Polyene macrolide compositions and uses thereof

Abstract

This invention relates to lyophilized pharmaceutical compositions that include therapeutic polyene macrolides to increase bioavailability and shelf-life of the compositions.

Description

[0001] POLYENE MACROLIDE COMPOSITIONS AND USES THEREOF

[0002] FIELD OF INVENTION

[0003] This invention relates to lyophilized pharmaceutical compositions.

[0004] BACKGROUND

[0005] Macrolide compounds are often overlooked for medicinal applications and therapeutics because of their low shelf life. Moreover, challenges in delivering the macrolide compounds occur due to low or poor bioavailability.

[0006] Compound 1 is a therapeutic polyene macrolide:

[0007] Compound 1 .

[0008] There is a need for new compositions that include therapeutic polyene macrolides to increase bioavailability and shelf-life.

[0009] SUMMARY OF THE INVENTION

[0010] In one aspect, the invention features a lyophilized pharmaceutical composition including a cryoprotectant and a compound of Formula (I): or a pharmaceutically acceptable salt thereof. In the above aspect, the compound is Compound 1 :

[0011] Compound 1 , or a pharmaceutically acceptable salt thereof.

[0012] In one embodiment, the cryoprotectant is a saccharide. In some embodiments, the cryoprotectant is a sugar alcohol. In some embodiments, the saccharide is glucose (e.g., D-glucose), mannose, maltose, lactose, xylose, sucrose, trehalose, or erythrose. In some embodiments, the sugar alcohol is mannitol (e.g., D-mannitol), sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol.

[0013] In some embodiments, the composition includes at least 80% (w / w) of the cryoprotectant, e.g., 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 99.9% (w / w). In some embodiments, the composition includes 90% (w / w) to 99.9% (w / w) of the cryoprotectant, e.g., from 90% (w / w) to 91% (w / w), from 91 % (w / w) to 92% (w / w), from 92% (w / w) to 93% (w / w), from 93% (w / w) to 94% (w / w), from 94% (w / w) to 95% (w / w), from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), from 98% (w / w) to 99% (w / w), or from 99% (w / w) to 99.9% (w / w), e.g., 90% (w / w), 91 ± 1 % (w / w), 92 ± 1 % (w / w), 93 ± 1 % (w / w), 94 ± 1 % (w / w), 95 ± 1 % (w / w), 96 ± 1 % (w / w), 97 ± 1 % (w / w), 99 ± 0.5% (w / w), or 99.9% (w / w).

[0014] In some embodiments, the composition further includes a stabilizer. In some embodiments, the stabilizer is an antioxidant. In some embodiments, the antioxidant is ascorbic acid (e.g., L-(+)-ascorbic acid), sodium bisulfite, sodium metabisulfite, or sodium thiosulfate. In some embodiments, the composition includes 0.01 % (w / w) to 2% (w / w) of the stabilizer, e.g., 0.01 % (w / w) to 0.05% (w / w), 0.05% (w / w) to 0.15% (w / w), 0.15% (w / w) to 0.25% (w / w), 0.25% (w / w) to 0.35% (w / w), 0.35% (w / w) to 0.45% (w / w), 0.45% (w / w) to 0.55% (w / w), 0.55% (w / w) to 0.65% (w / w), 0.65% (w / w) to 0.75% (w / w), 0.75% (w / w) to 0.85% (w / w), 0.85% (w / w) to 0.95% (w / w), 0.95% (w / w) to 1 .05% (w / w), 1 .05% (w / w) to 1.15% (w / w), 1.15% (w / w) to 1 .25% (w / w), 1 .25% (w / w) to 1 .35% (w / w), 1 .35% (w / w) to 1 .45% (w / w), 1 .45% (w / w) to 1 .55% (w / w), 1 .55% (w / w) to 1 .65% (w / w), 1 .65% (w / w) to 1 .75% (w / w), 1 .75% (w / w) to 1 .85% (w / w), 1 .85% (w / w) to 1 .95% (w / w), or 1 .95% (w / w) to 2% (w / w), e.g., 0.01 % (w / w), 0.05 ± 0.02% (w / w), 0.15 ± 0.05% (w / w), 0.25 ± 0.05% (w / w), 0.35 ± 0.05% (w / w), 0.45 ± 0.05% (w / w), 0.55 ± 0.05% (w / w),

[0015] 0.65 ± 0.05% (w / w), 0.75 ± 0.05% (w / w), 0.85 ± 0.05% (w / w), 0.95 ± 0.05% (w / w), 1 .05 ± 0.05% (w / w),

[0016] 1 .15 ± 0.05% (w / w), 1 .25 ± 0.05% (w / w), 1 .35 ± 0.05% (w / w), 1 .45 ± 0.05% (w / w), 1 .55 ± 0.05% (w / w),

[0017] 1 .65 ± 0.05% (w / w), 1 .75 ± 0.05% (w / w), 1 .85 ± 0.05% (w / w), 1 .95 ± 0.05% (w / w), or 2% (w / w).

[0018] In some embodiments, the composition includes 0.1 % (w / w) to 7.5% (w / w) of a compound of Formula (I) or Compound 1 , e.g., 0.1 % (w / w) to 1 % (w / w), 1 % (w / w) to 1 .5% (w / w), 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), 4.5% (w / w) to 5% (w / w), 5% (w / w) to 5.5% (w / w), 5.5% (w / w) to 6% (w / w), 6% (w / w) to 6.5% (w / w), 6.5% (w / w) to 7% (w / w), or 7% (w / w) to 7.5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 0.1 % (w / w), 1 ± 0.1 % (w / w), 1 .5 ± 0.2% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), 5 ± 0.5% (w / w), 5.5 ± 0.5% (w / w), 6 ± 0.5% (w / w), 6.5 ± 0.5% (w / w), 7 ± 0.5% (w / w), or 7.5% (w / w) of the compound of formula (I) or Compound 1.

[0019] In some embodiments, the lyophilized pharmaceutical composition includes the compound of Formula (I) or Compound 1 in a pharmaceutically acceptable salt.

[0020] In some embodiments, the lyophilized pharmaceutical composition includes an acetate buffer.

[0021] In some embodiments, the compound of Formula (I) or Compound 1 is in substantially amorphous form.

[0022] In some embodiments, the lyophilized pharmaceutical composition includes:

[0023] (a) 90% (w / w) to 99% (w / w) of the cryoprotectant, e.g., from 90% (w / w) to 91 % (w / w), from 91 % (w / w) to 92% (w / w), from 92% (w / w) to 93% (w / w), from 93% (w / w) to 94% (w / w), from 94% (w / w) to 95% (w / w), from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), or from 98% (w / w) to 99% (w / w), e.g., 90% (w / w), 91 ± 1 % (w / w), 92 ± 1 % (w / w), 93 ± 1 % (w / w), 94 ± 1 % (w / w), 95 ± 1 % (w / w), 96 ± 1 % (w / w), 97 ± 1 % (w / w), or 99% (w / w);

[0024] (b) 0.05% (w / w) to 2% (w / w) of the stabilizer, e.g., 0.05% (w / w) to 0.15% (w / w), 0.15% (w / w) to 0.25% (w / w), 0.25% (w / w) to 0.35% (w / w), 0.35% (w / w) to 0.45% (w / w), 0.45% (w / w) to 0.55% (w / w), 0.55% (w / w) to 0.65% (w / w), 0.65% (w / w) to 0.75% (w / w), 0.75% (w / w) to 0.85% (w / w), 0.85% (w / w) to 0.95% (w / w), 0.95% (w / w) to 1 .05% (w / w), 1 .05% (w / w) to 1 .15% (w / w), 1 .15% (w / w) to 1 .25% (w / w),

[0025] 1 .25% (w / w) to 1 .35% (w / w), 1 .35% (w / w) to 1 .45% (w / w), 1 .45% (w / w) to 1 .55% (w / w), 1 .55% (w / w) to 1 .65% (w / w), 1 .65% (w / w) to 1 .75% (w / w), 1 .75% (w / w) to 1 .85% (w / w), 1 .85% (w / w) to 1 .95% (w / w), or 1 .95% (w / w) to 2% (w / w), e.g., 0.05% (w / w), 0.15 ± 0.05% (w / w), 0.25 ± 0.05% (w / w), 0.35 ± 0.05% (w / w), 0.45 ± 0.05% (w / w), 0.55 ± 0.05% (w / w), 0.65 ± 0.05% (w / w), 0.75 ± 0.05% (w / w), 0.85 ± 0.05%

[0026] (w / w), 0.95 ± 0.05% (w / w), 1 .05 ± 0.05% (w / w), 1 .15 ± 0.05% (w / w), 1 .25 ± 0.05% (w / w), 1 .35 ± 0.05%

[0027] (w / w), 1 .45 ± 0.05% (w / w), 1 .55 ± 0.05% (w / w), 1 .65 ± 0.05% (w / w), 1 .75 ± 0.05% (w / w), 1 .85 ± 0.05%

[0028] (w / w), 1.95 ± 0.05% (w / w), or 2% (w / w); and

[0029] (c) 1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 1 % (w / w) to

[0030] 1 .5% (w / w), 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), 4.5% (w / w) to 5% (w / w), 5% (w / w) to 5.5% (w / w), 5.5% (w / w) to 6% (w / w), 6% (w / w) to 6.5% (w / w), 6.5% (w / w) to 7% (w / w), or 7% (w / w) to 7.5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 1 % (w / w), 1.5 ± 0.5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), 5 ± 0.5% (w / w), 5.5 ± 0.5% (w / w), 6 ± 0.5% (w / w), 6.5 ± 0.5% (w / w), 7 ± 0.5% (w / w), or 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0031] In some embodiments, the lyophilized pharmaceutical composition includes:

[0032] (a) 90% (w / w) to 99% (w / w) of the cryoprotectant, e.g., from 90% (w / w) to 91 % (w / w), from 91 % (w / w) to 92% (w / w), from 92% (w / w) to 93% (w / w), from 93% (w / w) to 94% (w / w), from 94% (w / w) to 95% (w / w), from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), or from 98% (w / w) to 99% (w / w), e.g., 90% (w / w), 91 ± 1 % (w / w), 92 ± 1 % (w / w), 93 ± 1 % (w / w), 94 ± 1 % (w / w), 95 ± 1 % (w / w), 96 ± 1 % (w / w), 97 ± 2% (w / w), or 99% (w / w), wherein the cryoprotectant is selected from mannose, maltose, lactose, xylose, sucrose, trehalose, erythrose, mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol;

