmaceutical compositions and methods of use that allow local applications in vivo of doses that provide antimicrobial effectiveness with low risk of local tissue toxicities and / or low risk of systemic / distant organ toxicities. U.S. Patent No.11,285,189 indicates that various embodiments of the cationic antimicrobial pharmaceutical compositions have excellent antimicrobial and safety profiles as demonstrated by successful intraperitoneal application.

[0007] While U.S. Patent Nos. 9,017,730, 9,446,090, and 11,285,189 describe significant advances in the art, a number of challenges remain, particularly with respect to developing pharmaceutically acceptable preparations of locally applied cationic polymers for treating fungal colonization, overgrowth, and infection. SUMMARY

[0008] In a first aspect of the present disclosure, provided herein is a method of preventing or treating fungal colonization, overgrowth, or infection, comprising: topical administration of an effective amount of an antimicrobial pharmaceutical composition to a subject in need thereof, wherein: the antimicrobial pharmaceutical composition comprises: a synthetic cationic amino acid polymer comprising at least 40 amino acid units; wherein the synthetic cationic polymer comprises a blocky sequence arrangement of a segment comprising a plurality of positively charged amino acid units and a segment of a plurality of hydrophobicamino acid units; wherein the segment comprising a plurality of positively charged amino acid units has at least twice the number of amino acid units as the segment comprising a plurality of hydrophobic amino acid units.

[0009] In another aspect of the present disclosure, provided herein is an antimicrobial pharmaceutical composition for preventing or treating fungal colonization, overgrowth, or infection, comprising: an synthetic cationic amino acid polymer comprising at least 40 amino acid units; wherein the synthetic cationic polymer comprises a blocky sequence arrangement of a segment comprising a plurality of positively charged amino acid units and a segment of a plurality of hydrophobic amino acid units; wherein the segment comprising a plurality of positively charged amino acid units has at least twice the number of amino acid units as the segment comprising a plurality of hydrophobic amino acid units. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGURE 1 is a graphical representation of additives that further increase foaming of compositions comprising poly(L-lysine hydrochloride)-b-poly(D,L-leucine) polymers.

[0011] FIGURE 2 is a graphical representation of surfactants that further increase foaming of compositions comprising poly(L-lysine hydrochloride)-b-poly(D,L-leucine) polymers and hydroxyethyl cellulose (HEC).

[0012] FIGURE 3 shows additional components that increase viscosity of poly(L- lysine hydrochloride)-b-poly(D,L-leucine) polymer formulations at a concentration of 1 mg / mL.

[0013] FIGURE 4 shows additional components that improve retention of poly(L- lysine hydrochloride)-b-poly(D,L-leucine) polymer formulations at a concentration of 1 mg / mL on tissue mimic.

[0014] FIGURE 5 shows antimicrobial activity of compositions containing poly(L- lysine hydrochloride)-b-poly(D,L-leucine) polymer alone and in combination with nonionic surfactants against S. epidermidis.

[0015] FIGURE 6 shows antimicrobial activity of compositions containing poly(L- lysine hydrochloride)-b-poly(D,L-leucine) polymer alone and in combination with nonionic surfactants against E. coli.

[0016] FIGURE 7 shows antimicrobial activity of compositions containing poly(L- lysine hydrochloride)-b-poly(D,L-leucine) polymer alone and in combination with hydroxyethyl cellulose and polyvinyl alcohol additives against S. epidermidis.

[0017] FIGURE 8 shows antimicrobial activity of compositions containing poly(L- lysine hydrochloride)-b-poly(D,L-leucine) polymer alone and in combination with hydroxyethyl cellulose and polyvinyl alcohol additives against E. coli.

[0018] FIGURE 9 shows antimicrobial activity of compositions containing poly(L-lysine hydrochloride)-b-poly(D,L-leucine) polymer alone and in combination with hydroxyethyl cellulose, polyethylene glycol, glycerol, and / or Kolliphor HS15against S. epidermidis.

[0019] FIGURE 10 showsantimicrobial activity of compositions containing poly(L-lysine hydrochloride)-b-poly(D,L-leucine) polymer alone and in combination with hydroxyethyl cellulose, polyethylene glycol, glycerol, and / or Kolliphor HS15 against E. coli.

[0020] FIGURE 11 shows antimicrobial activity of compositions containing poly(L-lysine hydrochloride)-b-poly(D,L-leucine) polymer alone and in combination with hydroxyethyl cellulose, polyethylene glycol, glycerol, and / or Kolliphor HS15 against S. epidermidis.

[0021] FIGURE 12 shows antimicrobial activity of compositions containing poly(L-lysine hydrochloride)-b-poly(D,L-leucine) polymer alone and in combination with hydroxyethyl cellulose, polyethylene glycol, glycerol, and / or Kolliphor HS15 against E. coli.

[0022] FIGURE 13 shows antimicrobial activity of compositions containing poly(L-lysine hydrochloride)-b-poly(D,L-leucine) alone (Amicidin-beta), or in combination with hydroxyethyl cellulose and polyvinyl alcohol (PVA) in a rat closed wound model. These data indicate that formulation of antimicrobial cationic polymers with other polymers like hydroxyethyl cellulose and polyvinyl alcohol can enhance performance in vivo.

[0023] FIGURE 14 shows no dermal sensitization for poly(L-lysine hydrochloride)-b-poly(D,L-leucine) viscous solutions containing HEC and PVA in rabbits.

[0024] FIGURE 15 shows no dermal sensitization for poly(L-lysine hydrochloride)-b-poly(D,L-leucine) viscous solutions containing HEC and PVA in guinea pigs.

[0025] FIGURE 16 shows similar uterine tissue histopathology to controls for poly(L-lysine hydrochloride)-b-poly(D,L-leucine) foams containing HEC and HEC + PVA in locally-treated porcine surgical models.

[0026] FIGURE 17 shows no test article histopathology findings for esophagus or tongue after rats drank water containing poly(L-lysine hydrochloride)-b-poly(D,L-leucine) for five days.

[0027] FIGURE 18 shows heat stability of powder formulations comprising poly(L-lysine hydrochloride)-b-poly(L-leucine). Panel (A) shows various binary formulations showed no qualitative differences following heat treatment for 10 minutes at 100°C. Panel (B) shows poly(L-lysine hydrochloride)-b-poly(L-leucine) powder formulations retain gelling properties after being heated for 10 minutes at 100°C.

[0028] FIGURE 19 shows physical properties of powder formulations comprising poly(L-lysine hydrochloride)-b-poly(L-leucine) and various celluloses. The yellow color observed with HEC is an artifact of non-pharmaceutical grade material used in this initial test. Subsequent tests with hydroxyethyl cellulose utilized pharmaceutical-grade material and showed minimal discoloration.

[0029] FIGURE 20 shows physical properties of powder formulations comprising poly(L-lysine hydrochloride)-b-poly(L-leucine) and various hemostatic agents.

[0030] FIGURE 21 shows the appearance of hydrated poly(L-lysine hydrochloride)-b-poly(L-leucine) powder formulations with HEC and mannitol. The ratio of powder to water is 1:3.

[0031] FIGURE 22 shows the appearance of hydrated poly(L-lysine hydrochloride)-b-poly(L-leucine) powder formulations with HEC and polyvinyl pyrrolidone (PVP). The ratio of powder to water is 1:3.

[0032] FIGURE 23 shows the appearance of hydrated poly(L-lysine hydrochloride)-b-poly(L-leucine) powder formulations with HEC, mannitol, and / or kaolin. The ratio of powder to water is 1:3.

[0033] FIGURE 24 graphically depicts the hydration capacity of poly(L-lysine hydrochloride)-b-poly(L-leucine) (i.e., Amicidin alpha) powder formulations with various celluloses.

[0034] FIGURE 25 graphically depicts the hydration capacity of poly(L-lysine hydrochloride)-b-poly(L-leucine) (i.e., Amicidin alpha) powder formulations with hydroxyethyl cellulose, mannitol, and / or kaolin.

[0035] FIGURE 26 shows images of tissue retention of poly(L-lysine hydrochloride)-b-poly(L-leucine) powder formulations with hydroxyethyl cellulose.

[0036] FIGURE 27 shows tissue retention of hydrated poly(L-lysine hydrochloride)-b-poly(L-leucine) powder formulations with hydroxyethyl cellulose on tissue mimic.

[0037] FIGURE 28 shows antimicrobial activity of compositions containing poly(L-lysine hydrochloride)-b-poly(L-leucine) alone and in combination with kaolin, povidone, mannitol, or hydroxyethyl cellulose

[0038] FIGURE 29 shows antimicrobial activity of hydroxyethyl cellulose alone, poly(L-lysine hydrochloride)-b-poly(L-leucine) polymer alone, and the combination thereof.

[0039] FIGURE 30 shows antimicrobial activity of compositions containing poly(L-lysine hydrochloride)-b-poly(L-leucine) alone (Amicidin-alpha Surgical), or in a powder formulation with hydroxyethyl cellulose (Amicidin-alpha PFC) in a porcine incision model. These data indicate that formulation of antimicrobial cationic polymers with other polymers like hydroxyethyl cellulose can enhance performance in vivo.

[0040] FIGURE 31 shows similar histopathology in 72 hour porcine incision models. Persistence of poly(L-lysine hydrochloride)-b-poly(L-leucine) powder formulation with hydroxyethyl cellulose (Amicidin-alpha PFC) (amorphous material) is observed.

[0041] FIGURE 32 shows the effect of poly(L-lysine hydrochloride)-b-poly(L- leucine) powder formulation with hydroxyethyl cellulose (Amicidin-alpha PFC) in deep porcine wound to damaged bone. No observed adverse effect level (NOAEL) was observed at the highest dose in the study. DETAILED DESCRIPTION

[0042] Fungal colonization, overgrowth, and infection of tissues, including skin, skin structures, and mucosa (e.g., oral cavity, vaginal cavity) can be quite difficult to prevent and treat. Various fungi, including, but not limited to, yeast forms like Candida and Malassezia, are well-adapted to live on human skin and skin structures (e.g., hair follicles), aswell as mucosal surfaces. Their ability to utilize available elements as food sources provides them with competitive advantages and may help determine preferred body regions for colonization, overgrowth, or infection. By example, Malassezia are known to play a role in the development of tinea versicolor or pityriasis versicolor (commonly seen on chest and shoulders), fungal acne or pityrosporum folliculitis (commonly seen on face), and dandruff or seborrheic dermatitis (commonly seen on scalp). This regional predilection is thought to occur, at least in part, because these areas tend to be more “oily”.

