Compositions and methods for treating fungal infections

Abstract

The present disclosure features a non-irritant pharmaceutical composition containing CD101 in a pharmaceutically acceptable salt (e.g., CD101 acetate) or neutral form, which can be administered intravenously to a subject to treat a fungal infection (e.g., candidiasis) in the subject. [Selection diagram] None

Description

[Background technology]

[0001] The present disclosure relates to the field of fungal infection treatment. Systemic infections caused by Candida are serious and life-threatening infections that represent a significant public health problem, especially in vulnerable patient populations (e.g., elderly patients, post-surgical patients, critically ill patients, and other seriously ill hospitalized patients). Recently, the Centers for Disease Control and Prevention warned that fluconazole-resistant Candida could pose a serious threat to public health. However, since 2007, no new antifungal agents have been approved for the treatment of candidemia. The development of new, more effective treatments for Candida and other fungal infections is urgently needed. Summary of the Invention

[0002] The present disclosure relates to compositions and methods for the treatment of fungal infections. Specifically, the inventors have discovered a pharmaceutical composition for intravenous administration of CD101 (e.g., a salt or neutral form) that exhibits reduced local irritation upon intravenous administration to a subject. CD101 is a broad-spectrum antifungal agent with excellent activity against fungal species (e.g., Candida spp. and Aspergillus spp.).

[0003] A first embodiment is a solution comprising at least 85% (w / w) water and between 0.4 mg / mL and 10 mg / mL of CD101 (e.g., between 0.4 mg / mL and 9 mg / mL, between 0.4 mg / mL and 8 mg / mL, between 0.4 mg / mL and 7 mg / mL, between 0.4 mg / mL and 6 mg / mL, between 0.4 mg / mL and 5 mg / mL, between 0.4 mg / mL and 4 mg / mL, between 0.4 mg / mL and 3 mg / mL, between 0.4 mg / mL and 2 mg / mL, between 0.4 mg / mL and 1 mg / mL, between 0.6 mg / mL and 10 mg / mL, between 0.7 ... between 0.8mg / mL and 10mg / mL, between 0.9mg / mL and 10mg / mL, between 1mg / mL and 10mg / mL, between 2mg / mL and 10mg / mL, between 3mg / mL and 10mg / mL, between 4mg / mL and 10mg / mL, between 5mg / mL and 10mg / mL, between 6mg / mL and 10mg / mL, between 7mg / mL and 10mg / mL, between 8mg / mL and 10mg / mL, or between 9mg / mL and 10mg / mL of CD101; about 0.4mg / mL, about 0.6mg / mL, about 0.8mg 1. A pharmaceutical composition for intravenous administration comprising an aqueous solution comprising about 1 mg / mL, about 1.2 mg / mL, about 1.4 mg / mL, about 1.6 mg / mL, about 1.8 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, or about 10 mg / mL of CD101; and an intravenous solubility enhancer. and wherein the weight:weight (w / w) ratio of intravenous solubility enhancer:CD101 in the pharmaceutical composition is at least 2 (e.g., between 2 and 8, e.g., 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, or 8), and wherein CD101 is in its salt or neutral form and the pharmaceutical composition is between 5 and 7 (e.g., 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.10, 6.11, 6.12, 6.13, 6.14, 6.15, 6.16, 6.17, 6.18, 6.19, 6.20, 6.21, 6.22, 6.23, 6.24, 6.25, 6.26, 6.27, 6.28, 6.29, 6.29, 6.29, 6.26, 6.29, 6.29, 6.21, 6.22, 6.23, 6.24, 6.25, 6.26, 6.27, 6.28, 6.29, 6.29, 6.29, 6.29, 6.29, 6.29, 6.The pharmaceutical composition has a pH of 9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7, and the pharmaceutical composition exhibits reduced local irritation upon intravenous administration to a subject.

[0004] In some embodiments of this aspect, the w / w ratio of intravenous solubility enhancer:CD101 in the pharmaceutical composition is between 2 and 8 (e.g., 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, or 8).

[0005] In some embodiments of this aspect, the concentration of CD101 in the pharmaceutical composition is between 0.4 mg / mL and 4 mg / mL (e.g., about 0.8 mg / mL (e.g., 0.8±0.2 mg / mL) or about 1.6 mg / mL (e.g., 1.6±0.2 mg / mL)).

[0006] A second aspect is a pharmaceutical composition comprising an effective amount of CD101 and an intravenous solubility enhancer in a lyophilized composition, wherein the weight:weight (w / w) ratio of intravenous solubility enhancer:CD101 in the lyophilized composition is between 2 and 8 (e.g., 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6. 5.8, 7, 7.2, 7.4, 7.6, 7.8, or 8), wherein CD101 is in its salt or neutral form, and the lyophilized composition, when reconstituted, results in an aqueous solution having a pH of between 5 and 7 (e.g., 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7).

[0007] In some embodiments, the intravenous solubility enhancer is polysorbate 20 (Tween 20; polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (Tween 40; polyoxyethylene (40) sorbitan monopalmitate), polysorbate 60 (Tween 60; polyoxyethylene (60) sorbitan monostearate), polysorbate 80 (Tween 80; polyoxyethylene (80) sorbitan monooleate), β-cyclodextrin, polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor RH 60), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sorbitan monooleate (Span 20), polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate), PEG 400 caprylic / capric glyceride (Labrasol), PEG 300 oleic glyceride (Labrafil M-1944CS), phosphatidylcholine (lecithin), alkyl glucoside, sucrose monolaurate, sucrose monooleate, and polyoxyethylene-polyoxypropylene block copolymer (poloxamer). In some embodiments, the alkyl glucoside is selected from the group consisting of alkyl monoglucoside (e.g., hexyl glucoside, heptaglucoside, octyl glucoside, nonaglucoside, decyl glucoside, dodecyl glucoside, or tetradecyl glucoside). In some embodiments, the alkyl glucoside is an alkyl diglucoside (e.g., hexyl maltoside, heptamaltoside, octyl maltoside, nonamaltoside, decyl maltoside, dodecyl maltoside (e.g., dodecyl-β-D-maltoside (DDM)), or tetradecyl maltoside (e.g., tetradecyl-β-D-maltoside (TDM))).

[0008] In some embodiments, the intravenous solubility enhancer is polysorbate 80 (Tween 80; polyoxyethylene (80) sorbitan monooleate).

[0009] In some embodiments of the first two aspects of the invention, the pharmaceutical composition further comprises a buffering agent. In some embodiments, the buffering agent is histidine, citrate, succinate, lactate, propanoate, arginine, tris(hydroxymethyl)aminomethane (Tris), glycine, acetate, or formate. In some embodiments of the first two aspects of the invention, the buffering agent comprises a monovalent molecule (e.g., acetate, lactate, formate, histidine, tris(hydroxymethyl)aminomethane (Tris), arginine, and / or glycine). In some embodiments of the first two aspects of the invention, the buffering agent comprises an amino acid (e.g., histidine, arginine, and / or glycine).

[0010] In some embodiments of the first aspect of the invention, the pharmaceutical composition further comprises between 0.12% and 0.6% (w / w) sugars (e.g., between 0.12% and 0.58% (w / w), between 0.12% and 0.56% (w / w), between 0.12% and 0.54% (w / w), between 0.12% and 0.52% (w / w), between 0.12% and 0.5% (w / w), between 0.12% and 0.48% (w / w), between 0.12% and 0.46% (w / w), between 0.12% and 0.58% (w / w), between 0.12% and 0.56% (w / w), between 0.12% and 0.54% (w / w), between 0.12% and 0.52 ... between 0.12% and 0.44% (w / w), between 0.12% and 0.42% (w / w), between 0.12% and 0.4% (w / w), between 0.12% and 0.38% (w / w), between 0.12% and 0.36% (w / w), between 0.12% and 0.34% (w / w), between 0.12% and 0.32% (w / w), between 0.12% and 0.3% (w / w), between 0.12% and 0.28% (w / w), between 0.12% and 0.26% (w / w), between 0.12% and 0.24% (w / Sugars between 0.12% and 0.22% (w / w), between 0.12% and 0.2% (w / w), between 0.12% and 0.18% (w / w), between 0.12% and 0.16% (w / w), or between 0.12% and 0.14% (w / w); about 0.12% (w / w), about 0.14% (w / w), about 0.16% (w / w), about 0.18% (w / w), about 0.2% (w / w), about 0.22% (w / w), about 0.24% (w / w), about 0.26% (w / w), about 0. 28% (w / w), about 0.3% (w / w), about 0.32% (w / w), about 0.34% (w / w), about 0.36% (w / w), about 0.38% (w / w), about 0.4% (w / w), about 0.42% (w / w), about 0.44% (w / w), about 0.46% (w / w), about 0.48% (w / w), about 0.5% (w / w), about 0.52% (w / w), about 0.54% (w / w), about 0.56% (w / w), about 0.58% (w / w), or about 0.6% (w / w) of a sugar). In some embodiments, the sugar is mannitol, sucrose, trehalose, maltose, dextrose, or lactose (e.g., mannitol).

[0011] In some embodiments of the second aspect of the invention, the pharmaceutical composition further comprises between 2% and 10% (w / w) sugars (e.g., between 2% and 9% (w / w), between 2% and 8% (w / w), between 2% and 7% (w / w), between 2% and 6% (w / w), between 2% and 5% (w / w), between 2% and 4%, or 2% to 3% (w / w) sugars; about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w) sugars).

[0012] In some embodiments, the salt form of CD101 in the pharmaceutical compositions and methods described herein is CD101 acetate.

[0013] Another aspect is a method of treating or preventing a fungal infection in a subject by intravenously administering to the subject a pharmaceutical composition according to the first aspect of the invention, wherein the method exhibits reduced local irritation upon intravenous administration of the pharmaceutical composition to the subject.