[0033] (b) 0.05% (w / w) to 2% (w / w) of the stabilizer, e.g., 0.05% (w / w) to 0.15% (w / w), 0.15% (w / w) to 0.25% (w / w), 0.25% (w / w) to 0.35% (w / w), 0.35% (w / w) to 0.45% (w / w), 0.45% (w / w) to 0.55% (w / w), 0.55% (w / w) to 0.65% (w / w), 0.65% (w / w) to 0.75% (w / w), 0.75% (w / w) to 0.85% (w / w), 0.85% (w / w) to 0.95% (w / w), 0.95% (w / w) to 1 .05% (w / w), 1 .05% (w / w) to 1 .15% (w / w), 1 .15% (w / w) to 1 .25% (w / w),

[0034] 1 .25% (w / w) to 1 .35% (w / w), 1 .35% (w / w) to 1 .45% (w / w), 1 .45% (w / w) to 1 .55% (w / w), 1 .55% (w / w) to 1 .65% (w / w), 1 .65% (w / w) to 1 .75% (w / w), 1 .75% (w / w) to 1 .85% (w / w), 1 .85% (w / w) to 1 .95% (w / w), or 1 .95% (w / w) to 2% (w / w), e.g., 0.05% (w / w), 0.15 ± 0.05% (w / w), 0.25 ± 0.05% (w / w), 0.35 ± 0.05% (w / w), 0.45 ± 0.05% (w / w), 0.55 ± 0.05% (w / w), 0.65 ± 0.05% (w / w), 0.75 ± 0.05% (w / w), 0.85 ± 0.05%

[0035] (w / w), 0.95 ± 0.05% (w / w), 1 .05 ± 0.05% (w / w), 1 .15 ± 0.05% (w / w), 1 .25 ± 0.05% (w / w), 1 .35 ± 0.05%

[0036] (w / w), 1 .45 ± 0.05% (w / w), 1 .55 ± 0.05% (w / w), 1 .65 ± 0.05% (w / w), 1 .75 ± 0.05% (w / w), 1 .85 ± 0.05%

[0037] (w / w), 1 .95 ± 0.05% (w / w), or 2% (w / w), wherein the stabilizer is selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; and

[0038] (c) 1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 1 % (w / w) to

[0039] 1 .5% (w / w), 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), 4.5% (w / w) to 5% (w / w), 5% (w / w) to 5.5% (w / w), 5.5% (w / w) to 6% (w / w), 6% (w / w) to 6.5% (w / w), 6.5% (w / w) to 7% (w / w), or 7% (w / w) to 7.5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 1 % (w / w), 1.5 ± 0.5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), 5 ± 0.5% (w / w), 5.5 ± 0.5% (w / w), 6 ± 0.5% (w / w), 6.5 ± 0.5% (w / w), 7 ± 0.5% (w / w), or 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0040] In some embodiments, the lyophilized pharmaceutical composition includes:

[0041] (a) 95% (w / w) to 98% (w / w) of the cryoprotectant, e.g., from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), or from 97% (w / w) to 98% (w / w), e.g., 95% (w / w), 96 ± 1 % (w / w), 97 ± 1 % (w / w), or 98% (w / w);

[0042] (b) 0.1 % (w / w) to 1% (w / w) of the stabilizer, e.g., 0.1 % (w / w) to 0.2% (w / w), 0.2% (w / w) to 0.3% (w / w), 0.3% (w / w) to 0.4% (w / w), 0.4% (w / w) to 0.5% (w / w), 0.5% (w / w) to 0.6% (w / w), 0.6% (w / w) to 0.7% (w / w), 0.7% (w / w) to 0.8% (w / w), 0.8% (w / w) to 0.9% (w / w), or 0.9% (w / w) to 1 % (w / w), e.g., 0.1 % (w / w), 0.2 ± 0.1 % (w / w), 0.3 ± 0.1 % (w / w), 0.4 ± 0.1 % (w / w), 0.5 ± 0.1 % (w / w), 0.6 ± 0.1 % (w / w), 0.7 ± 0.1 % (w / w), 0.8 ± 0.1 % (w / w), 0.9 ± 0.1 % (w / w), or 1 % (w / w); and

[0043] (c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), or 4.5% (w / w) to 5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 1 .5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), or 5% (w / w) of the compound of Formula (I) or Compound 1 .

[0044] In some embodiments, the lyophilized pharmaceutical composition includes:

[0045] (a) 95% (w / w) to 98% (w / w) of the cryoprotectant, e.g., from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), e.g., 95% (w / w), 96 ± 1 % (w / w), 97 ± 2% (w / w), or 98% (w / w), wherein the cryoprotectant is selected from mannose, maltose, lactose, xylose, sucrose, trehalose, erythrose, mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol; (b) 0.1 % (w / w) to 1% (w / w) of the stabilizer, e.g., 0.1 % (w / w) to 0.2% (w / w), 0.2% (w / w) to 0.3% (w / w), 0.3% (w / w) to 0.4% (w / w), 0.4% (w / w) to 0.5% (w / w), 0.5% (w / w) to 0.6% (w / w), 0.6% (w / w) to 0.7% (w / w), 0.7% (w / w) to 0.8% (w / w), 0.8% (w / w) to 0.9% (w / w), or 0.9% (w / w) to 1% (w / w), e.g., 0.1 % (w / w), 0.2 ± 0.1 % (w / w), 0.3 ± 0.1 % (w / w), 0.4 ± 0.1 % (w / w), 0.5 ± 0.1 % (w / w), 0.6 ± 0.1 % (w / w), 0.7 ± 0.1 % (w / w), 0.8 ± 0.1 % (w / w), 0.9 ± 0.1 % (w / w), or 1 % (w / w), wherein the stabilizer is selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; and

[0046] (c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), or 4.5% (w / w) to 5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 1 .5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), or 5% (w / w) of the compound of Formula (I) or Compound 1 .

[0047] In some embodiments, the stabilizer is ascorbic acid and the composition includes 0.25% ± 0.05% (w / w) of ascorbic acid.

[0048] In some embodiments, an aqueous solution is prepared by reconstituting the lyophilized composition with an aqueous carrier.

[0049] In some embodiments, the aqueous solution has a pH of 3.5 to 7.5, e.g., 3.5 to 4.0, e.g., 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.5 to 5.5, e.g., 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, or 5.5, or 4.0 to 7.0, e.g., 4 ± 0.5, 5 ± 0.5, 6 ± 0.5, or 7 ± 0.5, or 6.0 to 7.5, e.g., 6.0, 7.0, or 7.5.

[0050] In some embodiments, the aqueous solution has a pH of at least 4. In some embodiments, the aqueous solution has a pH of 4.5 to 5.5, e.g., 4.6 ± 0.1 , 4.7 ± 0.1 , 4.8 ± 0.1 , 4.9 ± 0.1 , 5.0 ± 0.5, 5.1 ± 0.1 , 5.2 ± 0.1 , 5.3 ± 0.1 , 5.4 ± 0.1 , or 5.5. In some embodiments, the pH is 5.0 ± 0.3.

[0051] In some embodiments, the aqueous carrier is water for injection (WFI). In some embodiments, the aqueous carrier is WFI supplemented with various excipients selected from citric acid, lactic acid, gluconic acid, glucose, or mannitol. In some embodiments, the aqueous solution is substantially free of saline.

[0052] In any of the above embodiments, the lyophilized pharmaceutical composition or aqueous solution thereof is stored in a container shielded from light (e.g., a sealed amber vial).

[0053] In some embodiments, the invention features a method of administering a compound of Formula (I) or Compound 1 to a subject in need thereof, including:

[0054] (a) providing a lyophilized pharmaceutical composition of the invention;

[0055] (b) reconstituting the composition of step (a) in an aqueous carrier to form a solution including the compound of Formula (I) or Compound 1 ; and

[0056] (c) within at least 5 minutes (e.g., within 10 minutes, within 15 minutes, within 30 minutes, within 1 hour, within 1.5 hours, or within 2 hours) of completing step (b), administering to the subject the reconstituted solution of step (b).

[0057] In some embodiments of the above method, the solution of step (c) is administered intravenously.

[0058] In some embodiments, the invention features a method of treating a fungal infection in a subject, wherein the method includes administering to the subject an effective amount of an aqueous solution of the invention. In some embodiments, the route of administration is intravenous.

[0059] In some embodiments, the invention features a method of preparing a lyophilized composition of the invention, including: (a) dissolving the compound of Formula (I) or Compound 1 in an organic solvent;

[0060] (b) dissolving a cryoprotectant and a stabilizer and in water in vessel 2, followed by mixing;

[0061] (c) combining the mixtures of step (a) and step (b) into a single vessel, followed by mixing;

[0062] (d) adjusting the pH of the mixture of step (c) between 4.4 to 5.5 (e.g., pH 4.4, pH 4.5, pH 4.6, pH 4.7, pH 4.8, pH 4.9, pH 5.0, pH 5.1 , pH 5.2, pH 5.3, pH 5.4, or pH 5.5) to achieve a fully dissolved mixture;

[0063] (e) filtering the mixture of step (d);

[0064] (f) lyophilizing the mixture of step (e); and

[0065] (g) storing the lyophilized composition of step (f) at a temperature starting at least -15 °C (e.g., storing at -15 °C, -20 °C, -25 °C, -30 °C, -35 °C, -40 °C, -45 °C, -50 °C, -55 °C, -60 °C, -65 °C, -70 °C, -75 °C, or -80 °C).

[0066] In some embodiments, the pH of the mixture of step (d) is 4.4.

[0067] In an aspect, the invention features a method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution of any of the above embodiments and a nonionic tonicity agent selected from glucose, glycerin, mannitol, sucrose, glycerol, sorbitol, and trehalose. In some embodiments, the nonionic tonicity agent is mannitol (e.g., D-mannitol). In some embodiments, the nonionic tonicity agent is glucose. In some embodiments, the isotonic solution is substantially free of saline. In some embodiments, the injection is a bolus or an infusion.

[0068] In one aspect, the invention features a lyophilized pharmaceutical composition including a stabilizer and a compound of formula (I): or a pharmaceutically acceptable salt thereof.