[0043] Of note, Candida spp. cause a large number and variety of diseases, some of which can be life-threatening. It is important to recognize that infection is a progression that is best stopped early. It begins with simple contamination or colonization of vulnerable tissue surfaces, including mucosal surfaces, such as those found in the oral cavity, esophagus, and vaginal cavity. This can be followed by tissue invasion, which causes focal infection. Well- known diseases include oral thrush, esophageal candidiasis, and candidal vaginosis. Further, if these diseases are unchecked locally, systemic invasion can follow, resulting in disseminated disease that can lead to sepsis and death. These challenges are becoming more and more difficult to handle with the emergence of resistant Candida albicans and particularly with the emergence and international spread of Candida auris.

[0044] Here, we describe compositions and uses of locally applied synthetic cationic amino acid polymers that are designed to directly kill or inhibit the growth of fungi when topically applied to tissues, including skin and mucosal surfaces. Targeted applications would be to areas that are known or suspected to have fungal colonization, overgrowth, or infection. Such compositions may also include one or more other active or inactive ingredients that can act directly or indirectly help address the condition. Of particular importance is that the synthetic cationic amino acid polymers and the compositions be safe enough for topical application at effective doses, which may involve high concentrations and / or repeat applications.

[0045] This may be achieved through compositions and uses of synthetic cationic amino acid polymers that have a direct antifungal mode of action, as well as a physical mode of action (e.g., barrier or surfactant). Specific embodiments are designed to optimize effectiveness and safety of topical applications to skin and mucosal surfaces. These may include:1.

[0046] Use of a synthetic cationic amino acid polymer that has been shown to be safe when applied topically to skin, as well as to mucosal surfaces. 2.

[0047] Combination of synthetic cationic amino acid polymers with other active ingredients that work to kill or inhibit the growth of fungi. Typical examples would include the azole antifungal compounds (e.g., clotrimazole, ketoconazole, metronidazole), allylamine antifungals (e.g., naftifine, terbinafine), zinc pyrithione, and selenium sulfide. 3.

[0048] Combination of synthetic cationic amino acid polymer(s) with other ingredients (e.g., cellulose) that can increase viscosity and retention time on the surface of tissues. 4.

[0049] Combination of synthetic cationic amino acid polymer(s) with other ingredients (e.g., cellulose, surfactants) that can increase foam formation to better fill cavities, such as the vaginal canal. 5.

[0050] Decreasing or disruption of fungal food sources, especially skin oils. This may be due to the synthetic cationic amino acid polymer(s), other active ingredients, or combinations thereof. Further, it may be achieved by providing an oil or emulsion that competes with skin oil and is a poor source of nutrition for fungi. 6.

[0051] Decreasing tissue responses and symptoms, such as itching and inflammation. This may be achieved with composition elements ranging from antihistamines to steroids to capsaicin. 7.

[0052] Supporting cellular health, including melanin formation by melanocytes, with components of the composition, such as vitamins (e.g., A, C, D, E), minerals (e.g., magnesium), and antioxidants (e.g. coenzyme Q10). Definitions

[0053] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0054] As used herein in the context of describing synthetic cationic polymers, the term “antimicrobial” has its usual meaning as understood by those skilled in the art and thus includes a polymer that kills, or inhibits the growth of, any microbial organism, including, but not limited to, Gram-positive bacteria, Gram-negative bacteria, and fungal organisms (e.g., Candida, Malassezia, Cryptococcus, various dermatophytes). Criteria for demonstrating antimicrobial activity include statistically significant lower colony forming units with at least a one log10reduction at a defined time point between 10 minutes and 72 hours in preparations of test article-treated microbial organisms versus control-treated organisms.

[0055] As used herein in the context of describing synthetic cationic polymers with antifungal properties, the term “antifungal” has its usual meaning as understood by those skilled in the art, and thus includes a polymer that kills, or inhibits the growth of, any fungal organism, including but not limited to Candida, Malassezia, Cryptococcus, and various dermatophytes. Criteria for demonstrating antifungal activity include statistically significant lower colony forming units with at least a one log10reduction at a defined time point between 10 minutes and 4 weeks in preparations of test article-treated microbial organisms versus control-treated organisms.

[0056] As used herein in the context of describing synthetic cationic amino acid polymers, the term “amino acid polymer” has its usual meaning as understood by those skilled in the art and thus includes a polymer that comprises two or more amino acid recurring units (also referred to as amino acid residues, or more simply units or residues) linked together by peptide bonds. A copolymer is a type of polymer that comprises two or more different amino acid recurring units. Molecular weights of polymers are weight average as determined by size exclusion chromatography (SEC) with molecular weight standards or using light scattering detection.

[0057] The term “block” or “blocky” amino acid copolymer has its usual meaning as understood by those skilled in the art and thus includes a sequence arrangement of amino acid units that includes a segment (“block”) or segments that is at least 10 amino acid units in length in which the amino acid copolymer is relatively enriched in one or more of the amino acid units as compared to overall composition of the copolymer. In general, synthetic block copolymers have a sequence arrangement that reflects deliberate control over the copolymerization process. Likewise, the term “random” amino acid copolymer has its usualmeaning as understood by those skilled in the art and thus includes a sequence arrangement of amino acid units that is a statistical distribution reflecting the concentration of the corresponding amino acid monomers in the polymerization mixture.

[0058] As used herein in the context of describing synthetic cationic block copolymers, the term “hydrophilic” block has its usual meaning as understood by those skilled in the art and thus includes a sequence arrangement in which a block or segment contains a plurality of hydrophilic amino acid units. Examples of hydrophilic amino acid units are known to those skilled in the art and include serine (S), threonine (T), aspartic acid (D) and glutamic acid (E), as well as the positively charged amino acids lysine (K), arginine (R), histidine (H) and ornithine (O). Likewise, the term “hydrophobic” block has its usual meaning as understood by those skilled in the art and thus includes a sequence arrangement in which a block or segment contains a plurality of hydrophobic amino acid units. Examples of hydrophobic amino acid units are known to those skilled in the art and include glycine (G), leucine (L), isoleucine (I), valine (V), proline (P), tryptophan (W), cysteine (C), methionine (M), phenylalanine (F) and alanine (A).

[0059] As used herein in the context of describing synthetic cationic polymers, the terms “positively charged” and “cationic” have their usual meanings as understood by those skilled in the art and thus includes an amino acid unit or a polymer that is positively charged at neutral pH. Examples of amino acid units that are positively charged at neutral pH include lysine, arginine, histidine and ornithine, and thus the presence of one or more of these positively charged units in the polymer (in an amount in excess of any anionic units) can render the polypeptide cationic.

[0060] As used herein in the context of describing a self-assembling polymer, the term “self-assembling” has its usual meaning as understood by those skilled in the art and thus includes configurations of the polymers when dispersed in a medium (such as the other ingredients of a pharmaceutical composition) in which intermolecular attractive forces between certain segments or blocks of the polymer causes those segments or blocks to loosely bind to one another. For example, as noted in US Patent No.9,017,730, self-assembly of block cationic copolypeptides was observed in aqueous solution, resulting in various hierarchical structures that depended on the configuration of the hydrophobic domains and their effect on attractive intermolecular interactions between the polymer chains. In contrast, US Patent No.9,017,730 indicates that random copolypeptides did not exhibit self-assembly. Those skilled in the art are aware of various techniques for determining whether a synthetic cationic polymer is self-assembling (see, e.g., US Patent No. 9,017,730). As compared to an otherwise comparable synthetic cationic polymer that exhibits random arrangements in dilute solution and does not exhibit self-assembly, a self-assembling synthetic cationic polymer generally exhibits a higher viscosity.

[0061] As used herein in the context of describing a molecular feature or parameter that promotes self-assembly of polymers, terms such as “promotes” and “promoting” have their usual meaning as understood by those skilled in the art and thus include allowing or enhancing such self-assembly. For example, U.S. Patent Nos. 9,017,730 and 9,446,090 describe various sequence arrangements of hydrophobic amino acid units and hydrophilic amino acid units that are configured to promote self-assembly of a copolypeptide in water. Similarly, a sterilization technique that is configured to produce a sterilization state that promotes self-assembly of a polymer is one that allows for self-assembly or enhances self- assembly when applied to such a polymer or to a composition of a polymer that is dispersed within an aqueous carrier. Likewise, a composition of an aqueous carrier that is selected to promote self-assembly of a polymer is one that allows for self-assembly or enhances self- assembly when such a polymer is dispersed within the aqueous carrier.

[0062] As used herein in the context of describing a self-assembling synthetic cationic amino acid block copolymers in comparison to an otherwise comparable random synthetic cationic amino acid copolymer, the term “otherwise comparable random synthetic cationic amino acid copolymer” has its usual meaning as understood by those skilled in the art and thus includes amino acid copolymers that have approximately the same molecular weight and relative numbers of the same hydrophobic and hydrophilic amino acid recurring units as the self-assembling synthetic cationic amino acid block copolymer, except the sequence arrangement of those amino acid recurring units in the comparable copolymer is random rather than block. For example, with respect to a self-assembling amino acid block copolymer having a hydrophilic (positively charged) lysine block with an average length of about 120 units and a hydrophobic leucine block with an average length of about 30 units, an otherwise comparable random synthetic cationic amino acid copolymer is one containing an average of about 120 lysine units and about 30 leucine units per copolymer chain except that the sequencearrangement of those units along the chain of the random copolymer is a statistical distribution reflecting the concentration of the lysine and leucine monomers in the polymerization mixture.