[0014] Another embodiment is a method of treating or preventing a fungal infection in a subject by (i) reconstituting a pharmaceutical composition according to the second embodiment of the present invention to form an aqueous solution, and (ii) intravenously administering the aqueous solution to the subject, wherein the concentration of CD101 in the aqueous solution is between 0.4 mg / mL and 10 mg / mL (e.g., between 0.4 mg / mL and 9 mg / mL, between 0.4 mg / mL and 8 mg / mL, between 0.4 mg / mL and 7 mg / mL, between 0.4 mg / mL and 6 mg / mL, between 0.4 mg / mL and 10 mg / mL). Between 0.4mg / mL and 5mg / mL, Between 0.4mg / mL and 4mg / mL, Between 0.4mg / mL and 3mg / mL, Between 0.4mg / mL and 2mg / mL, Between 0.4mg / mL and 1mg / mL, Between 0.6mg / mL and 10mg / mL, Between 0.7mg / mL and 10mg / mL, Between 0.8mg / mL and 10mg / mL, Between 0.9mg / mL and 10mg / mL, Between 1mg / mL and 10mg / mL, Between 2mg / mL and 10mg / mL, Between 3mg / mL and 1 CD101 between 0 mg / mL, between 4 mg / mL and 10 mg / mL, between 5 mg / mL and 10 mg / mL, between 6 mg / mL and 10 mg / mL, between 7 mg / mL and 10 mg / mL, between 8 mg / mL and 10 mg / mL, or between 9 mg / mL and 10 mg / mL; about 0.4 mg / mL, about 0.6 mg / mL, about 0.8 mg / mL, about 1 mg / mL, about 1.2 mg / mL, about 1.4 mg / mL, about 1.6 mg / mL, about 1.8 mg / mL, about 2 mg / mL, about 2.5 mg / mL and wherein the aqueous solution is about 10 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, or about 10 mg / mL of CD101), wherein CD101 is in its salt or neutral form, and the method exhibits reduced local irritation upon intravenous administration of the aqueous solution to a subject.

[0015] In some embodiments of this aspect, the concentration of CD101 in the pharmaceutical composition is about 0.4 mg / mL. In some embodiments of this aspect, the concentration of CD101 in the pharmaceutical composition is about 0.8 mg / mL. In some embodiments, the concentration of CD101 in the pharmaceutical composition is about 1.6 mg / mL.

[0016] In some embodiments of this aspect, the concentration of CD101 in the pharmaceutical composition is about 3.0 mg / mL, hi some embodiments, the concentration of CD101 in the pharmaceutical composition is about 4.0 mg / mL.

[0017] In some embodiments of the methods of the present invention, the method comprises administering intravenously to a subject by infusion at a constant infusion rate of between 2 mL / min and 9 mL / min (e.g., between 2 mL / min and 8 mL / min, between 2 mL / min and 7 mL / min, between 2 mL / min and 6 mL / min, between 2 mL / min and 5 mL / min, between 2 mL / min and 4 mL / min, between 2 mL / min and 3 mL / min, between 3 mL / min and 9 mL / min, between 4 mL / min and 9 mL / min, between 5 mL / min and 9 mL / min, between 6 mL / min and 9 mL / min, between 7 mL / min and 9 mL / min, or between 8 mL / min and 9 mL / min; e.g., 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9 mL / min). In some embodiments, the method comprises administering the compound intravenously to a subject by infusion over 30 to 120 minutes (e.g., 30, 40, 50, 60, 70, 80, 90, 100, 110, or 120 minutes).

[0018] In some embodiments of the methods of the invention, the methods involve intravenously administering at least one dose every 5 to 15 days (e.g., every 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days), hi some embodiments, the methods involve intravenously administering one dose every 5 to 15 days (e.g., every 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days).

[0019] In some embodiments of the methods of the present invention, the fungal infection being treated or prevented is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, periungual mycosis, tinea versicolor, thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, esophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis. In some embodiments, the infection is candidemia or invasive candidiasis.

[0020] In some embodiments of the methods of the invention, the fungal infection treated or prevented is an infection of Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C. orthopsilosis, C. guilliermondii, C. rugosa, C. auris, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.

[0021] In another aspect, the invention features a method of preventing or treating a biofilm in a subject, the method including administering to the subject a pharmaceutical composition including a CD101 salt or neutral form thereof and one or more pharmaceutically acceptable excipients.

[0022] In some embodiments of this aspect, the biofilm in the subject is a Candida biofilm (e.g., a Candida albicans biofilm). In some embodiments, the biofilm is attached to a mucosa of the subject.

[0023] In another aspect, the invention features a method for preventing biofilm growth on a catheter or killing biofilm attached to a catheter, the method comprising submerging the catheter in an aqueous solution containing a CD101 salt or its neutral form, or flowing an aqueous solution containing a CD101 salt or its neutral form through the lumen of the catheter.

[0024] In some embodiments of this aspect, the biofilm on the catheter is a Candida biofilm (eg, a Candida albicans biofilm).

[0025] Definition: As used herein, the term "intravenous administration" or "administering intravenously" refers to the intravenous infusion of a drug into a subject.

[0026] As used herein, the term "fungal infection" refers to an infection caused by a fungus (e.g., Candida spp. or Aspergillus spp.) that invades and causes damage to the cells, tissues, and / or organs of a subject. In some embodiments, the fungus grows, multiplies, and / or produces toxins within the cells, tissues, and / or organs of the subject. In some embodiments, a fungal infection can be any phase in which the presence of a fungal population(s) is latent within or damaging to the host body. Thus, a subject "suffers" from a fungal infection when a latent fungal population is detectable within or on the subject's body, when an excessive amount of a fungal population is present within or on the subject's body, or when the presence of a fungal population(s) is damaging to the subject's cells, tissues, and / or organs.

[0027] As used herein, the term "protecting against a fungal infection" or "preventing a fungal infection" refers to preventing a subject from developing a fungal infection or reducing the risk that a subject may develop a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.). Prophylactic agents used in methods for protecting against a fungal infection in a subject are often administered to the subject before any detection of a fungal infection. In some embodiments of the methods for protecting against a fungal infection, a subject (e.g., a subject at risk of developing a fungal infection) may be administered a pharmaceutical composition of the present invention to prevent the development of a fungal infection or reduce the risk of developing a fungal infection.

[0028] As used herein, the term "biofilm" refers to a three-dimensional structure composed of heterogeneous fungi (e.g., Candida) and hyphae that can adhere to various surfaces (e.g., mucous membranes or the inside of catheters). Biofilms can form on the surface of medical devices, causing biofilm device-associated infections. For example, biofilms on indwelling devices (e.g., vascular catheters) can lead to life-threatening infections.

[0029] As used herein, the term "treat" or "treating" refers to the therapeutic treatment of a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject. In some embodiments, the therapeutic treatment can slow the progression of the fungal infection, improve the subject's outcome, and / or eliminate the infection. In some embodiments, the therapeutic treatment of a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject can reduce or alleviate one or more symptoms or conditions associated with the fungal infection, attenuate the severity of the fungal infection, stabilize (i.e., do not worsen) the condition of the fungal infection, prevent the spread of the fungal infection, and / or delay or slow the progression of the fungal infection compared to the state and / or status of the fungal infection in the absence of the therapeutic treatment.

[0030] The term "local irritation" as used herein refers to any adverse reaction that a subject may experience at the intravenous injection site after administration of a drug. Local irritation at the injection site may include, for example, pain or tenderness at the injection site, skin itching, internal bleeding, and / or swelling, vein discoloration (e.g., darkening of the veins leading from the injection site), and skin rash. "Reduced local irritation" refers to a reduction or absence of local irritation when a subject is intravenously administered the pharmaceutical composition of the present invention compared to the irritation observed when other compositions are intravenously administered.

[0031] The term "intravenous solubility enhancer," as used herein, refers to an agent that enhances the intravenous solubility of CD101 (e.g., a salt or neutral form of CD101) in a subject's bloodstream when the pharmaceutical composition is administered intravenously. Intravenous precipitation of CD101 can cause local irritation at the injection site (e.g., pain or tenderness at the injection site, skin itching, internal bleeding, and / or swelling, vein discoloration (e.g., darkening of the veins leading from the injection site), and skin rash). The intravenous solubility enhancer in the pharmaceutical composition of the present invention functions to reduce intravenous precipitation of CD101 in a subject's bloodstream compared to the intravenous precipitation that occurs when CD101 (e.g., a salt or neutral form of CD101) is in a composition without the intravenous solubility enhancer. In some embodiments, the pharmaceutical composition of the present invention contains polysorbate 80 (Tween 80) as an intravenous solubility enhancer.

[0032] As used herein, the term "alkyl glucoside" refers to a surfactant having an alkyl chain (e.g., an alkyl chain ranging from 6 to 18 carbon atoms) attached to one or more glucose molecules. The alkyl glucoside can be an alkyl monoglucoside (e.g., an alkyl chain attached to one glucose molecule) or an alkyl diglucoside (e.g., an alkyl chain attached to a disaccharide (e.g., maltose) containing two glucose molecules joined by an interglycosidic bond).

[0033] As used herein, the term "immunocompromised" refers to a subject (e.g., a human) with a weakened immune system. The subject's immune system may be weakened or impaired by disease (e.g., HIV infection, autoimmune disease, cancer), medical procedure (e.g., organ transplant (e.g., solid organ transplant) or bone marrow transplant), drug (e.g., immunosuppressant), and / or pathogen (e.g., bacteria, fungi, viruses). The host's immune system may also have a congenital defect that renders the host more susceptible to infection.

[0034] As used herein, the term "immunosuppressive therapy" refers to therapy that uses one or more immunosuppressive agents to reduce the activity and / or effectiveness of a subject's (e.g., human) immune system. In some embodiments, immunosuppressive therapy is used to prevent the body from rejecting a transplant (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), to treat graft-versus-host disease after a bone marrow transplant, and / or to treat an autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, multiple sclerosis, myasthenia gravis, sarcoidosis, Behcet's disease). Immunosuppressants include, but are not limited to, calcineurin inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors (e.g., cyclosporine A, cyclosporine G, voclosporin, tacrolimus, pimecrolimus, sirolimus, temsirolimus, deforolimus, everolimus, zotarolimus, biolimus, imatinib, dasatinib, nilotinib, erlotinib, sunitinib, gefitinib, bosutinib, neratinib, axitinib, crizotinib, lapatinib, toceranib, and vatalanib).