[0069] In the above aspect, the compound can be further described by Compound 1 :

[0070] Compound 1 , or a pharmaceutically acceptable salt thereof. In some embodiments, the stabilizer is an antioxidant. In some embodiments, the antioxidant is ascorbic acid (e.g., L-(+)-ascorbic acid), sodium bisulfite, sodium metabisulfite, or sodium thiosulfate. In some embodiments, the composition includes 0.01 % (w / w) to 2% (w / w) of the stabilizer, e.g., 0.01 % (w / w) to 0.05% (w / w), 0.05% (w / w) to 0.15% (w / w), 0.15% (w / w) to 0.25% (w / w), 0.25% (w / w) to 0.35% (w / w), 0.35% (w / w) to 0.45% (w / w), 0.45% (w / w) to 0.55% (w / w), 0.55% (w / w) to 0.65% (w / w), 0.65% (w / w) to 0.75% (w / w), 0.75% (w / w) to 0.85% (w / w), 0.85% (w / w) to 0.95% (w / w), 0.95% (w / w) to 1 .05% (w / w), 1 .05% (w / w) to 1 .15% (w / w), 1 .15% (w / w) to 1 .25% (w / w), 1 .25% (w / w) to 1 .35% (w / w), 1 .35% (w / w) to 1 .45% (w / w), 1 .45% (w / w) to 1 .55% (w / w), 1 .55% (w / w) to 1 .65% (w / w), 1 .65% (w / w) to 1 .75% (w / w), 1 .75% (w / w) to 1 .85% (w / w), 1 .85% (w / w) to 1 .95% (w / w), or 1 .95% (w / w) to 2% (w / w), e.g., 0.01 % (w / w), 0.05 ± 0.02% (w / w), 0.15 ± 0.05% (w / w), 0.25 ± 0.05% (w / w), 0.35 ± 0.05% (w / w), 0.45 ± 0.05%

[0071] (w / w), 0.55 ± 0.05% (w / w), 0.65 ± 0.05% (w / w), 0.75 ± 0.05% (w / w), 0.85 ± 0.05% (w / w), 0.95 ± 0.05%

[0072] (w / w), 1 .05 ± 0.05% (w / w), 1 .15 ± 0.05% (w / w), 1 .25 ± 0.05% (w / w), 1 .35 ± 0.05% (w / w), 1 .45 ± 0.05%

[0073] (w / w), 1 .55 ± 0.05% (w / w), 1 .65 ± 0.05% (w / w), 1 .75 ± 0.05% (w / w), 1 .85 ± 0.05% (w / w), 1 .95 ± 0.05%

[0074] (w / w), or 2% (w / w).

[0075] In some embodiments, the composition includes 0.1 % (w / w) to 7.5% (w / w) of a compound of Formula (I) or Compound 1 , e.g., 0.1 % (w / w) to 1 % (w / w), 1 % (w / w) to 1 .5% (w / w), 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), 4.5% (w / w) to 5% (w / w), 5% (w / w) to 5.5% (w / w), 5.5% (w / w) to 6% (w / w), 6% (w / w) to 6.5% (w / w), 6.5% (w / w) to 7% (w / w), or 7% (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 0.1 % (w / w), 1 ± 0.5% (w / w), 1 .5 ± 0.5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), 5 ± 0.5% (w / w), 5.5 ± 0.5% (w / w), 6 ± 0.5% (w / w), 6.5 ± 0.5% (w / w), 7 ± 0.5% (w / w), or 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0076] In one embodiment, the cryoprotectant is a saccharide. In some embodiments, the cryoprotectant is a sugar alcohol. In some embodiments, the saccharide is glucose (e.g., D-glucose), mannose, maltose, lactose, xylose, sucrose, trehalose, or erythrose. In some embodiments, the sugar alcohol is mannitol (e.g., D-mannitol), sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol.

[0077] In some embodiments, the composition includes at least 80% (w / w) of the cryoprotectant, e.g., 80%, 81 ± 1 %, 82 ± 1 %, 83 ± 1 %, 84 ± 1 %, 85 ± 1 %, 86 ± 1 %, 87 ± 1 %, 88 ± 1 %, 89 ± 1 %, 90 ± 1 %, 91 ± 1 %, 92 ± 1 %, 93 ± 1 %, 94 ± 1 %, 95 ± 1 %, 96 ± 1 %, 97 ± 2%, 99 ± 0.5%, or 99.9% (w / w). In some embodiments, the composition includes 90% (w / w) to 99.9% (w / w) of the cryoprotectant, e.g., from 90% (w / w) to 91 % (w / w), from 91 % (w / w) to 92% (w / w), from 92% (w / w) to 93% (w / w), from 93% (w / w) to 94% (w / w), from 94% (w / w) to 95% (w / w), from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), or from 98% (w / w) to 99% (w / w), or from 99% (w / w) to 99.9% (w / w), e.g., 90% (w / w), 91 % (w / w), 92% (w / w), 93% (w / w), 94% (w / w), 95% (w / w), 96% (w / w), 97% (w / w), 99% (w / w), or 99.9% (w / w).

[0078] In some embodiments, the lyophilized pharmaceutical composition includes the compound of Formula (I) or Compound 1 in a pharmaceutically acceptable salt.

[0079] In some embodiments, the lyophilized pharmaceutical composition includes an acetate buffer.

[0080] In some embodiments, the compound of Formula (I) or Compound 1 is in substantially amorphous form. In some embodiments, the lyophilized pharmaceutical composition includes:

[0081] (a) 90% (w / w) to 99% (w / w) of the cryoprotectant, e.g., from 90% (w / w) to 91 % (w / w), from 91 % (w / w) to 92% (w / w), from 92% (w / w) to 93% (w / w), from 93% (w / w) to 94% (w / w), from 94% (w / w) to 95% (w / w), from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), or from 98% (w / w) to 99% (w / w), e.g., 90% (w / w), 91 % (w / w), 92% (w / w), 93% (w / w), 94% (w / w), 95% (w / w), 96% (w / w), 97% (w / w), or 99% (w / w);

[0082] (b) 0.05% (w / w) to 2% (w / w) of the stabilizer, e.g., 0.05% (w / w) to 0.15% (w / w), 0.15% (w / w) to 0.25% (w / w), 0.25% (w / w) to 0.35% (w / w), 0.35% (w / w) to 0.45% (w / w), 0.45% (w / w) to 0.55% (w / w), 0.55% (w / w) to 0.65% (w / w), 0.65% (w / w) to 0.75% (w / w), 0.75% (w / w) to 0.85% (w / w), 0.85% (w / w) to 0.95% (w / w), 0.95% (w / w) to 1 .05% (w / w), 1 .05% (w / w) to 1 .15% (w / w), 1 .15% (w / w) to 1 .25% (w / w),

[0083] 1 .25% (w / w) to 1 .35% (w / w), 1 .35% (w / w) to 1 .45% (w / w), 1 .45% (w / w) to 1 .55% (w / w), 1 .55% (w / w) to 1 .65% (w / w), 1 .65% (w / w) to 1 .75% (w / w), 1 .75% (w / w) to 1 .85% (w / w), 1 .85% (w / w) to 1 .95% (w / w), or 1 .95% (w / w) to 2% (w / w), e.g., 0.05% (w / w), 0.15 ± 0.5% (w / w), 0.25 ± 0.5% (w / w), 0.35 ± 0.5% (w / w), 0.45 ± 0.5% (w / w), 0.55 ± 0.5% (w / w), 0.65 ± 0.5% (w / w), 0.75 ± 0.5% (w / w), 0.85 ± 0.5% (w / w), 0.95 ± 0.5% (w / w), 1 .05 ± 0.5% (w / w), 1 .15 ± 0.5% (w / w), 1 .25 ± 0.5% (w / w), 1 .35 ± 0.5% (w / w), 1 .45 ± 0.5% (w / w), 1 .55 ± 0.5% (w / w), 1 .65 ± 0.5% (w / w), 1 .75 ± 0.5% (w / w), 1 .85 ± 0.5% (w / w), 1 .95 ± 0.5% (w / w), or 2% (w / w); and

[0084] (c) 1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 1 % (w / w) to

[0085] 1 .5% (w / w), 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), 4.5% (w / w) to 5% (w / w), 5% (w / w) to 5.5% (w / w), 5.5% (w / w) to 6% (w / w), 6% (w / w) to 6.5% (w / w), 6.5% (w / w) to 7% (w / w), or 7% (w / w) to 7.5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 1 % (w / w), 1.5 ± 0.5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), 5 ± 0.5% (w / w), 5.5 ± 0.5% (w / w), 6 ± 0.5% (w / w), 6.5 ± 0.5% (w / w), 7 ± 0.5% (w / w), or 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0086] In some embodiments, the lyophilized pharmaceutical composition includes:

[0087] (a) 90% (w / w) to 99% (w / w) of the cryoprotectant, e.g., from 90% (w / w) to 91 % (w / w), from 91 % (w / w) to 92% (w / w), from 92% (w / w) to 93% (w / w), from 93% (w / w) to 94% (w / w), from 94% (w / w) to 95% (w / w), from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), or from 98% (w / w) to 99% (w / w), e.g., 90% (w / w), 91 ± 1 % (w / w), 92 ± 1 % (w / w), 93 ± 1 % (w / w), 94 ± 1 % (w / w), 95 ± 1 % (w / w), 96 ± 1 % (w / w), 97 ± 2% (w / w), or 99% (w / w), wherein the cryoprotectant is selected from mannose, maltose, lactose, xylose, sucrose, trehalose, erythrose, mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol;

[0088] (b) 0.05% (w / w) to 2% (w / w) of the stabilizer, e.g., 0.05% (w / w) to 0.15% (w / w), 0.15% (w / w) to 0.25% (w / w), 0.25% (w / w) to 0.35% (w / w), 0.35% (w / w) to 0.45% (w / w), 0.45% (w / w) to 0.55% (w / w), 0.55% (w / w) to 0.65% (w / w), 0.65% (w / w) to 0.75% (w / w), 0.75% (w / w) to 0.85% (w / w), 0.85% (w / w) to 0.95% (w / w), 0.95% (w / w) to 1 .05% (w / w), 1 .05% (w / w) to 1 .15% (w / w), 1 .15% (w / w) to 1 .25% (w / w),