[0063] As used herein in the context of describing the administration of an antifungal pharmaceutical composition to a site on a mammalian body in an abundant amount effective to at least partially prevent and / or treat fungal colonization, overgrowth, or infection, the terms “abundant” and “abundance” have their usual meaning as understood by those skilled in the art and thus include the administration of amounts of the copolymer that are at least 2 times greater than the dosage needed to achieve the desired prevention and / or treatment effect. Typically, a total treatment dose of antifungal pharmaceutical composition that includes the administration of 1 g of synthetic cationic polymer(s) or more for a 70 kg person, which represents 14.3 mg / kg, is considered to be an abundant administration. Those skilled in the art recognize that biologically active compounds are generally administered in a “therapeutic window” that includes a range of doses over which a desired therapeutic response is achieved without causing significant adverse effects in the subjects to which they are administered. This dosage range is generally between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC) and is typically determined in advance for each biologically active compound, and communicated to the subject and / or caregiver in the form of a dosage recommendation. However, in some situations, such as topical application of an antifungal composition to bodily orifices and / or open wounds of mammalian subjects, it may be impractical to determine the MEC and thus highly advantageous to have the flexibility to administer the antifungal in abundance. For example, when treating an open wound in an emergency setting where time may be of the essence, it is highly advantageous for a caregiver to have the flexibility to apply the antifungal to the open wound in abundance (e.g., in an amount at least ten times greater than the MEC) without being concerned about administering an amount that exceeds the MTC. The MEC for a particular sterilized antifungal pharmaceutical composition can be determined by methods known to those skilled in the art, such as those described in the examples below (e.g., amount effective to achieve 3-log CFU killing in an in vitro time-kill assay).

[0064] As used herein in the context of describing an antifungal pharmaceutical composition that comprise or consist of an aqueous carrier and an antimicrobial synthetic cationic polymer(s) that is dispersed in the aqueous carrier, the term “aqueous carrier” has itsusual meaning as understood by those skilled in the art and thus includes various water-based carrier systems that can optionally contain a dispersed substance such as an ionic additive (e.g., a salt) or a non-ionic additive (e.g., polymer, alcohol, sugar and / or surfactant). Substances that are dispersed in the aqueous carrier may be dissolved therein and / or dispersed in the form of small particles.

[0065] As used herein in the context of antifungal pharmaceutical compositions or other materials having antifungal activity, the term “antifungal” has its usual meaning as understood by those skilled in the art and thus includes an effect of the presence of the antifungal pharmaceutical composition or other material that inhibits production of fungal organisms, typically by directly killing or inhibiting the growth of these organisms. In certain embodiments, the antifungal pharmaceutical composition is an antifungal composition that has antifungal activity against multiple different fungi, e.g., against Candida albicans, Candida auris, Cryptococcus spp. and / or Malassezia spp.

[0066] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Antifungal pharmaceutical compositions

[0067] Various embodiments provide antimicrobial pharmaceutical compositions with activity against bacteria, fungi, or both that comprise or consist of an aqueous carrier and an synthetic cationic polypeptide that has antimicrobial activity against bacteria, fungi, or both dispersed in the aqueous carrier. The amount of cationic polypeptide dispersed in the aqueous carrier can vary over a broad range that depends primarily on the desired viscosity of the antimicrobial pharmaceutical composition. For example, in various embodiments the amount of synthetic cationic polypeptide in the antimicrobial pharmaceutical composition is in the range of about 0.001% to about 10%, by weight based on total weight of the antimicrobial pharmaceutical composition. In some embodiments the amount of synthetic cationicpolypeptide dispersed in the aqueous carrier is in the range of about 0.01% to about 5%, by weight based on total weight of the antimicrobial pharmaceutical composition.

[0068] In various embodiments the synthetic cationic polypeptide that is dispersed in the aqueous carrier comprises a plurality of positively charged amino acid units (at neutral pH). In an embodiment, the synthetic cationic polypeptide comprises at least 40 amino acid units, of which at least some are positively charged. In some embodiments, the synthetic cationic polypeptide comprises at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acid units, of which at least some are positively charged. In an embodiment, the number of positively charged amino acid units in the synthetic cationic polypeptide is at least 10, at least 15, at least 20, at least 25, or at least 30. Lysine, arginine, histidine and combinations thereof are examples of suitable amino acid units that are positively charged at neutral pH. In an embodiment, the plurality of positively charged amino acid units in the synthetic cationic polypeptide comprises positively charged lysine units.

[0069] In various embodiments, the synthetic cationic polypeptide has a viscosity of 2 centistokes (cSt) or greater, as measured at a concentration of 2 wt% in deionized water and at a temperature of 37°C. Suitable synthetic cationic polypeptide having a range of higher and lower viscosities (e.g., from about 1.5 cSt to about 16,000 cSt, or about 2.0 cSt to about 16,000 cSt) can be made by adjusting the molecular weight of the polypeptide, the level of positively charged amino acid units, and / or the degree to which the polypeptide self-assembles. In an embodiment, the synthetic cationic polypeptide has a viscosity that is greater than that of bovine serum albumin, as measured at a concentration of 2 wt% in deionized water and at a temperature of 37°C.

[0070] In an embodiment, the aqueous carrier, containing the antimicrobial synthetic cationic polypeptide at 2 wt%, has a viscosity at 37°C that is greater than that of the aqueous carrier containing albumin at 2 wt% in place of the antimicrobial synthetic cationic polypeptide. In an embodiment, the aqueous carrier, containing the antimicrobial synthetic cationic polypeptide at 2 wt%, has a viscosity at 37°C that is at least about 20% greater than that of the aqueous carrier containing albumin at 2 wt% in place of the antimicrobial synthetic cationic polypeptide. In an embodiment, the aqueous carrier, containing the antimicrobial synthetic cationic polypeptide at 2 wt%, has a viscosity at 37°C that is at least about 50% greater than that of the aqueous carrier containing albumin at 2 wt% in place of theantimicrobial synthetic cationic polypeptide. In an embodiment, the aqueous carrier, containing the antimicrobial synthetic cationic polypeptide at 2 wt%, has a viscosity at 37°C that is at least about 100% greater than that of the aqueous carrier containing albumin at 2 wt% in place of the antimicrobial synthetic cationic polypeptide. In an embodiment, the aqueous carrier, containing the antimicrobial synthetic cationic polypeptide at 2 wt%, has a viscosity at 37°C that is at least about any one or more of the following values: 3 cSt, 5 cSt, 10 cSt, 25 cSt, 50 cSt, or 100 cSt, or that is within a range defined by endpoints having any two of the aforementioned values.

[0071] Synthetic cationic polypeptides with antimicrobial activity against bacteria, fungi, or both, can be copolypeptides that comprise other monomer units in addition to the positively charged amino acid units. For example, in various embodiments the antimicrobial synthetic cationic polypeptide may further comprise a plurality of hydrophobic amino acid units. In various embodiments, the number of hydrophobic amino acid units in the cationic copolypeptide is at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30. Examples of suitable hydrophobic amino acid units include leucine (L), isoleucine (l), valine (V), phenylalanine (F), alanine (A), and combinations thereof. In an embodiment, the plurality of hydrophobic amino acid units in the synthetic cationic polypeptide comprises leucine units.

[0072] The sequence arrangement of amino acid units in the synthetic cationic polypeptide can be random, blocky or a combination thereof. For example, in an embodiment, the sequence arrangement of hydrophobic amino acid units and positively charged amino acid units in the synthetic cationic polypeptide is blocky. In a number of embodiments, such a block copolypeptide can comprise various hydrophobic and hydrophilic amino acid units. For example, in an embodiment, the synthetic cationic polypeptide is a block copolypeptide that comprises hydrophobic leucine units and positively charged lysine units.

[0073] In some embodiments, the synthetic cationic polypeptide is a block copolypeptide having segment comprising a plurality of positively charged amino acid units that has at least twice the number of amino acid units as the segment comprising a plurality of hydrophobic amino acid units.

[0074] In various embodiments, the antimicrobial synthetic cationic polypeptide self-assembles into multimeric structures in water and other aqueous carriers. Examples of multimeric structures include micelles, sheets, vesicles, and fibrils (see US Patent No.9,017,730). In an embodiment, the antimicrobial synthetic cationic polypeptide, in deionized water at 37°C at a concentration of 3 wt%, forms a self-supporting hydrogel. In an embodiment, the antimicrobial synthetic cationic polypeptide displays surfactant activity in deionized water at 37°C, as measured by a decrease in surface tension of at least 10% or at least 20% as compared to deionized water alone. In an embodiment, self-assembly of an antimicrobialsynthetic cationic polypeptide is evidenced by a critical aggregation concentration for the polypeptide that is below 1000 ^g / mL at 37°C in deionized water. In an embodiment, self-assembly of an antimicrobialsynthetic cationic polypeptide is evidenced by a critical aggregation concentration for the polypeptide that is below 100 ^g / mL at 37°C in deionized water.

[0075] Self-assembly of the antimicrobialsynthetic cationic polypeptide can be controlled in various ways. For example, in an embodiment, the antimicrobialsynthetic cationic polypeptide comprises a sequence arrangement of hydrophobic amino acid units and positively charged amino acid units that is configured to promote self-assembly of the antimicrobialsynthetic cationic polypeptide into multimeric structures. For example, self- assembly of the polypeptide is enhanced by a blocky sequence arrangement of hydrophobic amino acid units and positively charged amino acid units. A higher hydrophobic amino acid unit content and / or longer blocks of hydrophobic amino acid units in the polypeptide tend to enhance self-assembly in aqueous carriers.

[0076] The antimicrobial synthetic cationic polypeptide described herein can be dispersed in an aqueous carrier to form antimicrobial pharmaceutical compositions active against bacteria, fungi, or both. In various embodiments the aqueous carrier is water. In other embodiments the aqueous carrier is an aqueous solution that comprises a pharmaceutically acceptable salt, a non-ionic additive, or a combination thereof. Salt tends to inhibit self- assembly of the polypeptide and thus excessive salt is to be avoided. Normal saline, half normal saline, quarter normal saline and phosphate buffered saline are examples of suitable aqueous carriers that contain a pharmaceutically acceptable salt. In an embodiment, the aqueous carrier comprises sodium chloride.

[0077] In various embodiments, the aqueous carrier is an aqueous solution that comprises an additive. Examples of suitable additives include various oils, various other polymers (natural or synthetic), cellulose- or cellulose-derivatives, non-ionic or ionicsurfactants, stabilizing agents, viscosity-increasing agents (e.g., polyethylene glycol), various alcohols (including but not limited to stearyl alcohol and / or cetyl alcohol), and combinations thereof. In various embodiments, the aqueous carrier is an aqueous solution that comprises a non-ionic additive. Examples of suitable non-ionic additives include dextrose, mannitol, glycerol, xylitol, sorbitol, surfactant, and combinations thereof. Salts and certain sugars or sugar alcohols (e.g., glycerol and xylitol) may be used in amounts effective to modify tonicity and / or osmolality.