[0035] The term "effective amount" as used herein means the amount of drug required to treat or prevent an infection or a disease associated with an infection. The effective amount of a drug used to practice the methods described herein for the therapeutic or prophylactic treatment of a condition caused or contributed to by a microbial infection varies depending on the mode of administration, the age, weight, and general health of the subject. Ultimately, the attending physician will determine the appropriate amount and dosage regimen. Such an amount is referred to as an "effective amount."

[0036] As used herein, the term "CD101 salt" refers to a salt of a compound of Formula 1. CD101 has a structure (below) in which, in its salt form, the positive charge of the tertiary ammonium ion of CD101 is balanced by a negative counterion (e.g., acetate). [ka]

[0037] As used herein, the term "CD101 neutral form" includes the zwitterionic form of CD101, in which the compound of Formula 1 has no net positive or negative charge. Zwitterions exist in a higher proportion in basic media (e.g., pH 9) compared to CD101 or a salt of CD101. In some embodiments, zwitterions may also exist in the salt form of CD101.

[0038] The term "concentration of CD101" as used herein is calculated based on the molecular weight of CD101 shown in Formula 1 (not including the negative counterion (e.g., acetate) when CD101 is in its salt form). For example, in some embodiments of the present invention, the concentration of CD101 in the pharmaceutical composition is between 0.4 mg / mL and 4 mg / mL (e.g., about 0.8 mg / mL (e.g., 0.8±0.2 mg / mL) or about 1.6 mg / mL (e.g., 1.6±0.2 mg / mL)). These concentrations are calculated based on the molecular weight of CD101 shown in Formula 1.

[0039] As used herein, the term "weight:weight (w / w) ratio" is calculated based on the molecular weight of CD101 (not including the negative counterion (e.g., acetate) when CD101 is in its salt form) as shown in Formula 1. For example, in some embodiments of the present invention, the weight:weight (w / w) ratio of blood solubilizing agent to CD101 in the pharmaceutical composition is at least 2 (e.g., between 2 and 8, e.g., 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, or 8). The w / w ratio of blood solubilizing agent to CD101 is calculated based on the molecular weight of CD101 as shown in Formula 1.

[0040] The term "salt" as used herein refers to any pharmaceutically acceptable salt commonly used in the pharmaceutical industry, such as a non-toxic acid addition salt, metal salt, or metal complex. Examples of acid addition salts include organic acids (e.g., acetic acid, lactic acid, palmoic acid, maleic acid, citric acid, cholic acid, capric acid, caprylic acid, lauric acid, glutaric acid, glucuronic acid, glyceric acid, glycocholic acid, glyoxylic acid, isocitric acid, isovaleric acid, lactic acid, malic acid, oxaloacetic acid, oxalosuccinic acid, propionic acid, pyruvic acid, ascorbic acid, succinic acid, benzoic acid, palmitic acid, suberic acid, salicylic acid, tartaric acid, methanesulfonic acid, toluenesulfonic acid, and trifluoroacetic acid) and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid). Representative alkali metal and alkaline earth metal salts include, among others, sodium, lithium, potassium, calcium, and magnesium.

[0041] As used herein, the term "dose" refers to the amount of CD101 administered to a subject. As used herein, the amount in each dose refers to the amount of CD101 (Formula 1 above) (not including the negative counterion (e.g., acetate) when CD101 is in its salt form).

[0042] As used herein, the term "between" refers to any amount within the stated range, including each of the endpoints of the stated range. For example, a pH between 5 and 7 refers to any amount within the range of 5 to 7, as well as a pH of 5 and a pH of 7.

[0043] As used herein, the term "subject" or "patient" means a human.

[0044] Except in the working examples or where otherwise indicated, all numbers expressing the amount of ingredients, concentrations, or reaction conditions used herein should be understood to be modified in all instances by the term "about." As used herein, the term "about" refers to a deviation of ±10%. For example, about 10% refers to 9.5% to 10.5%. As used herein, the term "about" refers to a deviation of ±10%. For example, about 10% refers to 9% to 11%.

[0045] Other features and advantages of the present disclosure will be apparent from the following detailed description, and from the claims. [Brief explanation of the drawings]

[0046] [Figure 1] 1 is a graph showing percent survival over time in mice infected with Candida auris and treated with 20 mg / kg CD101 (intraperitoneal), 20 mg / kg fluconazole (oral), or 0.3 mg / kg amphotericin B (intraperitoneal). [Figure 2] 1 is a bar graph showing the effect of CD101 (0.25 or 1 μg / ml) (A) and fluconazole (1 or 4 μg / ml) (B) on the metabolic activity of adherent-phase C. albicans biofilms compared to untreated controls. [Figure 3-1] A–E are confocal scanning microscopy images showing the effects (prevention) of CD101 and fluconazole on adherent-phase C. albicans biofilms. Three-dimensional top-down (upper panels) and side-on (lower panels) views of biofilms formed by C. albicans treated with no drug (control; A), 0.25 μg / ml CD101 (B), 1 μg / ml CD101 (C), 1 μg / ml fluconazole (D), and 4 μg / ml fluconazole (E) are shown. [Figure 3-2] F and G are bar graphs showing the thickness of C. albicans biofilms exposed to CD101 (F) and fluconazole (G). [Figure 4] A and B are bar graphs showing the effect of CD101 (0.25 or 1 μg / ml) (A) and fluconazole (1 or 4 μg / ml) (B) on the metabolic activity of mature C. albicans biofilms compared to untreated controls. [Figure 5-1] (A–E) Confocal scanning microscopy images showing the effects of CD101 and fluconazole on mature C. albicans biofilms (treatments). The images show three-dimensional top (upper panels) and side (lower panels) views of biofilms exposed to no drug (control; A), 0.25 μg / ml CD101 (B), 1 μg / ml CD101 (C), 1 μg / ml fluconazole (D), and 4 μg / ml fluconazole (E). Arrows indicate raised / broken cells. [Figure 5-2] F and G are bar graphs showing the thickness of C. albicans biofilms exposed to: CD101 (F) and fluconazole (G). [Figure 6-1] A–F are images showing the time course effect of CD101 (0.25 μg / ml) on C. albicans biofilm formation. Images were followed from time 0 to 16 hours after incorporation for biofilms treated with no drug (A and B), CD101 (low magnification, 20x) (C and D), and CD101 (high magnification, 63x) (E and F). Arrows indicate raised, deformed, and broken cells. [Figure 6-2] A–F are images showing the time course effect of CD101 (0.25 μg / ml) on C. albicans biofilm formation. Images were followed from time 0 to 16 hours after incorporation for biofilms treated with no drug (A and B), CD101 (low magnification, 20x) (C and D), and CD101 (high magnification, 63x) (E and F). Arrows indicate raised, deformed, and broken cells. [Figure 7](A and B) Images showing the time course effect of CD101 (0.25 μg / ml) on C. albicans biofilms formed at 3 hours. CD101 was added after 3 hours of biofilm formation, and images were taken immediately after CD101 addition (A) and followed for 16 hours (B) (63x magnification). Arrows indicate raised, deformed, and broken cells. DETAILED DESCRIPTION OF THE INVENTION

[0047] Methods are provided for treating a fungal infection in a subject in need thereof by intravenously administering to the subject CD101 (e.g., a salt or neutral form of CD101) formulated as an aqueous composition.

[0048] Pharmaceutical Composition CD101 is a semisynthetic echinocandin that inhibits the synthesis of 1,3-β-D-glucan. 1,3-β-D-glucan is an essential component of the fungal cell wall of yeast-form Candida species and the active cell growth zone of Aspergillus hyphae. 1,3-β-D-glucan synthesis is dependent on the activity of the enzyme complex 1,3-β-D-glucan synthase, whose catalytic subunits are encoded by the FKS1, FKS2, and FKS3 genes. Inhibition of this enzyme results in rapid, concentration-dependent fungicidal activity against Candida spp. The structure of CD101 is shown in the figure above.

[0049] The present disclosure features pharmaceutical compositions for intravenously administering CD101 (e.g., a salt or neutral form of CD101) to a subject. In some embodiments, the pharmaceutical composition for intravenous administration contains between 0.4 mg / mL and 10 mg / mL of CD101 (e.g., between 0.4 mg / mL and 9 mg / mL, between 0.4 mg / mL and 8 mg / mL, between 0.4 mg / mL and 7 mg / mL, between 0.4 mg / mL and 6 mg / mL, between 0.4 mg / mL and 5 mg / mL, between 0.4 mg / mL and 4 mg / mL, between 0.4 mg / mL and 3 mg / mL, between 0.4 mg / mL and 2 mg / mL, between 0.4 mg / mL and 1 mg / mL, between 0.6 mg / mL and 10 mg / mL). , between 0.7 mg / mL and 10 mg / mL, between 0.8 mg / mL and 10 mg / mL, between 0.9 mg / mL and 10 mg / mL, between 1 mg / mL and 10 mg / mL, between 2 mg / mL and 10 mg / mL, between 3 mg / mL and 10 mg / mL, between 4 mg / mL and 10 mg / mL, between 5 mg / mL and 10 mg / mL, between 6 mg / mL and 10 mg / mL, between 7 mg / mL and 10 mg / mL, between 8 mg / mL and 10 mg / mL, or between 9 mg / mL and 10 mg / mL of CD101) and an intravenous solubility enhancer.