[0089] 1 .25% (w / w) to 1 .35% (w / w), 1 .35% (w / w) to 1 .45% (w / w), 1 .45% (w / w) to 1 .55% (w / w), 1 .55% (w / w) to 1 .65% (w / w), 1 .65% (w / w) to 1 .75% (w / w), 1 .75% (w / w) to 1 .85% (w / w), 1 .85% (w / w) to 1 .95% (w / w), or 1 .95% (w / w) to 2% (w / w), e.g., 0.05% (w / w), 0.15 ± 0.05% (w / w), 0.25 ± 0.05% (w / w), 0.35 ± 0.05% (w / w), 0.45 ± 0.05% (w / w), 0.55 ± 0.05% (w / w), 0.65 ± 0.05% (w / w), 0.75 ± 0.05% (w / w), 0.85 ± 0.05% (w / w), 0.95 ± 0.05% (w / w), 1 .05 ± 0.05% (w / w), 1 .15 ± 0.05% (w / w), 1 .25 ± 0.05% (w / w), 1 .35 ± 0.05%

[0090] (w / w), 1 .45 ± 0.05% (w / w), 1 .55 ± 0.05% (w / w), 1 .65 ± 0.05% (w / w), 1 .75 ± 0.05% (w / w), 1 .85 ± 0.05%

[0091] (w / w), 1 .95 ± 0.05% (w / w), or 2% (w / w), wherein the stabilizer is selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; and

[0092] (c) 1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 1 % (w / w) to 1 .5% (w / w), 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), 4.5% (w / w) to 5% (w / w), 5% (w / w) to 5.5% (w / w), 5.5% (w / w) to 6% (w / w), 6% (w / w) to 6.5% (w / w), 6.5% (w / w) to 7% (w / w), or 7% (w / w) to 7.5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 1 % (w / w), 1.5 ± 0.5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), 5 ± 0.5% (w / w), 5.5 ± 0.5% (w / w), 6 ± 0.5% (w / w), 6.5 ± 0.5% (w / w), 7 ± 0.5% (w / w), or 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0093] In some embodiments, the lyophilized pharmaceutical composition includes:

[0094] (a) 95% (w / w) to 98% (w / w) of the cryoprotectant, e.g., from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), e.g., 95% (w / w), 96 ± 1 % (w / w), 97 ± 1 % (w / w), or 98% (w / w);

[0095] (b) 0.1 % (w / w) to 1% (w / w) of the stabilizer, e.g., 0.1 % (w / w) to 0.2% (w / w), 0.2% (w / w) to 0.3% (w / w), 0.3% (w / w) to 0.4% (w / w), 0.4% (w / w) to 0.5% (w / w), 0.5% (w / w) to 0.6% (w / w), 0.6% (w / w) to 0.7% (w / w), 0.7% (w / w) to 0.8% (w / w), 0.8% (w / w) to 0.9% (w / w), or 0.9% (w / w) to 1% (w / w), e.g., 0.1 % (w / w), 0.2 ± 0.1 % (w / w), 0.3 ± 0.1 % (w / w), 0.4 ± 0.1 % (w / w), 0.5 ± 0.1 % (w / w), 0.6 ± 0.1 % (w / w), 0.7 ± 0.1 % (w / w), 0.8 ± 0.1 % (w / w), 0.9 ± 0.1 % (w / w), or 1 % (w / w); and

[0096] (c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), or 4.5% (w / w) to 5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 1 .5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), or 5% (w / w) of the compound of Formula (I) or Compound 1 .

[0097] In some embodiments, the lyophilized pharmaceutical composition includes:

[0098] (a) 95% (w / w) to 98% (w / w) of the cryoprotectant, e.g., from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), e.g., 95% (w / w), 96 ± 1 % (w / w), 97 ± 1 % (w / w), or 98% (w / w), wherein the cryoprotectant is selected from mannose, maltose, lactose, xylose, sucrose, trehalose, erythrose, mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol;

[0099] (b) 0.1 % (w / w) to 1% (w / w) of the stabilizer, e.g., 0.1 % (w / w) to 0.2% (w / w), 0.2% (w / w) to 0.3% (w / w), 0.3% (w / w) to 0.4% (w / w), 0.4% (w / w) to 0.5% (w / w), 0.5% (w / w) to 0.6% (w / w), 0.6% (w / w) to 0.7% (w / w), 0.7% (w / w) to 0.8% (w / w), 0.8% (w / w) to 0.9% (w / w), or 0.9% (w / w) to 1 % (w / w), e.g., 0.1 % (w / w), 0.2 ± 0.1 % (w / w), 0.3 ± 0.1 % (w / w), 0.4 ± 0.1 % (w / w), 0.5 ± 0.1 % (w / w), 0.6 ± 0.1 % (w / w), 0.7 ± 0.1 % (w / w), 0.8 ± 0.1 % (w / w), 0.9 ± 0.1 % (w / w), or 1 % (w / w), wherein the stabilizer is selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; and

[0100] (c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 , e.g., 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), or 4.5% (w / w) to 5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 1 .5% (w / w), 2 ± 0.5% (w / w), 2.5 ± 0.5% (w / w), 3 ± 0.5% (w / w), 3.5 ± 0.5% (w / w), 4 ± 0.5% (w / w), 4.5 ± 0.5% (w / w), or 5% (w / w) of the compound of Formula (I) or Compound 1 .

[0101] In some embodiments, the stabilizer is ascorbic acid and the composition includes 0.25% ± 0.05% (w / w) of ascorbic acid.

[0102] In some embodiments, an aqueous solution is prepared by reconstituting the lyophilized composition with an aqueous carrier.

[0103] In some embodiments, the aqueous solution has a pH of 3.5 to 7.5, e.g., 3.5 to 4.0, e.g., 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.5 to 5.5, e.g., 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, or 5.5, or 4.0 to 7.0, e.g., 4 ± 0.5, 5 ± 0.5, 6 ± 0.5, or 7 ± 0.5, or 6.0 to 7.5, e.g., 6.0, 7.0, or 7.5.

[0104] In some embodiments, the aqueous solution has a pH of at least 4. In some embodiments, the aqueous solution has a pH of 4.5 to 5.5, e.g., 4.5, 4.6 ± 0.1 , 4.7 ± 0.1 , 4.8 ± 0.1 , 4.9 ± 0.1 , 5.0 ± 0.1 , 5.1 ± 0.1 , 5.2 ± 0.1 , 5.3 ± 0.1 , 5.4 ± 0.1 , or 5.5. In some embodiments, the pH is 5.0 ± 0.3, e.g., 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, or 5.3.

[0105] In some embodiments, the aqueous carrier is water for injection (WFI). In some embodiments, the aqueous carrier is WFI supplemented with various excipients selected from citric acid, lactic acid, gluconic acid, glucose, or mannitol. In some embodiments, the aqueous solution is substantially free of saline.

[0106] In any of the above embodiments, the lyophilized pharmaceutical composition or aqueous solution thereof is stored in a container shielded from light (e.g., a sealed amber vial).

[0107] In some embodiments, the invention features a method of administering a compound of Formula (I) or Compound 1 to a subject in need thereof, including:

[0108] (a) providing a lyophilized pharmaceutical composition of the invention;

[0109] (b) reconstituting the composition of step (a) in an aqueous carrier to form a solution including the compound of Formula (I) or Compound 1 ; and

[0110] (c) within at least 5 minutes (e.g., within 10 minutes, within 15 minutes, within 30 minutes, within 1 hour, within 1.5 hours, or within 2 hours) of completing step (b), administering to the subject the reconstituted solution of step (b).

[0111] In some embodiments of the above method, the solution of step (c) is administered intravenously.

[0112] In some embodiments, the invention features a method of treating a fungal infection in a subject, wherein the method includes administering to the subject an effective amount of an aqueous solution of the invention. In some embodiments, the route of administration is intravenous.

[0113] In some embodiments, the invention features a method of preparing a lyophilized composition of the invention, including:

[0114] (a) dissolving the compound of Formula (I) or Compound 1 in an organic solvent;

[0115] (b) dissolving a cryoprotectant and a stabilizer and in water in vessel 2, followed by mixing;

[0116] (c) combining the mixtures of step (a) and step (b) into a single vessel, followed by mixing;

[0117] (d) adjusting the pH of the mixture of step (c) between 4.4 to 5.5 (e.g., pH 4.4, pH 4.5 ± 0.1 , pH 4.6 ± 0.1 , pH 4.7 ± 0.1 , pH 4.8 ± 0.1 , pH 4.9 ± 0.1 , pH 5.0 ± 0.1 , pH 5.1 ± 0.1 , pH 5.2 ± 0.1 , pH 5.3 ± 0.1 , pH 5.4 ± 0.1 , or pH 5.5) to achieve a fully dissolved mixture;

[0118] (e) filtering the mixture of step (d);

[0119] (f) lyophilizing the mixture of step (e); and (g) storing the lyophilized composition of step (f) at a temperature starting at least -15 °C (e.g., storing at -15 °C, -20 °C, -25 °C, -30 °C, -35 °C, -40 °C, -45 °C, -50 °C, -55 °C, -60 °C, -65 °C, -70 °C, -75 °C, or -80 °C).

[0120] In some embodiments, the pH of the mixture of step (d) is 4.4.

[0121] In an aspect, the invention features a method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution of any of the above embodiments and a nonionic tonicity agent selected from glucose, glycerin, mannitol, sucrose, glycerol, sorbitol, and trehalose. In some embodiments, the nonionic tonicity agent is glucose. In some embodiments, the nonionic tonicity agent is mannitol (e.g., D-mannitol). In some embodiments, the isotonic solution is substantially free of saline. In some embodiments, the injection is a bolus or an infusion.

[0122] DEFINITIONS

[0123] The term “cryoprotectant,” as used herein, refers to a chemical or molecule that protects or minimizes damage associated from cold temperatures, freezing, or the like. Cryoprotectants may operate to form one or more hydrogen bonds with a compound of Formula (I) or Compound 1 to prevent actual freezing of the compound, in which some flexibility of the molecule is maintained. The cryoprotectant may maintain the physiological structure and function of the compound of Formula (I) or Compound 1 . Cryoprotectants may include a glycol (e.g., ethylene glycol, propylene glycol, or glycerol), and / or a saccharide (e.g., mannose, maltose, lactose, xylose, sucrose, trehalose, or erythrose), and / or a sugar alcohol (e.g., mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol).