[0078] In some embodiments, the antimicrobial pharmaceutical composition may comprise additives including by not limited to stearic acid, gelatin, xanthan gum, carnauba wax, stearyl alcohol, cetyl alcohol, ammonium lauryl sulfate, sodium laureth sulfate, ammonium laureth sulfate, sodium trideceth sulfate, sarcosines, suflosuccinates,, long-chain amino esters, ammonioesters, cetyltrimethylammonium chloride, polyoxyethylene fatty alcohols, polyoxyethylene sorbitol esters, alkanolamides, betaines, sultaines, imidazolinium derivatives, saponins, glycerin, dimethicone, simethicone, polyvinylpyrrolidone, propylene glycol, polyethylene glycol, cocodiethanolamide, polyphosphates, ethylenediaminetetra-acetic acid, glycolic acid, citric acid, benzoate, methylparaben, isopropylparaben, ethylparaben, isobutylparaben, butylparaben, propylparaben, emollients, 1,3-deimethyol-5,5-dimethyl (DMDM) hydantoin, tetrasodium EDTA, methylisothiazolinone, aloe vera, vegetable oils, mineral oils, and panthenol.

[0079] In some embodiments, the antimicrobial pharmaceutical composition described herein further may further comprise another polymer. In some such embodiments, another polymer may include cellulose, alginate, collagen, polymeric surfactant, polyethylene glycol, polyvinyl alcohol, polyurethane, polyvinyl pyrolidinone (PVP), fibrin(ogen), hyaluronic acid, blood proteins, or tissue proteins.

[0080] The aqueous carrier can comprise various amounts of an additive, such as a pharmaceutically acceptable salt, a non-ionic additive, or a combination thereof. In various embodiments, the aqueous carrier comprises an amount of a pharmaceutically acceptable salt that is 9.0 g / L or less; or 8.0 g / L or less; or 7.0 g / L or less; or 6.0 g / L or less; or 5.0 g / L or less; or 4.5 g / L or less; or 4.0 g / L or less; or 3.0 g / L or less. In an embodiment, the amount of additive in the aqueous carrier is selected to control the viscosity of the antimicrobialpharmaceutical composition. In an embodiment, the aqueous carrier comprisesan additive in an amount that increases the viscosity of the antimicrobialpharmaceutical composition. In an embodiment, the aqueous carrier comprises an additive in an amount that decreases the viscosity of the antimicrobialpharmaceutical composition. In an embodiment, the non-ionic additive is present in an amount effective to increase the osmotic concentration of the antimicrobial pharmaceutical composition to a value that is at least 10% greater than that of the antimicrobial pharmaceutical composition without said additive. In various embodiments the concentration of the additive in the antimicrobial pharmaceutical composition is in the range of about 0.1 wt% to about 10 wt%, based on total weight. In various embodiments the concentration of the non-ionic additive in the antimicrobial pharmaceutical composition is in the range of about 0.01 wt% to about 2 wt%, or in the range of about 0.05 wt% to about 5 wt%, based on total weight.

[0081] In various embodiments, an antimicrobial pharmaceutical composition as described herein is sterilized by a sterilization technique configured to achieve a sterilized antifungal pharmaceutical composition. In an embodiment, the sterilization technique is configured to have minimal impact on the chemical structure of the synthetic cationic polypeptide and / or the tendency for the synthetic cationic polypeptide to self-assemble. Examples of such sterilization techniques are described in PCT Publication WO 2018 / 187617. In an embodiment, an antimicrobial pharmaceutical composition as described herein is sterilized by a sterilization technique configured to achieve a sterilized antimicrobial pharmaceutical composition with the antimicrobial synthetic cationic polypeptide having a weight average molecular weight and / or a dispersity comparable to (e.g., within about 10%) that of the antimicrobial synthetic cationic polypeptide of the antifungal pharmaceutical composition without sterilization by said sterilization technique. In an embodiment, the antimicrobial pharmaceutical composition is sterilized by a sterilization technique configured to achieve a sterilized antimicrobial pharmaceutical composition having a viscosity level at 37°C that is comparable to that of the antimicrobial pharmaceutical composition without sterilization by this sterilization technique. In an embodiment, the viscosity of the sterilized antimicrobial pharmaceutical composition at 37°C is in the range of 20% to 200% of the viscosity of an otherwise comparable unsterilized antimicrobial pharmaceutical composition.

[0082] In an embodiment, the antimicrobial pharmaceutical composition has a low toxicity after being infused into the peritoneal cavity of a plurality of mice at a dose of 10mL / kg, as measured by a mouse survival rate of 50% or greater at 72 hours after being infused. In an embodiment, the antimicrobial pharmaceutical composition has a low toxicity after being infused into the peritoneal cavity of a plurality of mice at a dose of 20 mL / kg, as measured by a mouse survival rate of 50% or greater at 72 hours after being infused. In an embodiment, the antimicrobial pharmaceutical composition has a low toxicity after being infused into the peritoneal cavity of a plurality of mice at a dose of 40 mL / kg, as measured by a mouse survival rate of 50% or greater at 72 hours after being infused. Those skilled in the art appreciate that the dosing may also be expressed in terms of mg / kg instead of mL / kg, and that a mouse survival rate of 50% or greater at 72 hours can include values up to 100%, such as 60% or greater, 70% or greater, 80% or greater, or 90% or greater. For example, in an embodiment, the antimicrobial pharmaceutical composition has a low toxicity after being infused into the peritoneal cavity of a plurality of mice at a dose of 50 mg / kg, as measured by a mouse survival rate of 80% or greater at 72 hours after being infused.

[0083] The inclusion of other active pharmaceutical ingredients to the antimicrobial pharmaceutical compositions described herein may enhance antimicrobial performance and / or decrease the risk of toxicities, both local and systemic. In particular, the inclusion of other antimicrobial agents, including antibiotics, antiseptics, iodine compounds, and / or silver compounds, may act cooperatively with the synthetic cationic polypeptide to help prevent and / or treat infection. Further, the inclusion of one or more anti-inflammatory agents may enhance performance and / or decrease the risk of toxicities, both local and systemic. Local inflammation may contribute to pathogenesis of various disease settings that also involve microbial contamination or infection by bacteria, fungi, or both. Examples include otitis externa, chronic sinusitis, pulmonary conditions, and certain wound conditions. Such conditions could be treated by a combination of synthetic cationic polypeptide and anti- inflammatory agents, such as corticosteroids, anti-histamines, and / or anti-cytokines. As such, including anti-inflammatory agents in an antimicrobial composition containing synthetic cationic polypeptide may provide benefits.

[0084] Inclusion of one or more additional antifungal agents enhance antifungal performance and / or decrease the risk of toxicities, both local and systemic. In some embodiments, the one or more additional antifungal agents is an azole antifungal agent, including but not limited to agent is clotrimazole, ketoconazole, or metronidazole. In someembodiments, the one or more additional antifungal agents is selected from the group consisting of naftifine, terbinafine, zinc pyrithione, and selenium sulfide, sulfur, niacinamide, salicylic acid, clioquinol, haloprogin, povidone-iodine, tolnaftate, and undecylenic acid.

[0085] Other pharmaceutical ingredients that may be included in the antimicrobial pharmaceutical compositions described herein include lipids, Vitamin D, zinc, sialic acid or sialic acid-containing compounds, nitric oxide or nitric oxide-producing compounds, anesthetics (such as benzocaine), protease inhibitors, mucolytic agents, nucleic acid polymer- disrupting enzymes (such as DNAse), ȕ-agonists (e.g., salmeterol, salbutamol, etc., which may be in amounts effective to raise intracellular cAMP levels), methylxanthines (e.g., theophylline, aminophylline, etc., which may be in amounts effective to inhibit phosphodiesterase and / or increase cAMP levels), PDE4 inhibitors (such as rofulumilast, which may be in amounts effective to increase cilia beat frequency), topical corticosteroids (which may be in amounts effective to provide anti-inflammatory effects and / or increase in cilia beat frequency), cytokines or cytokine inhibitors (including interferons), IL-1 receptor antagonists, IL-1 inhibitors (including anti-IL-1 antibodies), TNF inhibitors (including anti-TNF antibodies), IL-6 inhibitors, and combinations thereof.

[0086] In an embodiment, the antimicrobial pharmaceutical composition comprises an anti-inflammatory compound. For example, in an embodiment, the inflammatory compound is selected from the group consisting of a corticosteroid, a histamine inhibitor and a cytokine inhibitor. Examples of corticosteroids include betamethasone dipropionate, clobetasol propionate, diflorasone diacetate, fluocinonide, and halobetasol propionate. Examples of histamine inhibitors include those that inhibit the histamine H1, H2, H3 and H4 receptors. Examples of cytokine inhibitors include glucocorticoids and pentoxifylline.

[0087] The antimicrobial pharmaceutical compositions described herein can be made in various ways. In an embodiment, the antimicrobial synthetic cationic polypeptide is made in the general manner taught in PCT Publication WO 2018 / 187617, US Patent No. 9,017,730 and / or US Patent No. 9,446,090, each of which are expressly incorporated herein by reference for all purposes including the teaching of such general methods for making cationic polypeptides and antifungal pharmaceutical compositions containing them. The antimicrobial pharmaceutical composition can be made combining the antimicrobial synthetic cationic polypeptide with the aqueous carrier to thereby disperse (e.g., dissolve) thepolypeptide in the aqueous carrier. For example, such combining can be accomplished by mixing the ingredients (cationic polypeptide, aqueous carrier and optional ingredients such as inflammatory compound) with agitation at a temperature in the range of about 20º C to 90º C, for a length of time that is effective to disperse (e.g., dissolve) the polypeptide. The ingredients can be mixed together in any order, although those skilled in the art may prefer a particular order in individual cases. Various forms of the antifungal pharmaceutical compositions described herein can be made, such as hydrogels, solutions, dispersions, emulsions, dry fibers, dressings, thin films, and / or foams. Methods of treating fungal colonization, overgrowth, or infection

[0088] Various embodiments provide a method of treating fungal colonization, overgrowth, or infection, comprising administering an effective amount of an antimicrobial pharmaceutical composition with antimicrobial activity against fungi to a subject in need thereof. In some embodiments, the fungal infection may be caused by a fungal organism selected from the group consisting of Candida albicans, Candida auris, and Malassezia pachydermatis. In some specific embodiments, the Candida albicans is drug-resistant Candida albicans.