[0050] The intravenous solubility enhancer functions to promote the intravenous solubility of CD101 (e.g., a salt or neutral form of CD101) in a subject's bloodstream when the pharmaceutical composition is administered intravenously. In some embodiments, intravenous precipitation of CD101 causes local irritation at the injection site (e.g., pain or tenderness at the injection site, skin itching, bruising, and / or swelling, vein discoloration (e.g., darkening of the veins leading from the injection site), and skin rash). The intravenous solubility enhancer in the pharmaceutical composition of the present invention reduces intravenous precipitation of CD101 in a subject's bloodstream compared to the intravenous precipitation that occurs when CD101 is in a composition without the intravenous solubility enhancer. In some embodiments, a pharmaceutical composition comprising between 0.4 mg / mL and 10 mg / mL of CD101 and an intravenous solubility enhancer exhibits reduced local irritation when administered intravenously to a subject.

[0051] The amount of intravenous solubility enhancer in the pharmaceutical composition can depend, for example, on the concentration of CD101 in the pharmaceutical composition and / or the pH of the pharmaceutical composition. In some embodiments, the weight:weight (w / w) ratio of intravenous solubility enhancer:CD101 in the pharmaceutical composition is at least 2 (e.g., between 2 and 8, e.g., 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, or 8).Examples of intravenous solubility enhancers that may be included in the pharmaceutical compositions described herein include, but are not limited to, polysorbate 20 (Tween 20; polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (Tween 40; polyoxyethylene (40) sorbitan monopalmitate), polysorbate 60 (Tween 60; polyoxyethylene (60) sorbitan monostearate), polysorbate 80 (Tween 80; polyoxyethylene (80) sorbitan monooleate), β-cyclodextrin, polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor RH 60), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sorbitan monooleate (Span 20), Polyoxyl 8 Stearate (PEG 400 Monostearate), Polyoxyl 40 Stearate (PEG 1750 Monostearate), PEG 400 Caprylic / Capric Glyceride (Labrasol), PEG 300 Oleic Glyceride (Labrafil M-1944CS), phosphatidylcholine (lecithin), alkyl glucosides, sucrose monolaurate, sucrose monooleate, and polyoxyethylene-polyoxypropylene block copolymers (poloxamers (e.g., poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate)). In some embodiments, the alkyl glucoside is an alkyl monoglucoside (eg, hexyl glucoside, heptaglucoside, octyl glucoside, nonaglucoside, decyl glucoside, dodecyl glucoside, or tetradecyl glucoside).In some embodiments, the alkyl glucoside is an alkyl diglucoside (e.g., hexyl maltoside, heptamaltoside, octyl maltoside, nonamaltoside, decyl maltoside, dodecyl maltoside (e.g., dodecyl-β-D-maltoside (DDM)), or tetradecyl maltoside (e.g., tetradecyl-β-D-maltoside (TDM))). In some embodiments, the intravenous solubility enhancer in the pharmaceutical composition is polysorbate 80.

[0052] The concentration of CD101 in the pharmaceutical compositions for intravenous administration described herein can be between 0.4 mg / mL and 4 mg / mL (e.g., 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 mg / mL). In some embodiments, the concentration of CD101 in the pharmaceutical compositions for intravenous administration described herein is 0.8±0.2 mg / mL. In some embodiments, the concentration of CD101 in the pharmaceutical compositions for intravenous administration described herein is 1.6±0.2 mg / mL.

[0053] The pharmaceutical compositions of the present invention for intravenous administration can also contain a buffering agent. The buffering agent functions to maintain the pH of the composition. In some embodiments, the pharmaceutical compositions of the present invention for intravenous administration have a pH between 5 and 7 (e.g., 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7). The buffering agent contained in the pharmaceutical compositions for intravenous administration described herein can be, for example, histidine, citrate, succinate, lactate, propanoate, arginine, tris(hydroxymethyl)aminomethane (Tris), glycine, acetate, or formate.

[0054] Additionally, sugars (e.g., mannitol, sucrose, trehalose, maltose, dextrose, or lactose) can also be included in the pharmaceutical compositions of the present invention. Pharmaceutical compositions for intravenous administration, including aqueous solutions containing between 0.4 mg / mL and 10 mg / mL of CD101, can contain between 0.12% and 0.6% (w / w) of sugars (e.g., between 0.12% and 0.58% (w / w), between 0.12% and 0.56% (w / w), between 0.12% and 0.54% (w / w), between 0.12% and 0.52% (w / w), between 0.12% and 0.5% (w / w), between 0.12% and 0.48% (w / w), between 0.12% and 0.46% (w / w)). ), between 0.12% and 0.44% (w / w), between 0.12% and 0.42% (w / w), between 0.12% and 0.4% (w / w), between 0.12% and 0.38% (w / w), between 0.12% and 0.36% (w / w), between 0.12% and 0.34% (w / w), between 0.12% and 0.32% (w / w), between 0.12% and 0.3% (w / w), between 0.12% and 0.28% (w / w), between 0.12% and 0.26% (w / w), between 0.12% and 0.2 between 0.4% (w / w), between 0.12% and 0.22% (w / w), between 0.12% and 0.2% (w / w), between 0.12% and 0.18% (w / w), between 0.12% and 0.16% (w / w), or between 0.12% and 0.14% (w / w); about 0.12% (w / w), about 0.14% (w / w), about 0.16% (w / w), about 0.18% (w / w), about 0.2% (w / w), about 0.22% (w / w), about 0.24% (w / w), about 0.26% (w / w), about 0.2 In some embodiments, the sugar in the pharmaceutical composition may comprise about 8% (w / w), about 0.3% (w / w), about 0.32% (w / w), about 0.34% (w / w), about 0.36% (w / w), about 0.38% (w / w), about 0.4% (w / w), about 0.42% (w / w), about 0.44% (w / w), about 0.46% (w / w), about 0.48% (w / w), about 0.5% (w / w), about 0.52% (w / w), about 0.54% (w / w), about 0.56% (w / w), about 0.58% (w / w), or about 0.6% (w / w) of a sugar. In some embodiments, the sugar in the pharmaceutical composition is mannitol.

[0055] Pharmaceutical compositions comprising an effective amount of CD101 (e.g., a salt or neutral form of CD101) and an intravenous solubility enhancer in a lyophilized composition contain between 2% and 10% (w / w) sugars (e.g., between 2% and 9% (w / w), between 2% and 8% (w / w), between 2% and 7% (w / w), between 2% and 6% (w / w), between 2% and 5% (w / w), between 2% and 4%, or between 2% and 3% (w / w) sugars; about 2% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w) sugars).

[0056] The pharmaceutical composition of the present invention can also comprise an effective amount of CD101 and an intravenous solubility enhancer in a lyophilized composition. The lyophilized composition can comprise a weight:weight (w / w) ratio of intravenous solubility enhancer:CD101 of between 2 and 8 (e.g., 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8, 5, 5.2, 5.4, 5.6, 5.8, 6, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.6, 7.8, or 8). CD101 in the lyophilized composition can be in its salt or neutral form. The lyophilized composition can be reconstituted to provide an aqueous solution having a pH between 5 and 7 (e.g., 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7).

[0057] Therapy Methods of the present invention include, for example, methods of treating or preventing a fungal infection in a subject (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) by intravenously administering to the subject a pharmaceutical composition described herein. When using a pharmaceutical composition comprising CD101 (e.g., a salt or neutral form of CD101) and an intravenous solubility enhancer in a lyophilized composition, the pharmaceutical composition can first be reconstituted to form an aqueous solution (e.g., an aqueous solution having a CD101 concentration of between 0.4 mg / mL and 10 mg / mL) and then administered intravenously to the subject.

[0058] The methods for treating or preventing fungal infections described herein exhibit reduced local irritation upon intravenous administration of the pharmaceutical compositions of the present invention to a subject. When a subject is intravenously administered a pharmaceutical composition of the present invention, the subject may experience reduced or no local irritation compared to the local irritation experienced when other compositions are administered intravenously (e.g., pain or tenderness at the injection site, itchy skin, bruising and / or swelling, vein discoloration (e.g., darkening of the veins leading from the injection site), and skin rash).

[0059] In some embodiments of the methods of the present invention, the pharmaceutical compositions described herein can be administered intravenously to a subject by infusion. The intravenous infusion can be performed at a constant infusion rate of between 2 mL / min and 9 mL / min (e.g., 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9 mL / min). In some embodiments, the pharmaceutical composition can be administered to a subject over 30 to 120 minutes (e.g., 30, 40, 50, 60, 70, 80, 90, 100, 110, or 120 minutes). In some embodiments of the methods of the present invention, the amount of water to be used is 100 mL to 500 mL (e.g., 100, 105, 110, 115, 120, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, 345, 355, 365, 375, 385, 395, 405, 415, 425, 435, 445, 455, 465, 475, 485, 495, 505, 515, 525, 535, 545, 555, 565, 575, 585, 595, 605, 615, 625, 635, 645, 655, 665, 675, 685, 695, 705, 715, 725, 735, 745, 755, 765, 775, 785, 795, 805, 815, 825, 835, 845, 855, 865, 875, 885, 895, 905, 915, 925, 935, 945, 955, 965, 975, 985, 995, 1005, 101 5, 445, 455, 465, 475, 485, 495, or 500 mL; 100-480 mL, 100-460 mL, 100-440 mL, 100-420 mL, 100-400 mL, 100-380 mL, 100-360 mL, 100-340 mL, 100-320 mL, 100-300 mL, 100-280 mL, 100-260 mL, 100-240 mL, 100-220 mL, 100-200 mL, 100 ~190mL, 100~180mL, 100~170mL, 100~160mL, 100~150mL, 100~140mL, or 100~130mL; 120~500mL, 140~500mL, 160~500mL, 180~500mL, 200~500mL, 220~500mL, 240~500mL, 260~500mL, 280~500mL, 300~500mL, 320~500mL, 340~500mL L, 360-500 mL, 380-500 mL, 400-500 mL, 420-500 mL, 440-500 mL, 460-500 mL, or 480-500 mL) of a pharmaceutical composition (e.g., a pharmaceutical composition having CD101 at a concentration of 0.4 mg / mL, 0.8 mg / mL, or 1.6 mg / mL) is administered to a subject over 20 to 60 minutes (e.g., 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes).In some embodiments, 100 mL to 250 mL (e.g., 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, or 250 mL) of a pharmaceutical composition (e.g., a pharmaceutical composition having a concentration of CD101 of 0.4 mg / mL, 0.8 mg / mL, or 1.6 mg / mL) is administered to a subject in 30 minutes. In some embodiments, 125 mL to 250 mL (e.g., 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, or 250 mL) of a pharmaceutical composition (e.g., a pharmaceutical composition having a concentration of CD101 of 0.4 mg / mL, 0.8 mg / mL, or 1.6 mg / mL) is administered to a subject over 60 minutes. In some embodiments, 250 mL of a pharmaceutical composition (e.g., a pharmaceutical composition having a concentration of CD101 of 0.4 mg / mL, 0.8 mg / mL, or 1.6 mg / mL) is administered to a subject over 30 minutes. In some embodiments, 250 mL of a pharmaceutical composition (e.g., a pharmaceutical composition having a concentration of CD101 of 0.4 mg / mL, 0.8 mg / mL, or 1.6 mg / mL) is administered to a subject over 60 minutes.