[0124] The term “lyophilize” or “lyophilization,” as used herein, refers to the process of freeze drying or removing water from a product after it is frozen. Lyophilization may occur by sublimation of a frozen product when placed under a vacuum. Lyophilization may produce one or more dry powers, remove water without heating, enhance product stability in a dry state, or the like. As a non-limiting example, lyophilization may include freezing a solution having one or more chemicals or compounds in a solvent, such as water or 1-methyl-2-pyrrolidone (NMP), placing the frozen solvent in a vacuum chamber, and allowing the frozen solvent to sublime away from the one or more chemicals or compounds.

[0125] The term “pharmaceutical composition,” as used herein, represents a composition formulated with a pharmaceutically acceptable excipient, and used as part of a therapeutic regimen for the treatment of a disease or ailment in a mammal.

[0126] The term “pharmaceutically acceptable excipient,” as used herein, refers to any ingredient other than the active agent(s) described herein ( e.g., a vehicle capable of suspending or dissolving the active agent(s)) and having the properties of being substantially non-toxic and substantially non-inflammatory in a patient. Excipients may include, e.g., antioxidants, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents ), flavors, fragrances, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, liquid solvents, and buffering agents.

[0127] The term “pharmaceutically acceptable salt,” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J Pharmaceutical Sciences 66: 1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCR, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. Examples of suitable acids for the formation of such salts include acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic, and toluenesulfonic.

[0128] The term “stabilizer,” as used herein, represents a molecule or compound that acts as an antioxidant to prevent or reduce the oxidation of the compound of formula (I) or Compound 1 . In some embodiments, the stabilizer is an organic acid or inorganic acid that lowers the pH of an aqueous solution following reconstitution of the lyophilized sample. In some embodiments, the stabilizer is selected from one or more organic acids capable of lowering the pH of the aqueous solution, e.g., ascorbic acid, citric acid, gluconic acid, or lactic acid, or one or more inorganic acids selected from sulfurous acid, disulfuric acid, or thiosulfuric acid.

[0129] The term “subject,” as used herein, represents a human or non-human animal (e.g., a mammal) that is suffering from, or is at risk of, disease, disorder, or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the subject. Non-limiting examples of diseases, disorders, and conditions include fungal infections caused by a Candida species (e.g., C. albicans, C. auris, C. glabrata, C. krusei, C. parapsilosis, or C. tropicalis), by an Aspergillus species (e.g., A. niger, A. fumigatus, A. flavus, A. nidulans, or A. terreus), by a Cryptococcus species (e.g., C. neoformans var. grubii), by a Fusarium species (e.g., F. solan! or F. annulatum), by a Mucorales species (e.g., M. circinelloides / ramosissimus or Rhizopus spp.), or any other strain that is susceptible to the compound of formula (I) or Compound 1 .

[0130] “Treatment” and “treating,” as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent or cure a disease, disorder, or condition. This term includes active treatment (treatment directed to improve the disease, disorder, or condition); causal treatment (treatment directed to the cause of the associated disease, disorder, or condition); palliative treatment (treatment designed for the relief of symptoms of the disease, disorder, or condition); preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, disorder, or condition); and supportive treatment (treatment employed to supplement another therapy).

[0131] As used herein, the term “substantially amorphous,” in reference to a compound of formula (I) or Compound 1 , refers to a sample of the compound in which less than 20% (w / w) (e.g., less than 15%, 12%, 10%, 8%, 5%, 3%, 2%, or 1% (w / w) is present in a crystalline form, such as between 0.01% and 20%, 0.01% and 15%, 0.01% and 12%, 0.01% and 10%, 0.01% and 8%, 0.01% and 5%, 0.01% and 3%, and 0.01 % and 1% (w / w)) of the compound is present in a crystalline form, e.g., as determined using X- ray powder diffraction. In some embodiments, the absence of crystalline compound is determined using differential scanning calorimetry (DSC).

[0132] The term “tonicity agent” as used herein denotes pharmaceutically acceptable tonicity agents that are used to modulate the tonicity of the formulation, so that, for example, the formulation is isotonic with respect to body fluids. The formulations of the present invention are preferably isosmotic, that is, the formulations have an osmotic pressure that is substantially the same as human blood serum. The tonicity agent used in the formulations are preferably non-ionic tonicity agents and are preferably selected from the group consisting of glucose, glycerin, mannitol, sucrose, glycerol, sorbitol, and trehalose. Preferably, the non-ionic tonicity agent is mannitol, e.g., D-mannitol, or glucose, e.g., D-glucose. The concentration of the tonicity agent will be dependent on the concentration of other components of the formulation, especially where the formulation is intended to be isosmotic.

[0133] As used herein, the term “substantially free of saline” in reference to a formulation disclosed herein, denotes that there is less than 0.1% (w / w) (e.g., less than 0.09% (w / w), less than 0.08% (w / w), less than 0.07% (w / w), less than 0.06% (w / w), less than 0.05% (w / w), less than 0.04% (w / w), less than 0.03% (w / w), less than 0.02% (w / w), or less than 0.01% (w / w)) of a saline in the formulation.

[0134] As used herein, the term “water for injection (WFI),” refers to pharmaceutical grade and sterilized water that is substantially free of saline, but may be supplemented with excipients selected from citric acid, lactic acid, gluconic acid, glucose, mannitol, or a combination thereof. As used herein, WFI is used as an aqueous carrier for the reconstitution of a lyophilizate for intravenous administration in a subject in need thereof.

[0135] BRIEF DESCRIPTION OF THE DRAWINGS

[0136] FIGs. 1A-1 D show high pressure liquid chromatography (HPLC) UV isoplots of formulations with four different concentrations of ascorbic acid after incubation at 6 °C for 20 h: 0 pg / mL (Formulation 18, FIG. 1A), 60 pg / mL (Formulation 19, FIG. 1 B), 100 pg / mL (Formulation 20, FIG. 1 C), and 280 pg / mL (Formulation 22, FIG. 1 D). Compound 1 elutes at 15.9 min, the degradation product formed in the formulation with 280 pg / mL ascorbic acid elutes at 14.5 min, and the oxidation products formed at 0 and 60 pg / mL elutes between 11 .5 and 14 min, with the main oxidized peak eluting at 11 .5 min.

[0137] FIGs. 2A-2C show mass spectra of Compound 1 (FIG. 2A), the degradation product of Compound 1 (FIG. 2B), and oxidized Compound 1 (FIG. 2C). HPLC was performed according to Example 13 with a QTOF mass spectrometer (MS) connected downstream of the DAD detector. The MS was run in negative mode using electrospray ionization. The measured mass [M-H]- of Compound 1 is 892.5054, the measured mass of the degradation product formed at 200 pg / mL ascorbic acid and above is [M-H] = 874.4900 and the measured mass of the main oxidation product is [M-H]- = 908.4987.

[0138] FIGs. 3A-3B show high pressure liquid chromatography (HPLC) UV isoplots of formulation 20 incubated without (FIG. 3A) and with (FIG. 3B) light at 4 °C for 48 hours.

[0139] DETAILED DESCRIPTION

[0140] In general, the invention provides lyophilized pharmaceutical compositions that include a stabilizer or a cryoprotectant and methods of using the same. The lyophilized pharmaceutical compositions of the invention include a compound of formula (I):

[0141] or a pharmaceutically acceptable salt thereof, or Compound 1 :

[0142] Compound 1 , or a pharmaceutically acceptable salt thereof. A pharmaceutical composition may include, e.g., 0.1 % (w / w) to 7.5% (w / w) of a compound of Formula (I) or Compound 1 , e.g., 0.1 % (w / w) to 1 % (w / w), 1 % (w / w) to 1 .5% (w / w), 1 .5% (w / w) to 2% (w / w), 2% (w / w) to 2.5% (w / w), 2.5% (w / w) to 3% (w / w), 3% (w / w) to 3.5% (w / w), 3.5% (w / w) to 4% (w / w), 4% (w / w) to 4.5% (w / w), 4.5% (w / w) to 5% (w / w), 5% (w / w) to 5.5% (w / w), 5.5% (w / w) to 6% (w / w), 6% (w / w) to 6.5% (w / w), 6.5% (w / w) to 7% (w / w), or 7% (w / w) to 7.5% (w / w) of the compound of formula (I) or Compound 1 , e.g., 0.1 % (w / w), 1 % (w / w), 1.5% (w / w), 2% (w / w), 2.5% (w / w), 3% (w / w), 3.5% (w / w), 4% (w / w), 4.5% (w / w), 5% (w / w), 5.5% (w / w), 6% (w / w), 6.5% (w / w), 7% (w / w), or 7.5% (w / w) of the compound of formula (I) or Compound 1 .

[0143] In one embodiment, the pharmaceutical composition may be produced by dissolving a compound of formula (I) or Compound 1 in a solution that may contain a cryoprotectant or a stabilizer, or both.

[0144] Stabilizers described herein may include any compound capable of stabilizing the compound of formula (I) or Compound 1 against, e.g., oxidation. Non-limiting examples of stabilizers include antioxidants, such as ascorbic acid (e.g., L-(+)-ascorbic acid), sodium bisulfite, sodium metabisulfite, and sodium thiosulfate. Preferably, the stabilizer is ascorbic acid. A pharmaceutical composition may include, e.g., 0.01 %% (w / w) to 2% (w / w) of the stabilizer, e.g., 0.01 % (w / w) to 0.05% (w / w), 0.05% (w / w) to 0.15% (w / w), 0.15% (w / w) to 0.25% (w / w), 0.25% (w / w) to 0.35% (w / w), 0.35% (w / w) to 0.45% (w / w), 0.45%

[0145] (w / w) to 0.55% (w / w), 0.55% (w / w) to 0.65% (w / w), 0.65% (w / w) to 0.75% (w / w), 0.75% (w / w) to 0.85%

[0146] (w / w), 0.85% (w / w) to 0.95% (w / w), 0.95% (w / w) to 1.05% (w / w), 1.05% (w / w) to 1.15% (w / w), 1.15%

[0147] (w / w) to 1 .25% (w / w), 1 .25% (w / w) to 1 .35% (w / w), 1 .35% (w / w) to 1 .45% (w / w), 1 .45% (w / w) to 1 .55%

[0148] (w / w), 1 .55% (w / w) to 1 .65% (w / w), 1 .65% (w / w) to 1 .75% (w / w), 1 .75% (w / w) to 1 .85% (w / w), 1 .85%

[0149] (w / w) to 1.95% (w / w), or 1.95% (w / w) to 2% (w / w), e.g., 0.01 % (w / w), 0.05% (w / w), 0.15% (w / w), 0.25% (w / w), 0.35% (w / w), 0.45% (w / w), 0.55% (w / w), 0.65% (w / w), 0.75% (w / w), 0.85% (w / w), 0.95% (w / w), 1.05% (w / w), 1.15% (w / w), 1.25% (w / w), 1.35% (w / w), 1.45% (w / w), 1.55% (w / w), 1.65% (w / w), 1.75% (w / w), 1.85% (w / w), 1.95% (w / w), or 2% (w / w).