[0089] Various embodiments provide a method for the treatment or prevention of a disease or disorder selected from the group of tinea versicolor, pityriasis versicolor, acne vulgaris, fungal acne, pityrosporum folliculitis, dandruff, seborrheic dermatitis, tinea pedis, tinea cruris, tinea corporis, onychomycosis, cutaneous candidiasis, fungal vaginosis, vaginal candidiasis, oral candidiasis, oral thrush, esophageal candidiasis, and otitis externa, comprising administering an effective amount of an antimicrobial pharmaceutical composition with antimicrobial activity against fungi disclosed herein to a subject in need thereof. As described in greater detail elsewhere herein, in various embodiments the antimicrobial pharmaceutical composition with antimicrobial activity against fungi comprises an aqueous carrier and an antimicrobial synthetic cationic polypeptide with activity against fungi dispersed in the aqueous carrier

[0090] Various routes may be used to administer an antimicrobial pharmaceutical composition with antimicrobial activity against fungi to a subject in need thereof. In an embodiment, the antimicrobial pharmaceutical composition with antimicrobial activity againstfungi is administered to the subject by local application to one or more tissues. For example, in an embodiment, the antimicrobial pharmaceutical composition with antimicrobial activity against fungi is administered to the subject by local application to one or more tissues in one or more of a pulmonary cavity, a nasal cavity and / or a sinus cavity. In some embodiments, the topical administration of the antimicrobial pharmaceutical composition with antimicrobial activity against fungi may be to the skin, oral cavity without swallowing, oral cavity with swallowing permitted, esophagus, lungs through inhalation, vaginal cavity; and or ear canal. EXAMPLES

[0091] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. Antimicrobial Pharmaceutical Compositions with activity against bacteria, fungi, or both

[0092] Examples of antimicrobial synthetic cationic polymers include Poly(L- lysine hydrochloride)-b-poly(L-leucine) of various overall lengths and lysine-to-leucine ratios. In all cases, ones tested had a plurality of positively charged amino acid units at neutral pH and a cationic segment to hydrophobic segment ratio of at least 2:1. A sample was prepared in accordance with the general procedures described in US Patent No.9,017,730. Two different poly(L-lysine hydrochloride)-b-poly(L-leucine) polymers were dispersed in water in separate preparations to form the antifungal pharmaceutical compositions referred to below as Composition A and Composition A’. The antimicrobial synthetic cationic polymer in Composition A has a poly(L-lysine hydrochloride) block of approximately 130 amino acids on average and a poly(L-leucine) block of approximately 40 amino acids on average. The antimicrobial synthetic cationic polymer in Composition A’ has a poly(L-lysine hydrochloride) block of approximately 100 amino acids on average and a poly(L-leucine) block of approximately 40 amino acids on average. In time-kill assays, Compositions A and A’ were prepared with poly(L-lysine hydrochloride)-b-poly(L-leucine) concentrations of 20 mg / mL and subsequently diluted with cell grade water to form solutions having a polymer concentration of 100 ^g / mL or 10 μg / mL for evaluation of antifungal activity.

[0093] Examples of antimicrobial synthetic cationic polymers include Poly(L- lysine hydrochloride)-b-poly(D,L-leucine) of various overall lengths and lysine-to-leucineratios. In all cases, ones tested had a plurality of positively charged amino acid units at neutral pH and a cationic segment to hydrophobic segment ratio of at least 2:1. A sample was prepared in accordance with the general procedures described in US Patent No.9,017,730. Two different poly(L-lysine hydrochloride)-b-poly(D,L-leucine) were dispersed in water in separate preparations to form the antimicrobial pharmaceutical compositions referred to below as Composition B and Composition B’. The antimicrobial synthetic cationic polymer in Composition B has a poly(L-lysine hydrochloride) block of approximately 100 amino acids on average and a poly(L-leucine) block of approximately 20 amino acids on average. The antimicrobial synthetic cationic polymer in Composition B’ has a poly(L-lysine hydrochloride) block of approximately 130 amino acids on average and a poly(L-leucine) block of approximately 40 amino acids on average. In time-kill assays, Compositions B and B’ were prepared with poly(L-lysine hydrochloride)-b-poly(D,L-leucine) concentrations of 10 mg / mL and subsequently diluted with cell grade water to form solutions having a polymer concentration of 100 ^g / mL or 10 μg / mL for evaluation of antifungal activity. Antifungal Activity

[0094] The antifungal activities of Compositions A, A’, B, and B’ were evaluated by challenging them with four different fungal organisms, Candida albicans (ATCC 2433), fluconazole-resistant Candida albicans (clinical isolate), Candida auris (SENTRY isolate 1247335), or Malassezia pachydermatis (clinical isolate 1097360). Time-kill assays based upon the ASTM E2315-16 (2016) document, "Standard Guide for Assessment of Antimicrobial Activity Using a Time-Kill Procedure" were used. The log10survival of the fungal strains were determined following exposure to these antifungal pharmaceutical compositions at multiple exposure times, including 0, 10, 30, 60, and 120 minutes. Tables 1, 2, 3, and 4 summarize the results. TABLE 1. ACTIVITY OF COMPOSITIONS A, A’, B, AND B’ AGAINST CANDIDA ALBICANS (ATCC 24433) WITH 60 MINUTE EXPOSURE Log CFU / mL Concentration Composition Composition Composition Composition A A’ B B’ 0 μg / mL 6.0 6.0 6.0 6.010 μg / mL 0.0 0.0 0.0 0.0 100 μg / mL 0.0 0.0 0.0 0.0 TABLE 2. ACTIVITY OF COMPOSITIONS A, A’, B, AND B’ AGAINST FLUCONAZOLE-RESISTANT CANDIDA ALBICANS (ATCC 24433) WITH 60 MINUTE EXPOSURE Log CFU / mL Concentration Composition Composition Composition Composition A A’ B B’ 0 μg / mL 6.0 6.0 6.0 6.0 10 μg / mL 0.0 0.0 0.0 0.0 100 μg / mL 0.0 0.0 0.0 0.0 TABLE 3. ACTIVITY OF COMPOSITION B AGAINST CANDIDA AURIS (SENTRY ISOLATE 1247335) Time Log CFU / mL (min) Composition B 0 5.4 10 1.24 30 1.24 60 0.7 120 0.7 TABLE 4. ACTIVITY OF COMPOSITION A AND COMPOSITION B AGAINST MALASSEZIA PACHYDERMATIS (SENTRY ISOLATE 1097360) Time Log CFU / mL (min) Composition A Composition B 0 5.7 5.7 10 3.43 2.24 30 * 1.7 60 * 1.5 120 * * *below limit of detection of 1.4 log CFU / mL

[0095] The results summarized in Tables 1, 2, 3, and 4 show that pharmaceutical compositions, containing synthetic cationic polymers that comprise a plurality of positivelycharged amino acid units at neutral pH, have surprising antifungal activity against different fungal organisms.

[0096] Poly(L-lysine hydrochloride)-b-poly(D,L-leucine) was also prepared in formulations with additives in an effort to improve foaming capacity for use in filling cavities (e.g. the vaginal cavity). Addition of various additives (e.g., HEC of different average weights, PEG, glycerol, poloxamer 407) was shown to improve the foaming capacity of the formulation over the foaming produced by Poly(L-lysine hydrochloride)-b-poly(D,L-leucine) alone. Additionally, combinations of HEC with surfactants (e.g., Kolliphor HS15, Tween20, and polyvinyl alcohol) demonstrated surprising, synergistic effects in both initial foaming and foam stability. Additional Embodiments

[0097] Additional embodiments of the present disclosure include:

[0098] Embodiment 1: An antifungal pharmaceutical composition for preventing or treating fungal colonization, overgrowth, or infection, comprising: an antifungal synthetic cationic amino acid polymer(s), wherein the antifungal synthetic cationic amino acid polymer(s) comprises a plurality of positively charged amino acid units at neutral pH; the antifungal synthetic cationic amino acid polymer(s) comprises a plurality of hydrophobic amino acid units.

[0099] Embodiment 2: The composition of embodiment 1 wherein the antifungal synthetic cationic amino acid polymer(s) comprises a sequence arrangement of hydrophobic amino acid units and positively charged amino acid units that is configured to promote self- assembly of the antifungal synthetic cationic amino acid polymer(s) into multimeric structures in aqueous media.

[0100] Embodiment 3: The composition of embodiment 1, wherein the antifungal synthetic cationic amino acid polymer(s) demonstrates activity against Candida spp., including both Candida albicans and Candida auris.

[0101] Embodiment 4: The composition of of any one of embodiments 1 to 3, wherein the antifungal synthetic cationic amino acid polymer(s) demonstrates activity against Malassezia spp.

[0102] Embodiment 5: The composition of any one of embodiments of 1 to 3, wherein the antifungal synthetic cationic amino acid polymer(s) comprises at least 40 amino acid units.

[0103] Embodiment 6: The composition of any one of embodiments 1 to 5, wherein the antifungal synthetic cationic polymer(s) comprises at least 5 positively charged amino acid units at neutral pH.

[0104] Embodiment 7: The composition of any one of embodiments 1 to 6, wherein the antifungal synthetic cationic polymer(s) comprises at least 5 hydrophobic amino acid units.

[0105] Embodiment 8: The composition of any one of embodiments 1 to 7, wherein the antifungal synthetic cationic polymer(s) comprises a blocky sequence arrangement of a segment of at least 5 positively charged amino acid units and a segment of at least 5 hydrophobic amino acid units that is configured to promote self-assembly of the antifungal synthetic cationic polymer(s) into multimeric structures in aqueous media.

[0106] Embodiment 9: The composition of any one of embodiments 1 to 8, wherein the antifungal synthetic cationic polymer(s) inhibits or kills bacteria.

[0107] Embodiment 10: The composition of any one of embodiments 1 to 9, wherein the antifungal pharmaceutical composition is considered a non-irritant after application to intact skin, as measured by a standard dermal irritation assay on rabbits.

[0108] Embodiment 11: The composition of any one of embodiments 1 to 10, wherein the antifungal pharmaceutical composition is considered a non-sensitizer after application to intact skin, as measured by a standard Buehler test on guinea pigs.