[0060] Further, in some embodiments, at least one dose (e.g., a dose of CD101 between 50 mg and 800 mg; about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450 , 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, or 800 mg of CD101) is administered intravenously to the subject every 5 to 15 days (e.g., every 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days). In some embodiments, a single dose (e.g., a dose of CD101 between 50 mg and 800 mg; about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, or 800 mg of CD101) is administered intravenously to the subject every 5 to 15 days (e.g., every 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days).

[0061] In some embodiments of the methods of the present invention, the subject may be immunocompromised and therefore at high risk of developing a fungal infection. In some embodiments, the subject is preparing for an invasive medical procedure or undergoing long-term antibiotic therapy. In some embodiments, the subject has been diagnosed with humoral immunity deficiency, T-cell deficiency, neutropenia, asplenia, or complement deficiency. In some embodiments, the subject is being treated or is about to be treated with an immunosuppressant. In some embodiments, the subject has been diagnosed with a disease that causes immunosuppression (e.g., cancer or acquired immune deficiency syndrome). In some embodiments, the subject has cancer (e.g., leukemia, lymphoma, or multiple myeloma). In some embodiments, the subject has undergone or is about to undergo immunosuppressive therapy. In some embodiments, the subject has undergone or is about to undergo hematopoietic stem cell transplantation. In some embodiments, the subject has undergone or is about to undergo organ transplantation. In some embodiments, a subject may receive prophylactic treatment while preparing for an invasive medical procedure (e.g., preparing for surgery, e.g., preparing to receive a transplant, stem cell therapy, graft, prosthetic organ, undergo long-term or frequent intravenous catheterization, or prepare to undergo treatment in an intensive care unit).

[0062] In some embodiments of the methods described herein, the fungal infection treated or prevented is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, periungual mycosis, tinea versicolor, thrush, vaginal candidiasis, respiratory candidiasis, biliary candidiasis, esophageal candidiasis, urinary candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis.

[0063] In some embodiments of the methods described herein, the fungal infection is candidemia or invasive candidiasis.

[0064] In some embodiments of the methods described herein, the fungal infection being treated or prevented is an infection with Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C. orthopsilosis, C. guilliermondii, C. rugosa, C. auris, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus. The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compositions claimed herein may be performed, made, and evaluated. These examples are intended to be merely illustrative of the present disclosure and are not intended to be limiting. [Example]

[0065] Example 1: Solubility of CD101 in various media Table 1 below shows the solubility of CD101 acetate in different solutions. [Table 1] TIFF0007779651000003.tif213162

[0066] CD101 acetate is soluble (>1 mg / mL) in 5% dextrose, 5% mannitol, and 0.22%–0.45% sterile saline, but exhibits a significant decrease in solubility at higher salt concentrations (e.g., normal saline (0.9% sterile saline) or lactated Ringer's solution) and is nearly insoluble in PBS buffer. The addition of nonionic surfactants (e.g., polysorbate 20 (Tween 20) and polysorbate 80 (Tween 80)) improves the solubility of CD101 acetate in high-salt solutions (e.g., 0.9% sterile saline, neutral pH phosphate buffer media), and lactated Ringer's solution.

[0067] Example 2: Investigation of the Use of Tween 80 for Use with CD101 Acetate Formulations method A 20 mg / kg dose of CD101 acetate was prepared w / w in 5% dextrose solution (CD101 acetate 4 mg / mL solution) using a salt:free base correction factor of 0.8784 for CD101 acetate for the following solutions: CD101 acetate control: No Tween 80. Adjust the solution pH to 5.14 (22.7 mg of CD101 acetate in 5 mL of 5% dextrose). CD101 acetate, 0.5% Tween 80: Use 0.5% w / w Tween 80. Adjust the solution pH to 5.21 (22.8 mg of CD101 acetate in 5 mL of 5% dextrose with 0.5% w / w Tween 80 (0.1 g Tween 80 + 19.9 g 5% dextrose)). CD101 acetate, 1.0% Tween 80: Use 1.0% w / w Tween 80. Adjust the solution pH to 5.27 (22.9 mg of CD101 acetate in 5 mL of 5% dextrose containing 1.0% w / w Tween 80 (0.2 g Tween 80 + 19.8 g 5% dextrose)). CD101 acetate, 2.5% Tween 80: Use 2.5% w / w Tween 80. Adjust the solution pH to 5.29 (22.7 mg of CD101 acetate in 5 mL of 5% dextrose with 2.5% w / w Tween 80 (0.5 g Tween 80 + 19.5 mL of 5% dextrose)). CD101 acetate, 1.0% Tween 80 (pH adjusted to 6.64) Contains 1.0% w / w Tween 80. The pH of the solution was adjusted to 6.64 using 0.1 N NaOH solution. (22.9 mg of CD101 acetate was placed in 5 mL of 5% dextrose containing 1.0% w / w Tween 80 (0.2 g Tween 80 + 19.8 g 5% dextrose))

[0068] Each 1.5 mL of the 20 mg / kg dose of CD101 acetate prepared above (CD101 acetate 4 mg / mL solution) was added dropwise via syringe to the following solutions, and insolubility of the drug was observed in solution (A) 5 mL of 0.9% saline or (B) 5 mL of PBS buffer.

[0069] result CD101 acetate (4 mg / mL CD101 acetate) prepared in 1.0% Tween 80 w / w in 5% dextrose solution (pH 5.4 solution) was added to (A) 5 mL of 0.9% saline and (B) 5 mL of PBS buffer. Both (A) and (B) remained clear after the addition of CD101 acetate. CD101 acetate (4 mg / mL CD101 acetate) prepared in 1.0% Tween 80 w / w in 5% dextrose solution (adjusted to pH 6.64 with 0.1 N NaOH solution) was added to (A) 5 mL of 0.9% saline and (B) 5 mL of PBS buffer. Both (A) and (B) remained clear after the addition of CD101 acetate. The results are summarized in Table 2 below. [Table 2]

[0070] Example 3: PBS buffer drop test Different concentrations of CD101 acetate were prepared in various solvents, as listed in Tables 2-5. These solutions were tested for solubility using a PBS drop test. This test involved adding the solution dropwise to a PBS solution (1:4.3 dilution) and visually inspecting the resulting solution for the presence or absence of precipitation. PBS buffer acts as a plasma surrogate, and the PBS drop test is used to assess the potential for a drug to become insoluble upon entering the bloodstream at the injection site.

[0071] Table 3 below shows what was observed about the solubility of CD101 acetate in different intravenous infusion solutions in the presence and absence of Tween 80 in a PBS infusion test. [Table 3]

[0072] Table 4 below shows what was observed about the solubility of CD101 acetate in different 5% dextrose intravenous infusion solutions in a PBS drip test. [Table 4]

[0073] Table 5 below shows what was observed about the solubility of CD101 acetate in different 5% mannitol intravenous infusion solutions in a PBS drip test. [Table 5]

[0074] Table 6 below shows what was observed about the solubility of CD101 at concentrations of 2 and 3 mg / mL in 0.76% mannitol human intravenous infusion solution containing 0.50% Tween 80 in a PBS drop test. [Table 6]

[0075] conclusion Solubility studies of intravenous (IV) formulations of CD101 when introduced into PBS buffer solution demonstrated that better solubility was readily achieved with higher Tween 80 concentrations. A 6 mg / mL CD101 solution formulated in a solvent of 1.25% Tween 80, 5% mannitol, and 0.3% glacial acetic acid (pH approximately 4.5) remained soluble in PBS for at least 1 hour at room temperature. The data indicate that Tween 80 concentrations greater than 1% w / w or w / v are required to avoid CD101 insolubility in PBS buffer (a plasma surrogate). Precipitation of CD101 at the injection site can lead to irritation in the tissues and veins leading to the injection site.

[0076] Example 4: Solubility of CD101 in intravenous (IV) formulations The solubility of CD101-containing formulations with different percentages of Tween 80 (also known as polysorbate 80) was evaluated using a "PBS drop test." This test involved preparing a formulation with known concentrations of CD101 and injecting the formulation into PBS to visually inspect for precipitation. This test was used to assess whether CD101-containing formulations remained soluble in blood during intravenous infusion.

[0077] Vehicle formulation to be tested (1) 1.25% Tween 80, 5% mannitol, 0.3% glacial acetic acid (pH approximately 4.5) (2) 3.5% dextrose solution in 0.50% Tween 80, 0.76% mannitol, and 0.125% sodium lactate (pH approximately 5.5) Different concentrations of CD101 acetate were prepared in solvents (1) and (2) and the solubility was tested in a PBS drop test.

[0078] Dilution into PBS buffer reservoir (PBS drop test) The formulated solution is added dropwise to the PBS solution (1:4 dilution), and the resulting solution is visually observed for the presence or absence of precipitation upon addition.