[0150] Cryoprotectants described herein may include a saccharide, e.g., furanose, pyranose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, maltose, gulose, iodose, galactose, talose, erythrose, or the like, or a complex carbohydrate, e.g., trehalose, sucrose, lactose, cellulose, chitin, starch, or the like. In some embodiments, the cryoprotectant is a sugar alcohol. In some embodiments, the sugar alcohol is mannitol (e.g., D-mannitol), sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol. In some embodiments, the cryoprotectant is mannitol. The cryoprotectant may be present in the composition such that at least 80% (w / w) of a cryoprotectant is present, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 99.9% (w / w). In some embodiments, the composition includes 90% (w / w) to 99.9% (w / w) of the cryoprotectant, e.g., from 90% (w / w) to 91% (w / w), from 91% (w / w) to 92% (w / w), from 92% (w / w) to 93% (w / w), from 93% (w / w) to 94% (w / w), from 94% (w / w) to 95% (w / w), from 95% (w / w) to 96% (w / w), from 96% (w / w) to 97% (w / w), from 97% (w / w) to 98% (w / w), or from 98% (w / w) to 99% (w / w), or from 99% (w / w) to 99.9% (w / w), e.g., 90% (w / w), 91% (w / w), 92% (w / w), 93% (w / w), 94% (w / w), 95% (w / w), 96% (w / w), 97% (w / w), or 99% (w / w), or 99.9% (w / w). In some embodiments, the composition includes 90% (w / w) to 99.9% (w / w) of the cryoprotectant. Preferably, the composition includes at least 90% (w / w) of the cryoprotectant.

[0151] In some embodiments, carriers may be used to reconstitute the lyophilized pharmaceutical composition. The carrier may be an aqueous carrier, such as water substantially free of saline, or the water for injection may be supplemented with various excipients (e.g., citric acid, lactic acid, gluconic acid, mannitol, glucose, or a combination thereof).

[0152] In some embodiments, an aqueous solution is prepared by reconstituting a lyophilized composition of the disclosure with an aqueous carrier. The pH of the reconstituted aqueous solution may be, e.g., 3.5 to 7.5. For example, the pH of the liquid composition may be 3.5 to 4.0, e.g., 3.5, 3.6, 3.7, 3.8, 3.9, 4.0; 4.5 to 5.5, e.g., 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, or 5.5; or 4.0 to 7.0, e.g., 4, 5, 6, or 7; or 6.0 to 7.5, e.g., 6.0, 7.0, or 7.5. In some embodiments, the pH of the reconstituted aqueous solution is 5.2. In some embodiments, the pH of the reconstituted aqueous solution is 5.0. In some embodiments, the pH of the reconstituted aqueous solution is 4.4.

[0153] The pharmaceutical compositions described herein may be used to treat a subject in need thereof. The method of treating the subject includes administering to the subject a therapeutically effective amount of the liquid or reconstituted lyophilized pharmaceutical composition described herein. The subject may be suffering from a fungal infection ( e.g., an invasive fungal infection), e.g., caused by a Candida species (e.g., C. albicans, C. auris, C. glabrata, C. krusei, C. parapsilosis, or C. tropicalis), by an Aspergillus species (e.g., A. niger, A. fumigatus, A. flavus, A. nidulans, or A. terreus), by a Cryptococcus species (e.g., C. neoformans var. grubii), by a Fusarium species (e.g., F. solan! or F. annulatum), by a Mucorales species (e.g., M. circinelloides / ramosissimus or Rhizopus spp.), or any other strain that is susceptible to the compound of formula (I) or Compound 1 .

[0154] The pharmaceutical compositions described herein may be administered to the subject in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1-12 hours, 1-24 hours, 1-7 days, or 1-4 weeks. The pharmaceutical composition may be administered according to a schedule, or the pharmaceutical composition may be administered without a predetermined schedule. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted overtime according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions.

[0155] An effective amount of a compound of the invention may be, for example, a total daily dosage of, e.g., between 0.02 mg and 3000 mg of a compound of Formula (I) or Compound 1 . Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the compounds of the invention can be dosed at 0.02 mg / kg body weight.

[0156] In some embodiments, doses of the pharmaceutical composition are administered to a subject on a daily basis, as needed. In some embodiments, the pharmaceutical compositions are administered to a subject at the onset of symptoms. When a pharmaceutical composition is administered daily, administration may occur, for example, 1-4 times per day.

[0157] Exemplary routes of administration of the pharmaceutical compositions described herein include intravenous, inhalation, intranasal, oral, sublingual, buccal, transdermal, intradermal, intramuscular, intravaginal, parenteral, intra-arterial, intracranial, intrathecal, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, and topical administration. Preferably, the route of administration is intravenous. The pharmaceutical compositions described herein include those formulated for intravenous or intra-arterial administration.

[0158] As mentioned above, the compounds of the invention may take the form of pharmaceutically acceptable salts. Such salts include acid addition salts with physiologically acceptable organic or inorganic acids. Examples of suitable acids for the formation of such salts include acetic, aspartic, benzene-sulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylre-sorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phos-phoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic. Glutamate salts are especially preferred. Alternatively, salts may be formed with bases.

[0159] Examples of suitable bases for the formation of such salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2 dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, tri-ethylamine, trimethylamine and tripropylamine. The pharmaceutically acceptable salts may be in hydrated form. Procedures for conversion of the compounds of the disclosure into such salts are conventional in the art.

[0160] EXAMPLES

[0161] The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, patents, and patent applications cited throughout this application are expressly incorporated herein by reference.

[0162] Example 1 : Preparation of the mannitol and acetate buffer formulation

[0163] In a flask, 5 mg of Compound 1 was dissolved in 25 pL of 1-methyl-2-pyrrolidone (NMP) to produce a 200 mg / mL solution of the compound of Compound 1. The solution was slowly added to 5 mL of 40 g / L mannitol in water buffered to either pH 4.3 or pH 5.0 with 50 mM sodium acetate. The final concentration of Compound 1 in the formulation was 1 g / L.

[0164] Example 2: Preparation of the glucose and acetate buffer formulation

[0165] In a flask, 5 mg of Compound 1 was dissolved in 25 pL NMP to produce a 200 mg / mL solution of the compound of Compound 1 . The solution was slowly added to 5 mL of 50 g / L glucose in water buffered to either pH 4.3 or pH 5.0 with 50 mM sodium acetate. The final concentration of Compound 1 in the formulation was 1 g / L.

[0166] Example 3: Preparation of the 1-4% (w / w) mannitol formulations

[0167] In a flask, 5 mg of Compound 1 was dissolved in 25 pL NMP to produce a 200 mg / mL solution of the compound of Compound 1 . The solution was slowly added to 5 mL of 10 g / L, 20 g / L, 30 g / L, or 40 g / L mannitol in water. The mannitol concentration in each formulation is specified in Table 2. To dissolve the compound of Compound 1 , the pH was adjusted to pH 4-5 by the addition of 2% (v / v) acetic acid. The final concentration of Compound 1 in each formulation was 1 g / L.

[0168] Example 4: Preparation of the 5% (w / w) glucose formulation

[0169] In a flask, 5 mg of Compound 1 was dissolved in 25 pL NMP to produce a 200 mg / mL solution of Compound 1 . The solution was slowly added to 5 mL of 50 g / L glucose in water solution. To dissolve the compound of Compound 1 , the pH was adjusted to 4-5 by the addition of 2% (v / v) acetic acid. The final concentration of Compound 1 in the formulation was 1 g / L.

[0170] Example 5: Preparation of the 4% (w / w) mannitol formulation

[0171] In a flask, 5 mg of Compound 1 was dissolved in 25 pL NMP to produce a 200 mg / mL solution of Compound 1. The solution was slowly added to 5 mL of a solution of 40 g / L mannitol in water. To dissolve the compound of Compound 1 , the pH was adjusted to pH 4-5 by the addition of 2% (v / v) acetic acid. The final concentration of Compound 1 in the formulation was 1 g / L.

[0172] Example 6: Preparation of the mannitol and citric acid formulation

[0173] In a flask, 5 mg of Compound 1 was dissolved in 25 pL NMP to produce a 200 mg / mL solution of Compound 1 . The solution was slowly added to 5 mL of a 40 g / L mannitol in water solution supplemented with 29 pg / mL citric acid. Compound 1 was dissolved upon adjustment to a pH of 4-5 by the addition of 2% (v / v) acetic acid. The final concentration of Compound 1 in the formulation was 1 g / L. Example 7: Preparation of the mannitol and gluconic acid formulation

[0174] In a flask, 5 mg of Compound 1 was dissolved in 25 pL NMP to produce a 200 mg / mL solution of Compound 1 . The solution was slowly added to 5 mL of a 40 g / L mannitol in water solution supplemented with 20 pg / mL gluconic acid. Compound 1 was dissolved upon adjustment to a pH of 4-5 by the addition of 2% (v / v) acetic acid. The final concentration of Compound 1 in the formulation was 1 g / L.

[0175] Example 8: Preparation of the mannitol and ascorbic acid formulations

[0176] In a flask, 5 mg of Compound 1 was dissolved in 25 pL NMP to produce a 200 mg / mL solution of Compound 1 . The solution was slowly added to 5 mL of a 40 g / L mannitol in water solution supplemented with 70 pg / mL (formulation 17), 100 pg / mL (formulation 20), 200 pg / mL (formulation 21), 280 pg / mL (formulation 22) or 694 pg / mL (formulation 23) ascorbic acid. Compound 1 was dissolved upon adjustment to a pH of 4-5 by the addition of 2% (v / v) acetic acid.