[0109] Embodiment 12: The composition of any one of embodiments 1 to 11, wherein the antifungal pharmaceutical composition has a low toxicity after being consumed in drinking water by a plurality of healthy, young adult rats at a concentration of 3 mg / mL per day for seven days, as measured by a rat survival rate of 100%.

[0110] Embodiment 13: The composition of any one of embodiments 1 to 12, wherein the antifungal pharmaceutical composition has a low toxicity after being administered in a single dose of 186 mg / kg or less by oral gavage to a plurality of healthy, young adult mice, as measured by a mouse survival rate of 100% at 72 hours.

[0111] Embodiment 14: The composition of any one of embodiments 1 to 13, wherein the antifungal pharmaceutical composition has a low toxicity after being infused intothe peritoneal cavity of a plurality of healthy, young adult mice at a dose of 50 mg / kg, as measured by a mouse survival rate of 50% or greater at 72 hours.

[0112] Embodiment 15: The composition of any one of embodiments 1 to 14, wherein the antifungal pharmaceutical composition further comprises water.

[0113] Embodiment 16: The composition of any one of embodiments 1 to 15, wherein the antifungal pharmaceutical composition further comprises other active ingredients selected from the group consisting of antifungal azoles (e.g., ketoconazole, metronidazole, clotrimazole).

[0114] Embodiment 17: The composition of any one of embodiments 1 to 16, wherein the antifungal pharmaceutical composition further comprises other active ingredients selected from the group consisting of antifungal non-azoles (e.g., allylamine antifungals, zinc pyrithione, selenium sulfide, sulfur, niacinamide, salicylic acid, clioquinol, haloprogin, povidone-iodine, tolnaftate, and undecylenic acid).

[0115] Embodiment 18: The composition of any one of embodiments 1 to 17, wherein the antifungal pharmaceutical composition further comprises one or more anti- inflammatory or anti-itching compounds.

[0116] Embodiment 19: The composition of embodiment 18, wherein the anti- inflammatory compound(s) is selected from the group consisting of a corticosteroid, an antihistamine, counterirritants (e.g., mint oil, menthol, camphor), local anesthetics (e.g., lidocaine, pramoxine, benzocaine), phosphodiesterase-4 inhibitors, capsaicin, a histamine inhibitor, and / or a cytokine inhibitor.

[0117] Embodiment 20: The composition of any one of embodiments 1 to 19, wherein the antifungal pharmaceutical composition further comprises surfactants with the ability to emulsify lipids.

[0118] Embodiment 21: The composition of any one of embodiments 1 to 20, wherein the antifungal pharmaceutical composition further comprises agents capable of improving cellular health.

[0119] Embodiment 22: The composition of any one of embodiments 1 to 21, wherein the antifungal pharmaceutical composition further comprises agents that stimulate skin cell repair

[0120] Embodiment 23: The composition of any one of embodiments 1 to 22, wherein the antifungal pharmaceutical composition further comprises agents capable of stimulating melanocyte production of melanin.

[0121] Embodiment 24: The composition of any one of embodiments 1 to 23, wherein the antifungal pharmaceutical composition further comprises vitamins, such as Vitamins A, C, D, and E.

[0122] Embodiment 25: The composition of any one of embodiments 1 to 24, wherein the antifungal pharmaceutical composition further comprises minerals, such as calcium and magnesium.

[0123] Embodiment 26: The composition of any one of embodiments 1 to 25, wherein the antifungal pharmaceutical composition further comprises antioxidants, such as polypodium leucotomos, lycopene, lutein, resveratrol, epigallocatechin gallate (green tea), lipoic acid, and delphinidin.

[0124] Embodiment 27: The composition of any one of embodiments 1 to 26, wherein the antifungal pharmaceutical composition further comprises ubiquinone (coenzyme Q10).

[0125] Embodiment 28: The composition of any one of embodiments 1 to 27, wherein the antifungal pharmaceutical composition further comprises another polymer selected from the group consisting of cellulose, alginate, collagen, polymeric surfactant, polyethylene glycol, polyvinyl alcohol, polyurethane, polyvinyl pyrolidinone (PVP), fibrin(ogen), hyaluronic acid, blood proteins, and tissue proteins.

[0126] Embodiment 29: The composition of any one of embodiments 1 to 28, wherein the antifungal pharmaceutical composition further comprises other ingredients selected from the group consisting of stearic acid, gelatin, xanthan gum, carnauba wax, stearyl alcohol, cetyl alcohol, ammonium lauryl sulfate, sodium laureth sulfate, ammonium laureth sulfate, sodium trideceth sulfate, sarcosines, suflosuccinates,, long-chain amino esters, ammonioesters, cetyltrimethylammonium chloride, polyoxyethylene fatty alcohols, polyoxyethylene sorbitol esters, alkanolamides, betaines, sultaines, imidazolinium derivatives, saponins, glycerin, dimethicone, simethicone, polyvinylpyrrolidone, propylene glycol, polyethylene glycol, cocodiethanolamide, polyphosphates, ethylenediaminetetra-acetic acid, glycolic acid, citric acid, benzoate, methylparaben, isopropylparaben, ethylparaben,isobutylparaben, butylparaben, propylparaben, emollients, 1,3-deimethyol-5,5-dimethyl (DMDM) hydantoin, tetrasodium EDTA, methylisothiazolinone, aloe vera, vegetable oils, mineral oils, and panthenol.

[0127] Embodiment 30: The composition of any one of embodiments 1 to 29, wherein the antifungal pharmaceutical composition does not include chemical preservatives.

[0128] Embodiment 31: The composition of any one of embodiments 1 to 30, wherein the antifungal pharmaceutical composition is an aqueous composition comprising: a mixture comprising one or more synthetic, cationic amino acid polymer with antimicrobial activity; and a second pharmaceutically acceptable polymer that is not a synthetic, cationic amino acid polymer(s); wherein the amounts of the one or more synthetic, cationic amino acid polymer(s) and the second pharmaceutically acceptable polymer are each at least about 100 ^g / mL based on the total volume of the aqueous composition; and wherein the amount of the second pharmaceutically acceptable polymer is at least about 10% by weight, based on the weight of the one or more synthetic, cationic amino acid polymer(s).

[0129] Embodiment 32: The composition of any one of embodiments 1 to 31, wherein the antifungal pharmaceutical composition is formulated as a solution, hydrogel, emulsion, cream, paste, dry powder, sheet, 3D-formed structure, bar soap, liquid soap, or shampoo.

[0130] Embodiment 33: The composition of any one of embodiments 1 to 32, wherein the multimeric structures formed in aqueous media are selected from the group consisting of multimers in solution, micelles, sheets, vesicles, and fibrils.

[0131] Embodiment 34: The composition of any one of embodiments 1 to 33, wherein the multimeric structures can be measured by a critical aggregation concentration less than that of a synthetic cationic polymer of the same composition with a statistical distribution of amino acids.

[0132] Embodiment 35: The composition of any one of embodiments 1 to 34, wherein the antifungal synthetic cationic polymer(s) self-assembles into multimeric structures, as measured by a critical aggregation concentration that is below 1000 ^g / mL at 37°C in deionized water.

[0133] Embodiment 36: The composition of any one of embodiments 1 to 35, wherein the antifungal synthetic cationic polymer(s) is dispersed in the aqueous carrier at aconcentration in the range of about 0.01% to about 5%, by weight based on total weight of the antifungal pharmaceutical composition.

[0134] Embodiment 37: The composition of any one of embodiments 1 to 36, wherein the aqueous carrier, containing the antifungal synthetic cationic polymer(s) at 2 wt%, has a viscosity at 37°C that is greater than that of the aqueous carrier containing albumin at 2 wt% in place of the antifungal synthetic cationic polymer(s)

[0135] Embodiment 38: The composition of any one of of embodiments 1 to 37, wherein the plurality of positively charged amino acid units at neutral pH is at least 10.

[0136] Embodiment 39: The composition of any one of embodiments 1 to 38, wherein the plurality of hydrophobic amino acid units comprises at least 5 hydrophobic amino acid units selected from leucine (L), isoleucine (l), valine (V), phenylalanine (F) or alanine (A).

[0137] Embodiment 40: The composition of any one of embodiments 1 to 39, wherein the plurality of hydrophobic amino acid units comprises at least 10 hydrophobic amino acid units selected from leucine (L), isoleucine (l), valine (V), phenylalanine (F) or alanine (A).

[0138] Embodiment 41: The composition of any one of embodiments 1 to 40, wherein the plurality of hydrophobic amino acid units comprises at least 15 hydrophobic amino acid units selected from leucine (L), isoleucine (l), valine (V), phenylalanine (F) or alanine (A).

[0139] Embodiment 42: The composition of any one of embodiments 1 to 41, wherein the hydrophobic amino acid units comprise leucine units.

[0140] Embodiment 43: The composition of any one of embodiments 1 to 42, wherein the plurality of positively charged amino acid units comprises lysine units.

[0141] Embodiment 44: The composition of any one of embodiments 1 to 43, wherein the antimicrobial synthetic cationic polypeptide is a block copolypeptide that comprises hydrophobic leucine units and positively charged lysine units.

[0142] Embodiment 45: A method of preventing or treating fungal colonization, overgrowth, or infection, comprising: topical administration of an effective amount of an antifungal pharmaceutical composition to a subject in need thereof, wherein: the antifungal pharmaceutical composition comprises: an antifungal synthetic cationic amino acidpolymer(s), wherein the antifungal synthetic cationic amino acid polymer(s) comprises a plurality of positively charged amino acid units at neutral pH; the antifungal synthetic cationic amino acid polymer(s) comprises a plurality of hydrophobic amino acid units; and the antifungal synthetic cationic amino acid polymer(s) comprises a sequence arrangement of hydrophobic amino acid units and positively charged amino acid units that is configured to promote self-assembly of the antifungal synthetic cationic amino acid polymer(s) into multimeric structures in aqueous media.

[0143] Embodiment 46: The method of embodiments 45, wherein the topical administration of the antifungal pharmaceutical composition is to skin.

[0144] Embodiment 47: The method of embodiments 45 or 46, wherein the topical administration of the antifungal pharmaceutical composition is to the oral cavity without swallowing.

[0145] Embodiment 48: The method of any one of embodiments 45 to 47, wherein the topical administration of the antifungal pharmaceutical composition is to the oral cavity with swallowing permitted.