[0079] result 1.25% Tween 80, 5% mannitol, 0.3% glacial acetic acid (pH approximately 4.5) One mL of a 6 mg / mL solution of CD101 acetate was prepared in a formulation (1.25% Tween 80, 5% mannitol, 0.3% glacial acetic acid (pH approximately 4.5)). After formulation, 0.25 mL of the formulated solution was introduced into 1 mL of PBS solution (PBS drop test). The PBS drop test showed that the formulated 6 mg / mL solution remained soluble in PBS for at least 1 hour. This test was repeated to confirm the observed results.

[0080] 3.5% dextrose solution in 0.50% Tween 80, 0.76% mannitol, and 0.125% sodium lactate (pH approximately 5.5) One mL of a 2 mg / mL solution of CD101 acetate was prepared in a formulation (0.50% Tween 80, 0.76% mannitol, 0.125% sodium lactate in 3.5% dextrose solution (pH approximately 5.5)). After formulation, 0.25 mL of the formulated solution was introduced into 1 mL of PBS solution (PBS drop test). The PBS drop test showed that the formulated 2 mg / mL solution remained soluble in PBS for at least 1 hour. This test was repeated to confirm the observed results.

[0081] One mL of a 3 mg / mL CD101 solution was prepared in the same formulation (0.50% Tween 80, 0.76% mannitol, 0.125% sodium lactate in 3.5% dextrose solution (pH approximately 5.5)). After formulation, 0.25 mL of the formulated solution was introduced into 1 mL of PBS solution (PBS drop test). The PBS drop test showed that the formulated 3 mg / mL solution remained soluble in PBS for 15-30 minutes. This test was repeated to confirm the observed results.

[0082] conclusion The solubility of intravenous CD101 formulations when introduced into phosphate-buffered saline (PBS) demonstrated that better solubility was readily achieved with higher Tween 80 concentrations. A 6 mg / mL CD101 acetate solution formulated in 1.25% Tween 80, 5% mannitol, and 0.3% glacial acetic acid (pH approximately 4.5) remained soluble in PBS for at least 1 hour. A lower concentration (2 mg / mL) CD101 solution formulated in 0.50% Tween 80, 0.76% mannitol, and 0.125% sodium lactate in 3.5% dextrose solution (pH approximately 5.5) remained soluble in PBS for at least 1 hour. In contrast, a 3 mg / mL CD101 solution prepared in 3.5% dextrose solution containing 0.50% Tween 80, 0.76% mannitol, and 0.125% sodium lactate (pH ∼5.5) remained soluble in PBS for only 15–30 min.

[0083] Example 5: 14-day repeated dose intravenous infusion toxicity study with CD101 acetate in Sprague-Dawley rats The primary objective of this study was to evaluate the toxicity of CD101 when administered intravenously as a 20-minute infusion into the tail vein of Sprague-Dawley rats for 14 consecutive days. A positive control group (Eraxis®) with similar structure and pharmacodynamic activity was included in the study design.

[0084] method The test article, CD101 acetate, was a white to off-white powder. The test article was prepared into a dosage formulation for intravenous administration. One hundred experimentally naive Sprague-Dawley rats (50 males, 50 females), aged 8 weeks or older at the start of the study and weighing 255-318 grams (males) and 192-215 grams (females), were assigned to treatment groups as shown in Table 7 below. [Table 7]

[0085] All animals were dosed on days 1 through 3 (inclusive). As a result of tail vein irritation observed in all study groups, dosing was discontinued on day 4 to allow the tails to recover. Dosing resumed on day 5 and continued for up to 10 additional days (days 5 through 14 (inclusive)). Animals that could no longer be dosed during this period remained on the study.

[0086] Results and Conclusions Male and female Sprague-Dawley rats were administered CD101 acetate at doses of 0, 2, 6, and 20 mg / kg / day (Groups 1, 3, 4, and 5, respectively) or Eraxis® (positive control, Group 2) at 40 mg / kg / day intravenously as a 20-minute infusion into the left or right lateral tail vein for 14 consecutive days. During the first three days of treatment, all animals were dosed with the first vehicle used in this study (1.75% Tween 80 / 5% dextrose: Groups 1 and 3-5; 5% dextrose: Group 2). As a result of localized tail swelling observed during the first three days of treatment, the fourth day of testing served as a washout day to reduce tail vein irritation. Dosing resumed on day 5, and the new vehicle (5% mannitol / 2.5% Tween 80 / 0.3% acetic acid: groups 1 and 3-5; 5% mannitol / 0.3% acetic acid: group 2) was used for the remainder of the treatment period (days 5-14). Animals that could no longer be medicated due to severe venous irritation were also retained on the study without treatment until the end of the study (day 15).

[0087] All animals were dosed on days 1-3. After day 5, some animals were unable to receive the medication as a result of tail swelling / lesions. Ten percent (10%) of the vehicle control males, 30 percent (30%) of the positive control (Group 2) males, and 30% of the high-dose (Group 5) males were dosed for less than the planned 10-day period, with the second vehicle control used on days 5-14. Ten percent (10%) of the low-dose (Group 3)-treated females, 10% of the medium-dose (Group 4)-treated females, and 90% of the high-dose (Group 5)-treated females were not treated with the second vehicle on days 5-14 for 10 consecutive days.

[0088] All animals in this study (Groups 1-5) were scored for clinical signs indicative of tail vein irritation, which included the following combinations: red or purple discoloration of the tail, presence of white and / or yellow spots on the tail, swelling of the tail, and abrasions or crusts. The incidence of tail vein irritation during Days 1-3 using the first vehicle (1.75% Tween 80 and 5% dextrose: Groups 1 and 3-5; 5% dextrose: Group 2) was highest in males and females treated with Eraxis® and CD101 acetate at doses of 6 and 20 mg / kg / day. The differences between dose groups when the second vehicle (5% mannitol, 2.5% Tween 80, and 0.3% acetic acid: Groups 1 and 3-5; 5% mannitol and 0.3% acetic acid: Group 2) was used between days 5 and 14 were less evident than when the first vehicle was used. The venous irritation observed between days 5 and 14 was only slightly higher in Groups 2 (Eraxis®) and 5 (20 mg / kg / day CD101 acetate) compared with Group 1 and Groups 3 and 4 treated with the test substance between days 5 and 14.

[0089] Example 6: Tolerance study of a single dose intravenous infusion of CD101 in cynomolgus monkeys The objective of this study was to evaluate and compare the tolerability of CD101 administered as a single intravenous infusion over either 20 or 60 minutes in cynomolgus monkeys, as well as a vehicle similar to the planned first clinical formulation, administered as a single intravenous infusion over 20 minutes up to the highest feasible dose (10 mg / kg).

[0090] method The study was divided into two phases (Table 8). In Phase 1, CD101 acetate was administered as a single 20-minute (±2-minute) intravenous infusion in vehicle-1 (1.25% Tween 80, 5% mannitol, 0.3% glacial acetic acid, adjusted to pH 4.5±0.1) at 0 and 30 mg / kg per animal / sex / group (Groups 1 and 2, respectively). In addition, CD101 acetate was administered as a single 60-minute (±5-minute) intravenous infusion in vehicle-1 at 0 and 30 mg / kg per animal / sex / group (Groups 3 and 4, respectively).

[0091] In Phase 2, CD101 acetate was administered at 10 mg / kg per animal / sex (Group 5) as a single 20-minute (±2-minute) intravenous infusion in vehicle-2 (3.5% dextrose solution, 0.50% Tween 80, 0.76% mannitol, 0.125% sodium lactate, pH 5.5±0.1). Dosing was staggered, with Group 5 dosing 2 days after Groups 1-4. [Table 8]

[0092] result No other significant clinical observations were observed, and no differences were noted that could be attributed to the infusion duration (i.e., 20 minutes vs. 60 minutes).

[0093] conclusion The results of this study showed no difference in tolerability between the 20-minute and 60-minute infusions. Additionally, the highest feasible dose (10 mg / kg) of vehicle could be safely administered to cynomolgus monkeys.

[0094] Example 7. Efficacy of CD101 in treating Candida auris infection in a mouse model of disseminated candidiasis method Six- to eight-week-old female CD-1 mice were immunosuppressed with cyclophosphamide at 200 mg / kg 3 days before infection and at 150 mg / kg 1 day after infection. On the day of infection, mice were injected with 3 × 107 Mice were inoculated with C. auris blastospores. Mice were randomized into five groups (n = 5 for colony-forming units (CFU) and n = 10 for survival): CD101 20 mg / kg (administered intraperitoneally (IP)), fluconazole 20 mg / kg (administered orally (PO)), amphotericin B 0.3 mg / kg IP, and vehicle control. Treatment was administered 2 hours post-infection (day 1) and again on study day 4, for a total of two doses. Mice were monitored daily, and survival curves were generated. The CFU group was sacrificed on study day 8. One kidney from each mouse was removed, homogenized, plated on potato dextrose agar (PDA), and incubated at 35°C for 2 days to quantitate CFU. The remaining surviving mice were monitored until the end of the study (day 14).

[0095] result CD101 demonstrated a mean 3-log reduction in kidney CFU compared with the fluconazole, amphotericin B, and vehicle-treated groups, which was statistically significant (P = 0.03, 0.03, and 0.04, respectively). At the end of the study, the survival percentages of mice in the CD101, fluconazole, amphotericin B, vehicle, and untreated groups were 80, 0, 30, 20, and 0%, respectively (Figure 1).

[0096] conclusion Taken together, our findings demonstrate that CD101 possesses potent antifungal activity against C. auris infection in a disseminated model of candidiasis. In addition, treatment with CD101 resulted in a significantly higher overall survival rate.

[0097] Example 8. Evaluating the ability of CD101 to prevent and treat Candida albicans biofilms and exploring the effects of CD101 over time using time-lapse photography In this study, we quantified the effect of CD101 on the prevention and treatment of biofilms formed by Candida albicans in vitro and assessed the effect of CD101 (at effective concentrations) on biofilm formation in real time using time-lapse microscopy (TLM).