[0177] Example 9: Preparation of formulations that include 100 pg / mL ascorbic acid

[0178] Compound 1 was dissolved in 250 pL of NMP to give a 200 mg / mL solution of Compound 1 . In a separate flask, 35 mL of a 40 g / L mannitol solution was mixed with 350 pL of 10 mg / mL ascorbic acid solution to give a final concentration of 100 pg / mL ascorbic acid. Then, 175 pL of the 200 mg / mL solution containing Compound 1 was slowly added to the mannitol solution under stirring to give a concentration of 1 .0 g / L of Compound 1 . To dissolve Compound 1 , approximately 100 pL of a 2% (v / v) acetic acid solution was added to decrease the pH from 5.5 to 4.4. The solution was filtered using a 0.22 pm filter and distributed into glass vials. The vials were covered in aluminum foil to avoid light exposure and were subsequently lyophilized according to Example 12 for 47 hours. The stability of Compound 1 in the formulations, prior to lyophilization and after reconstitution, were measured after storage at 6 °C and 22 °C, as described in Example 13.

[0179] Example 10: Preparation of mannitol formulations without NMP

[0180] Compound 1 (35 mg) was added to 35 mL of 40 g / L mannitol solution and 350 pL of 12 mg / mL ascorbic acid solution The final concentration of Compound 1 was 1 g / L and the final concentration of ascorbic acid was 120 pg / mL in the formulation. To dissolve Compound 1 , approximately 140 pL of a 2% (v / v) acetic acid solution was added to decrease the pH from 5.5 to 4.40. The solution was filtered using a 0.22 pm filter and distributed into vials. The formulation was lyophilized according to Example 12.

[0181] Example 11 : Preparation of formulations that include 120 pg / mL ascorbic acid

[0182] Compound 1 was dissolved in NMP to give a solution of 200 mg / mL of Compound 1 . The solution was added to a 40 g / L mannitol solution to give a final concentration of 1 .0 g / L of Compound 1 . To this solution, a solution of ascorbic acid was added to give a final ascorbic acid concentration of 120 pg / mL. To dissolve Compound 1 , approximately 2% acetic acid solution was added to decrease the pH from 5.5 to 4.40. The solution was filtered using a 0.22 pm filter and distributed into vials and lyophilized according to Example 12. After lyophilization and reconstitution to 1 mg / mL, the formulation had a pH of 5.2. Example 12: Lyophilization and reconstitution of formulations

[0183] Formulations of Compound 1 as produced in Examples 1-11 were frozen at -80 °C overnight. Lyophilization was performed using a lab-scale freeze dryer with vacuum pressure <0.01 mPa. After 3 days of lyophilization, the lyophilized powder was either stored at least -15 °C or reconstituted in an aqueous carrier to a final concentration of 0.6-1 mg / mL of Compound 1. The aqueous carrier was either pure water for injection (WFI), WFI supplemented with 236 mg / L citric acid (Formulation 12), WFI supplemented with 51 mg / L lactic acid (Formulation 13), or WFI supplemented with 309 mg / L gluconic acid (Formulation 14). The formulations can be diluted further in a mannitol solution (e.g., 4% (w / w) mannitol in water) or a glucose solution (e.g., 5% (w / w) glucose in water.

[0184] Example 13: Stability assay

[0185] When Compound 1 is stored in an aqueous solution, the compound oxidizes over time, and the rate of oxidation of the compound increases at a low pH. However, a low pH is necessary to solubilize Compound 1 . This experiment describes a stability assay to determine which formulations of the present disclosure are able to prevent or reduce the oxidation of Compound 1 when it is dissolved in an acidic aqueous formulation.

[0186] The concentrations of Compound 1 in each formulation were determined using an Agilent 1290 HPLC system coupled to a diode array detector (DAD). The HPLC analytical method for measuring the concentration of Compound 1 is summarized in Table 1 . The samples to be injected could be diluted to concentrations of 0.03-0.05 mg / mL in 4% mannitol, 5% glucose, or dimethylsulfoxide (DMSO) prior to injection of 5 pL diluted solution. Alternatively, 0.5 pL of undiluted formulations were injected.

[0187] Table 1. HPLC analytical method for measuring the concentration of Compound 1.

[0188] Each formulation recited in Table 2 was evaluated in the stability assay to determine the percent of degraded Compound 1 overtime. Each formulation was prepared according to the corresponding example. The “formulation composition and pH prior to freeze-drying” column shows the concentration of the cryoprotectant, the amount of NMP, the concentration of buffer or non-volatile acids, and the pH of the formulation. The “dry weight of non-volatile compounds” column summarizes the composition of each formulation after lyophilization, with the assumption that all volatile compounds are removed after lyophilization. The lyophilizate may be reconstituted in aqueous carriers, such as WFI or WFI supplemented with various excipients (e.g., citric acid, lactic acid, gluconic acid, glucose, or mannitol), and then further diluted prior to stability analyses or administration to a subject. The concentrations (g / L) or compositions ((w / w) percent) of the components after dilution will depend on dilution factors and are not provided in the table. Table 2. Summary of formulations evaluated in the stability assay.

[0189]

[0190]

[0191] To determine the degradation of the compound overtime, each aqueous formulation was incubated at a temperature (between 4 °C to 25 °C) for a specific amount of time (between 2.2 h to 39 h). After each timepoint, a sample from each formulation was analyzed by HPLC to determine the percent of degraded compound at that timepoint. Table 3 summarizes the stability data for each formulation shown in Table 2. For formulations 15-27 and 19-27, a stabilizer was added prior to pH adjustment using acetic acid, which occurs before lyophilization. The stabilizer concentrations provided in Table 3 are the concentrations in the liquid formulation prior to lyophilization. For each formulation, the pH and the temperature at which the stability study was performed are also provided in Table 3. The stability is given as the percentage of Compound 1 that was lost due to degradation at each time point (time point in parentheses).

[0192] Table 3. Summary of the stability data of each formulation.

[0193] The data in Table 3 show that there are specific variables that impact the stability of Compound 1 in each formulation. For example, formulations that lacked a stabilizer, formulations with a lower pH (e.g., a pH below 4.3), and formulations stored at higher temperatures generally resulted in poor stability and fast oxidation of Compound 1 . In contrast, formulations that included a stabilizer, formulations that included mannitol as a cryoprotectant, formulations with a higher pH (e.g., a pH above 4.3), and formulations stored at lower temperatures generally were superior at stabilizing Compound 1 and preventing its oxidation.

[0194] The data shown in Table 3 also demonstrated the importance of the stabilizer in the formulation with respect to stabilizing Compound 1 . For instance, formulations that included ascorbic acid (e.g., formulations 24, 26 and 27) were superior at stabilizing Compound 1 compared to formulations that included either gluconic acid (e.g., formulations 14 and 16), citric acid (e.g., formulation 15), or lactic acid (e.g., formulation 13). Formulation 15, which included citric acid, was not soluble in water, and so it was not suitable for stability testing. Thus, ascorbic acid was the best performing stabilizer with respect to stabilizing Compound 1.

[0195] The choice of cryoprotectant in the formulation also impacted the stability of Compound 1 . As shown in Table 3, formulations that included mannitol (e.g., formulations 5, 8, 9, 24, 26 and 27) were superior at stabilizing Compound 1 compared to formulations that included glucose (e.g., formulations 3, 4, and 6). Thus, mannitol was the best performing cryoprotectant with respect to stabilizing Compound 1 .

[0196] Furthermore, the concentration of ascorbic acid also influences the stability of Compound 1 : too little or too much ascorbic acid generally resulted in poorer stability of Compound 1 . For example, at concentrations of ascorbic acid of 60 pg / mL and below, oxidation byproducts were observed up-stream of Compound 1 at retention time 10-14 min in the LC-UV chromatogram (FIG. 1A-1 D), and these oxidation byproducts were confirmed by mass spectrometry (FIGs. 2A and 2C). At 280 pg / mL ascorbic acid and above, no oxidation products were observed, but instead a degradation product eluting at 14.5 min was formed (FIG. 1 D) and was confirmed by mass spectrometry (FIG. 2B). Thus, the data demonstrate that the optimal (w / w) percent of ascorbic acid to stabilize Compound 1 in a formulation is between 0.2% (w / w) and 0.3% (w / w) (i.e., 100-120 mg of ascorbic acid per gram of Compound 1).

[0197] In summary, the formulations in Table 2 that best stabilize Compound 1 are formulations 24, 26 and 27, which are supplemented with 100-120 mg of ascorbic acid per gram of Compound 1. Lower concentrations of ascorbic acid resulted in oxidation of Compound 1 and higher concentrations resulted in formation of a degradation product. Mannitol is the superior cryoprotectant compared to glucose. Thus, the data in Table 3 provides guidelines for developing a formulation that can best stabilize Compound 1 .

[0198] Example 14. Stability of the mannitol formulations when exposed to light

[0199] Compound 1 was formulated according to Example 15. The formulation was distributed into two clear glass vials, one was kept at 4 °C in dark, and the other sample was kept at 4 °C exposed to light by placing the samples under a lamp. The two samples were analyzed by HPLC-UV isoplots after 48 hours of incubation. For the sample stored at 4 °C in the dark, no degradation of Compound 1 was observed after 48 hours of incubation. For the sample exposed to light, 63% of Compound 1 was degraded after 24 hours and 85% of Compound 1 was degraded after 48 hours. The isoplots demonstrated that the formulation exposed to light was significantly degraded (FIG. 3B), whereas the formulation incubated in the dark only generated minor amounts of a degradation product (FIG. 3A).