[0146] Embodiment 49: The method of any one of embodiments 45 to 48, wherein the topical administration of the antifungal pharmaceutical composition is to the esophagus.

[0147] Embodiment 50: The method of any one of embodiments 45 to 49, wherein the topical administration of the antifungal pharmaceutical composition is to lungs through inhalation.

[0148] Embodiment 51: The method of any one of embodiments 45 to 50 wherein the topical administration of the antifungal pharmaceutical composition is to the vaginal cavity.

[0149] Embodiment 52: The method of any one of embodiments 45 to 51, wherein the topical administration of the antifungal pharmaceutical composition is to the ear canal.

[0150] Embodiment 53: The method of any one of embodiments 45 to 52, wherein the topical administration of the antifungal pharmaceutical composition is to a non-human mammal, including but not limited to dogs and cats.

[0151] Embodiment 54: The method of any one of embodiments 45 to 53, wherein the antifungal pharmaceutical composition is for the treatment or prevention of tinea versicolor and / or pityriasis versicolor.

[0152] Embodiment 55: The method of any one of embodiments 45 to 54, wherein the antifungal pharmaceutical composition is for the treatment or prevention of acne vulgaris, fungal acne and / or pityrosporum folliculitis, or a combination thereof.

[0153] Embodiment 56: The method of any one of embodiments 45 to 55, wherein the antifungal pharmaceutical composition is for the treatment or prevention of dandruff / seborrheic dermatitis.

[0154] Embodiment 57: The method of any one of embodiments 45 to 56, wherein the antifungal pharmaceutical composition is for the treatment or prevention of tinea pedis, tinea cruris, and / or tinea corporis.

[0155] Embodiment 58: The method of any one of embodiments 45 to 57 wherein the antifungal pharmaceutical composition is for the treatment or prevention of onychomycosis.

[0156] Embodiment 59: The method of any one of embodiments 45 to 58 wherein the antifungal pharmaceutical composition is for the treatment or prevention of cutaneous candidiasis.

[0157] Embodiment 60: The method of any one of embodiments 45 to 59 wherein the antifungal pharmaceutical composition is for the treatment or prevention of fungal vaginosis or vaginal candidiasis.

[0158] Embodiment 61: The method of any one of embodiments 45 to 60 wherein the antifungal pharmaceutical composition is for the treatment or prevention of fungal colonization, overgrowth, or infection of the oral cavity, including, but not limited to, oral candidiasis / oral thrush.

[0159] Embodiment 62: The method of any one of embodiments 45 to 61 wherein the antifungal pharmaceutical composition is for the treatment or prevention of otitis externa.

[0160] Embodiment 63: The method of any one of embodiments 45 to 62 wherein the antifungal pharmaceutical composition is for the treatment or prevention of a bacterial and fungal infection.

[0161] Embodiment 64: A method of preventing or treating fungal colonization, overgrowth, or infection, comprising: topical administration of an effective amount of an antimicrobial pharmaceutical composition to a subject in need thereof, wherein: the antimicrobial pharmaceutical composition comprises: an synthetic cationic amino acidpolymer comprising at least 40 amino acid units; wherein the synthetic cationic polymer comprises a blocky sequence arrangement of a segment comprising a plurality of positively charged amino acid units and a segment of a plurality of hydrophobic amino acid units, wherein the segment comprising a plurality of positively charged amino acid units has at least twice the number of amino acid units as the segment comprising a plurality of hydrophobic amino acid units.

[0162] Embodiment 65: The embodiments of embodiment 64, wherein the synthetic cationic amino acid polymer(s) comprises at least 80 amino acid units.

[0163] Embodiment 66: The method of embodiments 64 or 65, wherein the synthetic cationic polymer comprises at least 10 positively charged amino acid units at neutral pH.

[0164] Embodiment 67: The method of any one of embodiments 64 to 66, wherein the synthetic cationic polymer comprises at least 10 hydrophobic amino acid units.

[0165] Embodiment 68: The method of embodiment 67, wherein the segment comprising a plurality of hydrophobic amino acid units comprises from about 10 to about 100 hydrophobic amino acid units.

[0166] Embodiment 69: The method of embodiment 68, wherein the segment comprising a plurality of hydrophobic amino acid units comprises from about 20 to about 60 hydrophobic amino acid units.

[0167] Embodiment 70: The method of any one of embodiments 64 to 69, wherein the segment comprising a plurality of positively charged amino acid units comprises from about 10 to about 300 positively charged amino acid units.

[0168] Embodiment 71: The method of embodiment 70, wherein the segment comprising a plurality of positively charged amino acid units comprises from about 50 to about 200 positively charged amino acid units.

[0169] Embodiment 72: The method of any one of embodiments 64 to 71, wherein the hydrophobic amino acid units are selected from leucine (L), isoleucine (l), valine (V), phenylalanine (F), and alanine (A).

[0170] Embodiment 73: The method of any one of embodiments 64 to 72, wherein the hydrophobic amino acid units are leucine.

[0171] Embodiment 74: The method of any one of embodiments 64 to 73, wherein the positively charged amino acid units are selected from lysine (K), arginine (R), histidine (H), or ornithine (Orn).

[0172] Embodiment 75: The method of any one of embodiments 64 to 73, wherein the positively charged amino acid units are lysine.

[0173] Embodiment 76: The method of any one of embodiments 64 to 75, wherein the synthetic cationic polymer is dispersed in an aqueous carrier at a concentration in the range of about 0.01% to about 5%, by weight based on total weight of the antimicrobial pharmaceutical composition.

[0174] Embodiment 77 The method of any one of embodiments 64 to 76, wherein the aqueous carrier, containing the synthetic cationic polymer at 2 wt%, has a viscosity at 37°C that is greater than that of the aqueous carrier containing albumin at 2 wt% in place of the synthetic cationic polymer.

[0175] Embodiment 78: The method of any one of embodiments 64 to 77, wherein the cationic and hydrophobic segments are arranged to promote self-assembly of the synthetic cationic amino acid polymer into multimeric structures in aqueous media.

[0176] Embodiment 79: The method of any one of embodiments 64 to 78, wherein the synthetic cationic polymer has antimicrobial activity against bacteria and fungi

[0177] Embodiment 80: The method of any one of embodiments 64 to 79, wherein the antimicrobial pharmaceutical composition has antimicrobial activity against bacteria and fungi.

[0178] Embodiment 81: The method of any one of embodiments 64 to 80, wherein the topical administration of the antimicrobial pharmaceutical composition is to skin.

[0179] Embodiment 82: The method of any one of embodiments 64 to 81, wherein the topical administration of the antimicrobial pharmaceutical composition is to the oral cavity without swallowing or the oral cavity with swallowing permitted.

[0180] Embodiment 83: The method of any one of embodiments 64 to 82, wherein the topical administration of the antimicrobial pharmaceutical composition is to the esophagus.

[0181] Embodiment 84: The method of any one of embodiments 64 to 83, wherein the topical administration of the antimicrobial pharmaceutical composition is to lungs through inhalation.

[0182] Embodiment 85: The method of any one of embodiments 64 to 84, wherein the topical administration of the antimicrobial pharmaceutical composition is to the vaginal cavity.

[0183] Embodiment 86: The method any one of embodiments 64 to 85, wherein the topical administration of the antimicrobial pharmaceutical composition is to the ear canal.

[0184] Embodiment 87: The method of any one of embodiments 64 to 86, wherein the topical administration of the antimicrobial pharmaceutical composition is to a non-human mammal.

[0185] Embodiment 88: The method of embodiment 87, wherein the non-human mammal is a dog or cat.

[0186] Embodiment 89: The method of any one of embodiments 64 to 88, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of a disease or disorder selected from the group of tinea versicolor, pityriasis versicolor, acne vulgaris, fungal acne, pityrosporum folliculitis, dandruff, seborrheic dermatitis, tinea pedis, tinea cruris, tinea corporis, onychomycosis, cutaneous candidiasis, fungal vaginosis, vaginal candidiasis, oral candidiasis, oral thrush, esophageal candidiasis, or otitis externa.

[0187] Embodiment 90: The method of any one of embodiments 64 to 89, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of a bacterial infection.

[0188] Embodiment 91: The method of any one of embodiments 64 to 90, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of a fungal infection.

[0189] Embodiment 92: The method of any one of embodiments 64 to 91, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of a mixed bacterial and fungal infection.

[0190] Embodiment 93: The method of any one of embodiments 64 to 92, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of an infection of unknown microbial origin.

[0191] Embodiment 94: The method of any one of embodiments 64 to 93, wherein the infection is a fungal infection caused by a fungal organism selected from the group consisting of Candida albicans, Candida auris, and Malassezia pachydermatis.

[0192] Embodiment 95: The method of embodiment 94, wherein the Candida albicans is drug-resistant Candida albicans.

[0193] Embodiment 96: An antimicrobial pharmaceutical composition for preventing or treating fungal colonization, overgrowth, or infection, comprising: a synthetic cationic amino acid polymer comprising at least 40 amino acid units; wherein the synthetic cationic polymer comprises a blocky sequence arrangement of a segment comprising a plurality of positively charged amino acid units and a segment of a plurality of hydrophobic amino acid units; wherein the segment comprising a plurality of positively charged amino acid units has at least twice the number of amino acid units as the segment comprising a plurality of hydrophobic amino acid units.

[0194] Embodiment 97: The composition of embodiment 96, wherein the cationic and hydrophobic segments are plurality of positively charged amino acid units at neutral pH and a plurality of hydrophobic amino acid units sequentially arranged to promote self-assembly of the synthetic cationic amino acid polymer into multimeric structures in aqueous media.

[0195] Embodiment 98: The composition of embodiments 96 or 97, further comprising one or more additional antifungal agents.

[0196] Embodiment 99: The composition of embodiment 98, wherein the one or more additional antifungal agents is an azole antifungal.

[0197] Embodiment 100: The composition of embodiment 99, wherein the azole antifungal agent isclotrimazole, ketoconazole, or metronidazole.

[0198] Embodiment 101: The composition of embodiment 98, wherein the one or more additional antifungal agents is selected from the group consisting of naftifine, terbinafine, zinc pyrithione, and selenium sulfide, sulfur, niacinamide, salicylic acid, clioquinol, haloprogin, povidone-iodine, tolnaftate, and undecylenic acid.

[0199] Embodiment 102: The method of any one of embodiments 96 to 101, wherein the synthetic cationic polymer has antimicrobial activity against bacteria and fungi.