[0098] Materials and Methods Test Compound CD101 powder stock was reconstituted in water or yeast nitrogen base (YNB) medium and diluted with YNB to final working concentrations of 0.25 μg / ml and 1 μg / ml. YNB without CD101 was also prepared in parallel and used as a control. Fluconazole was used as a comparative substance.

[0099] Test medium YNB and Sabouraud dextrose agar (SDA) media CD101 (powder and reconstituted solution) (store at -80°C when not in use)

[0100] strain C. albicans SC-5314 was used for this study.

[0101] Activity of CD101 against Candida biofilms In this study, biofilms were grown in vitro using a biofilm model (Chandra et al., Nature Protocols 3:1909, 2008) and the effect of CD101 on adherent-phase biofilms (corresponding to biofilm prevention) or mature-phase biofilms (corresponding to biofilm treatment) was quantified.

[0102] Activity against sessile biofilms (prevention) or mature biofilms (treatment) Biofilms were formed on silicone elastomer (SE) discs using a catheter-associated biofilm model (Chandra et al., Nature Protocols 3:1909, 2008; Chandra et al., J. Bacteriol. 183:5385, 2001; Chandra et al., J. Dental Research 80:903, 2001). To assess activity against sessile biofilms (prevention), Candida cells were allowed to adhere to the catheter discs for 90 minutes. The discs were then incubated with CD101 (at 0.25 or 1 μg / ml) for 24 hours to allow biofilm formation. To assess activity against mature biofilms (treatment), Candida cells were allowed to adhere to the catheter discs for 90 minutes, then transferred to fresh medium and incubated for an additional 24 hours to allow biofilm formation. The mature biofilms were then exposed to CD101 (at 0.25 or 1 μg / ml) for an additional 24 hours. In all experiments, discs incubated with fluconazole or medium alone were used as controls.

[0103] At the end of drug exposure for both the attached and mature biofilms, biofilms were quantified by measuring their metabolic activity using the XTT assay (Chandra et al., Nature Protocols 3:1909, 2008; Chandra et al., J. Bacteriol. 183:5385, 2001; Chandra et al., J. Dental Research 80:903, 2001). After incubation with the drug, the discs were transferred to new plates containing XTT and phosphate-buffered saline with menadione, incubated at 37°C for 3 hours, and the optical density was read at 492 nm. Separate batches of biofilms were stained with fluorescent dyes (FUN1™, CONA) and observed under confocal laser scanning microscopy (CSLM) to assess biofilm architecture and thickness (Chandra et al., Nature Protocols 3:1909, 2008; Chandra et al., J. Bacteriol. 183:5385, 2001).

[0104] Time-lapse microscopy Using the effective CD101 concentrations obtained from the above experiments, the effect of CD101 on biofilm formation was monitored in real time using TLM. This involves capturing single-frame real-time images at specific time intervals, allowing for time-dependent monitoring of the interaction between the drug and Candida biofilms. The captured images were then time-sequentially stitched together to generate an animation depicting the sequence of events over time. Briefly, discs of C. albicans (adhered for 90 minutes as described above) were placed in 35 mm diameter glass-bottom Petri dishes (MatTek Corp., Ashland, MA). CD101 (dissolved in growth medium) was then added to the Petri dishes and incubated at 37°C to allow biofilm formation. Phase-contrast images of this interaction were captured immediately from time 0 until 16–17 hours later using a Leica DMI 6000 B inverted microscope connected to a Retiga EXi Aqua camera (Q-imaging Vancouver, British Columbia). To quantify structural changes in maturing biofilms, serial horizontal (xy) optical sections of the biofilms were both acquired and analyzed using Metamorph Imaging software (Molecular Devices, Downington, PA). Discs incubated with medium alone served as controls.

[0105] statistical analysis Statistical analysis of all data was performed using GraphPad Prism 6 software. Drug-treated groups were compared with the untreated control group using an unpaired t-test. A P value of <0.05 was considered significant.

[0106] result Activity against sessile biofilms (prevention) Our metabolic activity and CSLM results demonstrated that CD101 prevented robust biofilm formation at both concentrations tested (0.25 and 1 μg / ml). Metabolic activity assessment revealed that CD101-treated C. albicans formed significantly fewer biofilms than untreated C. albicans (Figure 2A, P<0.05). In contrast, fluconazole did not inhibit biofilm formation at either of the two concentrations tested (1 and 4 μg / ml, Figure 2B, P>0.05). CSLM images showed a highly heterogeneous biofilm architecture in the untreated control, with cells / hyphae embedded within an extracellular matrix (Figure 3A), whereas exposure to CD101 at both concentrations revealed only remnants of adherent cells and no biofilm formation (Figures 3B and 3C). In contrast, fluconazole did not inhibit biofilm formation (Figures 3D and 3E). In addition, exposure to CD101 significantly reduced biofilm thickness compared with untreated controls (36 μm vs. 4 μm, P < 0.05, Figure 3F), whereas fluconazole had no effect on biofilm thickness (Figure 3G).

[0107] Activity against mature biofilms (treatment) Metabolic activity and CSLM results indicated that CD101 was active against mature biofilms at both concentrations tested (0.25 and 1 μg / ml). Mature C. albicans biofilms exposed to CD101 exhibited significantly less metabolic activity than those formed by untreated biofilms (Fig. 4A, P < 0.05). In contrast, fluconazole had no effect on these biofilms at either concentration (1 and 4 μg / ml) (Fig. 4B, P > 0.05 compared to untreated controls). CSLM analysis revealed a highly heterogeneous biofilm architecture in the untreated control (Fig. 5A), whereas CD101-treated biofilms were eradicated, displaying raised, deformed, and broken cells (Fig. 5B and 5C). In contrast, fluconazole had no effect on Candida biofilms at any of the concentrations used (Fig. 5D and 5E). In addition, CD101 significantly reduced biofilm thickness compared to untreated controls (43 μm vs. 24 μm, P<0.05, FIG. 5F), whereas fluconazole had no effect (FIG. 5G).

[0108] Time Lapse Time-lapse videos showed that untreated biofilms formed a highly heterogeneous biofilm architecture, with cells / hyphae embedded within an extracellular matrix (screen frames in Figures 6A and 6B). In contrast, biofilms exposed to 0.25 μg / ml CD101 showed only adherent cells that were growth-arrested and failed to develop into mature biofilms (Figures 6C–6F). Under high magnification, raised, deformed, and broken cells were clearly visible (arrows, Figures 6D and 6F). The effect of CD101 (0.25 μg / ml) was also tested on biofilms formed at 3 hours. Images were captured immediately after drug addition and tracked for up to 16 hours. Screen frames in Figure 7A showed that 3-hour biofilm hyphal growth was still inhibited after drug addition and failed to develop into mature biofilms (Figure 7B). After 16 hours, raised, deformed, and broken cells / hyphae were clearly visible (arrows, Figure 7B).

[0109] conclusion Our results demonstrate that CD101 possesses antibiofilm activity against both sessile and mature biofilms formed by C. albicans, making this antifungal agent potentially useful in both the prevention and treatment of fungal biofilm infections.