[0200] Embodiment 103: The method of any one of embodiments 96 to 102, wherein the antimicrobial composition has antimicrobial activity against bacteria and fungi.

[0201] Embodiment 104: The composition of any one of embodiments 91 to 95, further comprising a second pharmaceutically acceptable polymer.

[0202] Embodiment 105: The composition of embodiment 104, wherein the pharmaceutical composition further comprises another polymer selected from the group consisting of cellulose, alginate, collagen, polymeric surfactant, polyethylene glycol, polyvinyl alcohol, polyurethane, polyvinyl pyrolidinone (PVP), fibrin(ogen), hyaluronic acid, blood proteins, and tissue proteins.

[0203] Embodiment 106: The composition of any one of embodiments 96 to 105, wherein the pharmaceutical composition further comprises other ingredients selected from the group consisting of stearic acid, gelatin, xanthan gum, carnauba wax, stearyl alcohol, cetyl alcohol, ammonium lauryl sulfate, sodium laureth sulfate, ammonium laureth sulfate, sodium trideceth sulfate, sarcosines, suflosuccinates,, long-chain amino esters, ammonioesters, cetyltrimethylammonium chloride, polyoxyethylene fatty alcohols, polyoxyethylene sorbitol esters, alkanolamides, betaines, sultaines, imidazolinium derivatives, saponins, glycerin, dimethicone, simethicone, polyvinylpyrrolidone, propylene glycol, polyethylene glycol, cocodiethanolamide, polyphosphates, ethylenediaminetetra-acetic acid, glycolic acid, citric acid, benzoate, methylparaben, isopropylparaben, ethylparaben, isobutylparaben, butylparaben, propylparaben, emollients, 1,3-deimethyol-5,5-dimethyl (DMDM) hydantoin, tetrasodium EDTA, methylisothiazolinone, aloe vera, vegetable oils, mineral oils, and panthenol.

Claims

WHAT IS CLAIMED IS:

1. A method of preventing or treating fungal colonization, overgrowth, or infection, comprising: topical administration of an effective amount of an antimicrobial pharmaceutical composition to a subject in need thereof, wherein: the antimicrobial pharmaceutical composition comprises: a synthetic cationic amino acid polymer comprising at least 40 amino acid units; wherein the synthetic cationic polymer comprises a blocky sequence arrangement of a segment comprising a plurality of positively charged amino acid units and a segment of a plurality of hydrophobic amino acid units; and wherein the segment comprising a plurality of positively charged amino acid units has at least twice the number of amino acid units as the segment comprising a plurality of hydrophobic amino acid units.

2. The method of claim 2, wherein the synthetic cationic amino acid polymer comprises at least 80 amino acid units.

3. The method of claim 1 or 2, wherein the synthetic cationic polymer comprises at least 10 positively charged amino acid units at neutral pH.

4. The method of any one of claims 1 to 3, wherein the synthetic cationic polymer comprises at least 10 hydrophobic amino acid units.

5. The method of claim 4, wherein the segment comprising a plurality of hydrophobic amino acid units comprises from about 10 to about 100 hydrophobic amino acid units.

6. The method of claim 5, wherein the segment comprising a plurality of hydrophobic amino acid units comprises from about 20 to about 60 hydrophobic amino acid units.

7. The method of claims any one of claims 1 to 6, wherein the segment comprising a plurality of positively charged amino acid units comprises from about 10 to about 300 positively charged amino acid units.

8. The method of claim 7, wherein the segment comprising a plurality of positively charged amino acid units comprises from about 50 to about 200 positively charged amino acid units.

9. The method of any one of claims 1 to 8, wherein the hydrophobic amino acid units are selected from leucine (L), isoleucine (l), valine (V), phenylalanine (F), and alanine (A).

10. The method of any one of claims 1 to 8, wherein the hydrophobic amino acid units are leucine.

11. The method of any one of claims 1 to 10, wherein the positively charged amino acid units are selected from lysine (K), arginine (R), histidine (H), or ornithine (Orn).

12. The method of any one of claims 1 to 10, wherein the positively charged amino acid units are lysine.

13. The method of any one of claims 1 to 12, wherein the synthetic cationic polymer is dispersed in an aqueous carrier at a concentration in the range of about 0.01% to about 5%, by weight based on total weight of the antimicrobial pharmaceutical composition.

14. The method of claim 13, wherein the aqueous carrier, containing the synthetic cationic polymer at 2 wt%, has a viscosity at 37°C that is greater than that of the aqueous carrier containing albumin at 2 wt% in place of the synthetic cationic polymer.

15. The method of any one of claims 1 to 14, wherein the cationic and hydrophobic segments are arranged to promote self-assembly of the synthetic cationic amino acid polymer into multimeric structures in aqueous media.

16. The method of any one of claims 1 to 15, wherein the synthetic cationic polymer has antimicrobial activity against bacteria and fungi 17. The method of any one of claims 1 to 16, wherein the antimicrobial pharmaceutical composition has antimicrobial activity against bacteria and fungi.

18. The method of any one of claims 1 to 17, wherein the topical administration of the antimicrobial pharmaceutical composition is to skin.

19. The method of any one of claims 1 to 18, wherein the topical administration of the antimicrobial pharmaceutical composition is to the oral cavity without swallowing or the oral cavity with swallowing permitted.

20. The method of any one of claims 1 to 19, wherein the topical administration of the antimicrobial pharmaceutical composition is to the esophagus.

21. The method of any one of claims 1 to 20, wherein the topical administration of the antimicrobial pharmaceutical composition is to lungs through inhalation.

22. The method of any one of claims 1 to 21, wherein the topical administration of the antimicrobial pharmaceutical composition is to the vaginal cavity.

23. The method any one of claims 1 to 22, wherein the topical administration of the antimicrobial pharmaceutical composition is to the ear canal.

24. The method of any one of claims 1 to 23, wherein the topical administration of the antimicrobial pharmaceutical composition is to a non-human mammal.

25. The method of any one of claims 1 to 24, wherein the non-human mammal is a dog or cat.

26. The method of any one of claims 1 to 25, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of a disease or disorder selected from the group of tinea versicolor, pityriasis versicolor, acne vulgaris, fungal acne, pityrosporum folliculitis, dandruff, seborrheic dermatitis, tinea pedis, tinea cruris, tinea corporis, onychomycosis, cutaneous candidiasis, fungal vaginosis, vaginal candidiasis, oral candidiasis, oral thrush, esophageal candidiasis, or otitis externa.

27. The method of any one of claims 1 to 26, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of a bacterial infection.

28. The method of any one of claims 1 to 27, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of a fungal infection.

29. The method of any one of claims 1 to 28, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of a mixed bacterial and fungal infection.

30. The method of any one of claims 1 to 29, wherein the antimicrobial pharmaceutical composition is for the treatment or prevention of an infection of unknown microbial origin.

31. The method of claim of any one of claims 1 to 30, wherein the infection is a fungal infection caused by a fungal organism selected from the group consisting of Candida albicans, Candida auris, and Malassezia pachydermatis.

32. The method of claim 28, wherein the Candida albicans is drug-resistant Candida albicans.

33. An antimicrobial pharmaceutical composition for preventing or treating fungal colonization, overgrowth, or infection, comprising: an synthetic cationic amino acid polymer comprising at least 40 amino acid units; wherein the synthetic cationic polymer comprises a blocky sequence arrangement of a segment comprising a plurality of positively charged amino acid units and a segment of a plurality of hydrophobic amino acid units; and wherein the segment comprising a plurality of positively charged amino acid units has at least twice the number of amino acid units as the segment comprising a plurality of hydrophobic amino acid units.

34. The composition of claim 56, wherein the cationic and hydrophobic segments are plurality of positively charged amino acid units at neutral pH and a plurality of hydrophobic amino acid units sequentially arranged to promote self-assembly of the synthetic cationic amino acid polymer into multimeric structures in aqueous media.

35. The composition of claim 33 or 34, further comprising one or more additional antifungal agents.

36. The composition of claim 35, wherein the one or more additional antifungal agents is an azole antifungal agent.

37. The composition of claim 36, wherein the azole antifungal agent isclotrimazole, ketoconazole, or metronidazole.

38. The composition of claim 35, wherein the one or more additional antifungal agents is selected from the group consisting of naftifine, terbinafine, zinc pyrithione, and selenium sulfide, sulfur, niacinamide, salicylic acid, clioquinol, haloprogin, povidone-iodine, tolnaftate, and undecylenic acid.

39. The method of any one of claims 33 to 38, wherein the synthetic cationic polymer has antimicrobial activity against bacteria and fungi.

40. The method of any one of claims 33 to 39, wherein the antimicrobial composition has antimicrobial activity against bacteria and fungi.

41. The composition of any one of claims 33 to 40, further comprising a second pharmaceutically acceptable polymer.

42. The composition of claim 31, wherein the antimicrobial pharmaceutical composition further comprises another polymer selected from the group consisting of cellulose, alginate, collagen, polymeric surfactant, polyethylene glycol, polyvinyl alcohol, polyurethane, polyvinyl pyrolidinone (PVP), fibrin(ogen), hyaluronic acid, blood proteins, and tissue proteins.

43. The composition of any one of claims 33 to 42, wherein the pharmaceutical composition further comprises other ingredients selected from the group consisting of stearic acid, gelatin, xanthan gum, carnauba wax, stearyl alcohol, cetyl alcohol, ammonium lauryl sulfate, sodium laureth sulfate, ammonium laureth sulfate, sodium trideceth sulfate, sarcosines, suflosuccinates,, long-chain amino esters, ammonioesters, cetyltrimethylammonium chloride, polyoxyethylene fatty alcohols, polyoxyethylene sorbitol esters, alkanolamides, betaines, sultaines, imidazolinium derivatives, saponins, glycerin, dimethicone, simethicone, polyvinylpyrrolidone, propylene glycol, polyethylene glycol, cocodiethanolamide, polyphosphates, ethylenediaminetetra-acetic acid, glycolic acid, citric acid, benzoate, methylparaben, isopropylparaben, ethylparaben, isobutylparaben, butylparaben, propylparaben, emollients, 1,3-deimethyol-5,5-dimethyl (DMDM) hydantoin, tetrasodium EDTA, methylisothiazolinone, aloe vera, vegetable oils, mineral oils, and panthenol.

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