[0110] Other embodiments All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0111] While the present disclosure has been described in connection with particular embodiments thereof, it will be understood that it is capable of further modifications, and that this application is intended to cover any variations, uses, or adaptations of the present disclosure that generally follow the principles of the disclosure and that may be applied to the essential features set forth above, which come within known or customary practice in the art to which the disclosure pertains, and include departures from the present disclosure that come within the scope of the claims. The present invention includes the following embodiments. (Embodiment 1) 1. A pharmaceutical composition for intravenous injection comprising an aqueous solution comprising at least 85% (w / w) water, between 0.4 mg / mL and 10 mg / mL of CD101, and an intravenous solubility enhancer, a weight:weight (w / w) ratio of said intravenous solubility enhancer to said CD101 in said pharmaceutical composition of at least 2; said CD101 in its salt or neutral form; the pharmaceutical composition has a pH between 5 and 7; The pharmaceutical composition, wherein the pharmaceutical composition exhibits reduced local irritation upon intravenous administration to a subject. (Embodiment 2) 2. The pharmaceutical composition of embodiment 1, wherein the w / w ratio of the intravenous solubility enhancer to the CD101 in the pharmaceutical composition is between 2 and 8. (Embodiment 3) The intravenous solubility enhancer may be selected from the group consisting of polysorbate 20 (Tween 20; polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (Tween 40; polyoxyethylene (40) sorbitan monopalmitate), polysorbate 60 (Tween 60; polyoxyethylene (60) sorbitan monostearate), polysorbate 80 (Tween 80; polyoxyethylene (80) sorbitan monooleate), β-cyclodextrin, polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor RH 60), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sorbitan monooleate (Span 20), polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate), PEG 400 caprylic / capric glyceride (Labrasol), PEG 300 oleic glyceride (Labrafil M-1944CS), phosphatidylcholine (lecithin), alkyl glucoside, sucrose monolaurate, sucrose monooleate, and polyoxyethylene-polyoxypropylene block copolymer (poloxamer). (Embodiment 4) 4. The pharmaceutical composition of embodiment 3, wherein the alkyl glucoside is an alkyl monoglucoside. (Embodiment 5) 5. The pharmaceutical composition of embodiment 4, wherein the alkyl monoglucoside is selected from the group consisting of hexylglucoside, heptaglucoside, octylglucoside, nonaglucoside, decylglucoside, dodecylglucoside, and tetradecylglucoside. (Embodiment 6) 4. The pharmaceutical composition of embodiment 3, wherein the alkyl glucoside is an alkyl diglucoside. (Embodiment 7) 7. The pharmaceutical composition of embodiment 6, wherein the alkyl diglucoside is selected from the group consisting of hexyl maltoside, heptamaltoside, octyl maltoside, nonamaltoside, decyl maltoside, dodecyl maltoside, and tetradecyl maltoside. (Embodiment 8) 4. The pharmaceutical composition of embodiment 3, wherein the intravenous solubility enhancer is polysorbate 80 (Tween 80). (Embodiment 9) The pharmaceutical composition according to any one of embodiments 1 to 8, wherein the concentration of CD101 in said pharmaceutical composition is between 0.4 mg / mL and 4 mg / mL. (Embodiment 10) 10. The pharmaceutical composition of embodiment 9, wherein the concentration of CD101 in the pharmaceutical composition is about 0.8 mg / mL. (Embodiment 11) 10. The pharmaceutical composition of embodiment 9, wherein the concentration of CD101 in the pharmaceutical composition is about 1.6 mg / mL. (Embodiment 12) 12. The pharmaceutical composition according to any one of embodiments 1 to 11, further comprising a buffering agent. (Embodiment 13) 13. The pharmaceutical composition of embodiment 12, wherein the buffering agent is histidine, citrate, succinate, lactate, propanoate, arginine, tris(hydroxymethyl)aminomethane (Tris), glycine, acetate, or formate. (Embodiment 14) 14. The pharmaceutical composition according to any one of embodiments 1 to 13, further comprising between 0.12% and 0.6% (w / w) of sugars. (Embodiment 15) 15. The pharmaceutical composition of embodiment 14, wherein the sugar is mannitol, sucrose, trehalose, maltose, dextrose, or lactose. (Embodiment 16) 16. The pharmaceutical composition of embodiment 15, wherein the saccharide is mannitol. (Embodiment 17) 17. The pharmaceutical composition according to any one of embodiments 1 to 16, wherein said CD101 in salt form is CD101 acetate. (Embodiment 18) A pharmaceutical composition comprising an effective amount of CD101 and an intravenous solubility enhancer in a lyophilized composition, wherein the weight:weight (w / w) ratio of the intravenous solubility enhancer to the CD101 in the lyophilized composition is between 2 and 8, the CD101 is in its salt or neutral form, and the lyophilized composition, when reconstituted, results in an aqueous solution having a pH between 5 and 7. (Embodiment 19) The intravenous solubility enhancer may be selected from the group consisting of polysorbate 20 (Tween 20; polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (Tween 40; polyoxyethylene (40) sorbitan monopalmitate), polysorbate 60 (Tween 60; polyoxyethylene (60) sorbitan monostearate), polysorbate 80 (Tween 80; polyoxyethylene (80) sorbitan monooleate), β-cyclodextrin, polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor RH 60), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sorbitan monooleate (Span 20), polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate), PEG 400 caprylic / capric glyceride (Labrasol), PEG 300 oleic glyceride (Labrafil M-1944CS), phosphatidylcholine (lecithin), alkyl glucoside, sucrose monolaurate, sucrose monooleate, and polyoxyethylene-polyoxypropylene block copolymer (poloxamer). (Embodiment 20) 20. The pharmaceutical composition of embodiment 19, wherein the alkyl glucoside is an alkyl monoglucoside. (Embodiment 21) 21. The pharmaceutical composition of embodiment 20, wherein the alkyl monoglucoside is selected from the group consisting of hexylglucoside, heptaglucoside, octylglucoside, nonaglucoside, decylglucoside, dodecylglucoside, and tetradecylglucoside. (Embodiment 22) 20. The pharmaceutical composition of embodiment 19, wherein the alkyl glucoside is an alkyl diglucoside. (Embodiment 23) 23. The pharmaceutical composition of embodiment 22, wherein the alkyl diglucoside is selected from the group consisting of hexyl maltoside, heptamaltoside, octyl maltoside, nonamaltoside, decyl maltoside, dodecyl maltoside, and tetradecyl maltoside. (Embodiment 24) 20. The pharmaceutical composition of embodiment 19, wherein the intravenous solubility enhancer is polysorbate 80 (Tween 80). (Embodiment 25) 25. The pharmaceutical composition according to any one of embodiments 18 to 24, further comprising a buffering agent. (Embodiment 26) 26. The pharmaceutical composition of embodiment 25, wherein the buffering agent is histidine, citrate, succinate, lactate, propanoate, arginine, tris(hydroxymethyl)aminomethane (Tris), glycine, acetate, or formate. (Embodiment 27) 27. The pharmaceutical composition according to any one of embodiments 18 to 26, further comprising between 2% and 10% (w / w) of sugars. (Embodiment 28) 28. The pharmaceutical composition of embodiment 27, wherein the sugar is mannitol, sucrose, trehalose, maltose, dextrose, or lactose. (Embodiment 29) 29. The pharmaceutical composition of embodiment 28, wherein the saccharide is mannitol. (Embodiment 30) 30. The pharmaceutical composition according to any one of embodiments 18 to 29, wherein said CD101 in salt form is CD101 acetate. (Embodiment 31) 18. A method of treating or preventing a fungal infection in a subject, comprising intravenously administering to the subject the pharmaceutical composition of any one of embodiments 1-17, wherein the method exhibits reduced local irritation upon intravenous administration of the pharmaceutical composition to the subject. (Embodiment 32) 1. A method of treating or preventing a fungal infection in a subject, comprising: (i) reconstituting the pharmaceutical composition according to any one of embodiments 18 to 30 to form an aqueous solution; (ii) intravenously administering the aqueous solution to the subject; The method, wherein the concentration of CD101 in the aqueous solution is between 0.4 mg / mL and 10 mg / mL, the CD101 is in its salt form or neutral form, and the method exhibits reduced local irritation upon intravenous administration of the aqueous solution to a subject. (Embodiment 33) 33. The method of embodiment 32, wherein the concentration of CD101 in the pharmaceutical composition is about 0.8 mg / mL. (Embodiment 34) 33. The method of embodiment 32, wherein the concentration of CD101 in the pharmaceutical composition is about 1.6 mg / mL. (Embodiment 35) 35. The method of any one of embodiments 31-34, comprising administering to said subject intravenously by infusion. (Embodiment 36) 36. The method of any one of embodiments 31-35, comprising administering to the subject intravenously by infusion at a constant infusion rate of between 2 mL / min and 9 mL / min. (Embodiment 37) 37. The method of any one of embodiments 31-36, comprising administering to said subject intravenously by infusion over 30 to 120 minutes. (Embodiment 38) 38. The method of any one of embodiments 31-37, comprising administering one dose intravenously every 5 to 15 days. (Embodiment 39) 39. The method of any one of embodiments 31-38, wherein the fungal infection being treated or prevented is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, periungual mycosis, tinea versicolor, thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, esophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis. (Embodiment 40) 40. The method of embodiment 39, wherein the infection is candidemia or invasive candidiasis. (Embodiment 41) 41. The method of any one of embodiments 31-40, wherein the fungal infection is an infection with Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C. orthopsilosis, C. guilliermondii, C. rugosa, C. auris, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus. (Embodiment 42) A method for preventing or treating a biofilm in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a CD101 salt or its neutral form and one or more pharmaceutically acceptable excipients. (Embodiment 43) 43. The method of embodiment 42, wherein the biofilm is a Candida biofilm. (Embodiment 44) 44. The method of embodiment 43, wherein said Candida biofilm is a Candida albicans biofilm. (Embodiment 45) The method of any one of embodiments 42 to 44, wherein the biofilm is attached to a mucosa of the subject. (Embodiment 46) A method for preventing biofilm growth on a catheter or killing biofilm attached to a catheter, the method comprising submerging the catheter in an aqueous solution containing a CD101 salt or its neutral form, or flowing an aqueous solution containing a CD101 salt or its neutral form into the lumen of the catheter. (Embodiment 47) 47. The method of embodiment 46, wherein the biofilm is a Candida biofilm. (Embodiment 48) 48. The method of embodiment 47, wherein said Candida biofilm is a Candida albicans biofilm.

[0112] Other embodiments are within the scope of the following claims.

[0113] The claims are as follows:

Claims

1. 1. A pharmaceutical composition for intravenous injection comprising an aqueous solution comprising at least 85% (w / w) water, between 0.8 mg / mL and 1.6 mg / mL CD101, between 0.12% and 0.6% (w / w) sugars, and at least 2.5% (w / w) polyoxyethylene (80) sorbitan monooleate, said CD101 in its salt or neutral form; The pharmaceutical composition, wherein the pharmaceutical composition has a pH between 5 and 7.

2. 10. The pharmaceutical composition of claim 1, further comprising a buffering agent.

3. 3. The pharmaceutical composition of claim 2, wherein the buffering agent is histidine, citrate, succinate, lactate, propanoate, arginine, tris(hydroxymethyl)aminomethane (Tris), glycine, acetate, or formate.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the sugar is mannitol, sucrose, trehalose, maltose, dextrose, or lactose.

5. The pharmaceutical composition of claim 4, wherein the sugar is mannitol.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the CD101 in salt form is CD101 acetate.

7. A medicament comprising the pharmaceutical composition of any one of claims 1 to 6 for use in a method for treating or preventing a fungal infection in a subject, the method comprising intravenously administering the medicament to the subject.

8. The pharmaceutical composition of claim 7, wherein the composition is administered intravenously to the subject by infusion.

9. 9. The method of claim 7 or 8, comprising administering the compound intravenously to the subject by infusion at a constant infusion rate of between 2 mL / min and 9 mL / min.

10. The method of any one of claims 7 to 9, wherein the method comprises administering the compound intravenously to the subject by infusion over a period of 30 to 120 minutes.

11. The method of any one of claims 7 to 10, comprising administering one dose intravenously every 5 to 15 days.

12. 12. The medicament of any one of claims 7 to 11, wherein the fungal infection to be treated or prevented is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, periungual mycosis, tinea versicolor, thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, esophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, and chronic sinusitis.

13. The method of claim 12, wherein the infection is candidemia or invasive candidiasis.

14. The medicament according to any one of claims 7 to 13, wherein the fungal infection is an infection with Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C. orthopsilosis, C. guilliermondii, C. rugosa, C. auris, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.

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