[0200] Example 15. Large scale production of a lyophilized composition

[0201] A large scale preparation of a lyophilized composition of formulation 27 is described. Vessel 1 is charged with 33.0 g to 33.6 g (e.g., 33.3 g) of a compound of formula (I) or Compound 1 , followed by the addition of 164.7 g to 168.0 g (e.g., 166.3 g) of NMP to dissolve the compound. Vessel 2 is charged with 1198 g to 1222 g (e.g., 1210 g) of a cryoprotectant (e.g., mannitol), which is dissolved in 90% of the final bulk volume with 26,950 g to 27,494 g (e.g., 27,222 g) of water (e.g., water for injection). To the mixture in vessel 2, 3.59 g to 3.67 g (e.g., 3.6296 g) of a stabilizer (e.g., ascorbic acid) is added, and the mixture is mixed to dissolve the stabilizer. The mixture in vessel 2 is then combined with the mixture of vessel 1 , and the combined mixtures are further mixed. The pH of the combined mixture is adjusted between 4.4 to 5.5 using 20% (v / v) acetic acid to dissolve the compound of formula (I) or Compound 1 . For example, the pH of the mixture can be adjusted to a pH of 5.0 ± 0.3. Lastly, water is added to the final bulk with a target weight from 29,944 g to 30,549 g (e.g., 30,247 g). The mixture is subsequently sparged with nitrogen gas, pre-filtered, then sterile filtered using 0.22 pm filters. The sterile formulation is aliquoted into 20-mL amber vials, 15 mL formulation / vial. The samples are lyophilized to generate lyophilizates, and are subsequently saturated with an atmosphere of nitrogen gas, sealed, and crimped. The vials are then stored at a temperature starting at least -15 °C (e.g., from -15 °C to -80 °C). The lyophilized composition can be reconstituted in water for injection for intravenous administration in a subject in need thereof.

[0202] Example 16. Solubility of formulation 27

[0203] Formulation 27, as described in Example 15, was reconstituted in two separate aqueous carriers: (1) normal saline; and (2) water for injection (WFI). The two reconstituted formulations were stored at room temperature. After two hours at room temperature, precipitation was observed in the normal saline formulation, whereas the WFI formulation remained clear after 8 hours at room temperature. Thus, formulation 27 was found to be soluble in WFI at room temperature for at least 8 hours.

[0204] Example 17. Stability of formulation 27 after reconstitution

[0205] Formulation 27, as described in Example 15, was transferred from a -40 °C freezer and was warmed to room temperature for 30 min. The lyophilizate was reconstituted in 15 mL of WFI to a final concentration of 1 .0 g / L of Compound 1 . The reconstituted formulation was kept at 4 °C for 19 hours, and then incubated at 25 °C. No significant degradation of Compound 1 in the reconstituted formulation was observed by HPLC after 8 hours of incubation at 25 °C (see Table 3).

[0206] Example 18. Preparation and stability of formulation 27 for intravenous administration

[0207] Formulation 27, described in Example 15, was transferred from a -40 °C freezer and was warmed to room temperature for 50 min. The lyophilizate was reconstituted in 15 mL of WFI to give a final concentration of 1 .0 mg / mL Compound 1 . To this solution, 14 mL of a nonionic tonicity agent (e.g., a 5% (w / w) glucose solution) was withdrawn from an infusion bag containing 100 mL of the nonionic tonicity agent, and 14 mL of reconstituted formulation was added to the bag. The bag was turned up-side-down several times to give a homogeneous yellow solution. The bag was covered in aluminum foil to protect the solution from light and kept at 4 °C for 19.0 hours. The bag was then incubated at 25 °C, and samples were collected from the bag after 0, 2, 4, and 8 hours and subjected to HPLC analysis to determine the percent of degraded Compound 1. Percent of Compound 1 degraded per timepoint was 0% (2 h), 3% (4h) and 4% (8 h), as measured by HPLC.

[0208] OTHER EMBODIMENTS

[0209] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth.

[0210] All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0211] Some embodiments are within the following numbered paragraphs.

[0212] 1 . A lyophilized pharmaceutical composition including a cryoprotectant and a compound of Formula

[0213] (I): or a pharmaceutically acceptable salt thereof.

[0214] 2. The lyophilized pharmaceutical composition of paragraph 1 , wherein the compound is Compound

[0215] 1 :

[0216] Compound 1 , or a pharmaceutically acceptable salt thereof.

[0217] 3. The lyophilized pharmaceutical composition of paragraph 1 or 2, wherein the cryoprotectant is a saccharide. 4. The lyophilized pharmaceutical composition of paragraph 1 or 2, wherein the cryoprotectant is a sugar alcohol.

[0218] 5. The lyophilized composition of paragraph 3, wherein the saccharide is glucose.

[0219] 6. The lyophilized composition of paragraph 3, wherein the saccharide is mannose.

[0220] 7. The lyophilized composition of paragraph 3, wherein the saccharide is maltose.

[0221] 8. The lyophilized composition of paragraph 3, wherein the saccharide is lactose.

[0222] 9. The lyophilized composition of paragraph 3, wherein the saccharide is xylose.

[0223] 10. The lyophilized composition of paragraph 3, wherein the saccharide is sucrose.

[0224] 11 . The lyophilized composition of paragraph 3, wherein the saccharide is trehalose.

[0225] 12. The lyophilized composition of paragraph 3, wherein the saccharide is erythrose.

[0226] 13. The lyophilized pharmaceutical composition of paragraph 4, wherein the sugar alcohol is mannitol.

[0227] 14. The lyophilized pharmaceutical composition of paragraph 4, wherein the sugar alcohol is sorbitol.

[0228] 15. The lyophilized pharmaceutical composition of paragraph 4, wherein the sugar alcohol is isomalt.

[0229] 16. The lyophilized pharmaceutical composition of paragraph 4, wherein the sugar alcohol is maltitol.

[0230] 17. The lyophilized pharmaceutical composition of paragraph 4, wherein the sugar alcohol is lactitol.

[0231] 18. The lyophilized pharmaceutical composition of paragraph 4, wherein the sugar alcohol is xylitol.

[0232] 19. The lyophilized pharmaceutical composition of paragraph 4, wherein the sugar alcohol is erythritol.

[0233] 20. The lyophilized pharmaceutical composition of any one of paragraphs 1 to 19, wherein the composition includes at least 80% (w / w) of the cryoprotectant.

[0234] 21 . The lyophilized pharmaceutical composition of paragraph 20, wherein the composition includes 90% (w / w) to 99.9% (w / w) of the cryoprotectant. 22. The lyophilized pharmaceutical composition of paragraph 21 , wherein the composition includes 90% (w / w) to 95% (w / w) of the cryoprotectant.

[0235] 23. The lyophilized pharmaceutical composition of paragraph 21 , wherein the composition includes 95% (w / w) to 99.9% (w / w) of the cryoprotectant.

[0236] 24. The lyophilized pharmaceutical composition of any one of paragraphs 1 to 23, wherein the composition further includes a stabilizer.

[0237] 25. The lyophilized pharmaceutical composition of paragraph 24, wherein the stabilizer is an antioxidant.

[0238] 26. The lyophilized pharmaceutical composition of paragraph 25, wherein the antioxidant is ascorbic acid.

[0239] 27. The lyophilized pharmaceutical composition of paragraph 25, wherein the antioxidant is sodium bisulfite.

[0240] 28. The lyophilized pharmaceutical composition of paragraph 25, wherein the antioxidant is sodium metabisulfite.

[0241] 29. The lyophilized pharmaceutical composition of paragraph 25, wherein the antioxidant is sodium thiosulfate.

[0242] 30. The lyophilized pharmaceutical composition of any one of paragraphs 24 to 29, wherein the composition includes 0.01% (w / w) to 2% (w / w) of the stabilizer.

[0243] 31 . The lyophilized pharmaceutical composition of paragraph 30, wherein the composition includes 0.01% (w / w) to 0.5% (w / w) of the stabilizer.

[0244] 32. The lyophilized pharmaceutical composition of paragraph 30, wherein the composition includes 0.5% (w / w) to 2% (w / w) of the stabilizer.

[0245] 33. The lyophilized pharmaceutical composition of any one of paragraphs 1 to 32, wherein the composition includes 0.1% (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1.

[0246] 34. The lyophilized pharmaceutical composition of paragraph 33, wherein the composition includes 0.1% (w / w) to 1% (w / w) of the compound of Formula (I) or Compound 1 .

[0247] 35. The lyophilized pharmaceutical composition of paragraph 33, wherein the composition includes 1% (w / w) to 4% (w / w) of the compound of Formula (I) or Compound 1 . 36. The lyophilized pharmaceutical composition of paragraph 33, wherein the composition includes 4% (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0248] 37. The lyophilized pharmaceutical composition of any one of paragraphs 1 to 36, wherein the compound of Formula (I) or Compound 1 is in a pharmaceutically acceptable salt.

[0249] 38. The lyophilized pharmaceutical composition of any one of paragraphs 1 to 37, wherein the composition further includes an acetate buffer.

[0250] 39. The lyophilized pharmaceutical composition of any one of paragraphs 1 to 38, wherein the compound is in substantially amorphous form.

[0251] 40. The lyophilized pharmaceutical composition of any one of paragraphs 1 to 39, wherein the composition includes:

[0252] (a) 90% (w / w) to 99% (w / w) of the cryoprotectant;

[0253] (b) 0.05% (w / w) to 2% (w / w) of the stabilizer; and

[0254] (c) 1% (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0255] 41 . The lyophilized composition of any one of paragraphs 1 to 40, wherein the composition includes:

[0256] (a) 95% (w / w) to 98% (w / w) of the cryoprotectant;

[0257] (b) 0.1% (w / w) to 1% (w / w) of the stabilizer; and

[0258] (c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 .

[0259] 42. The lyophilized pharmaceutical composition of paragraph 40 or 41 , wherein the composition includes:

[0260] (a) the cryoprotectant is selected from any one of paragraphs 5 to 19; and

[0261] (b) the stabilizer from any one of paragraphs 26 to 29.

[0262] 43. The lyophilized composition of any one of paragraphs 1 to 42, wherein the composition includes:

[0263] (a) 90% (w / w) to 99% (w / w) of the cryoprotectant, wherein the cryoprotectant is mannitol;

[0264] (b) 0.05% (w / w) to 2% (w / w) of the stabilizer, wherein the stabilizer is ascorbic acid; and

[0265] (c) 1% (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0266] 44. The lyophilized pharmaceutical composition of paragraph 43, wherein the composition includes 0.25% ± 0.05% (w / w) of ascorbic acid.

[0267] 45. The lyophilized pharmaceutical composition of paragraph 43, wherein the composition includes:

[0268] (a) 97.5% ± 1% (w / w) of mannitol;

[0269] (b) 0.2% ± 0.025% (w / w) of ascorbic acid; and

[0270] (c) 2.3% ± 0.25% (w / w) of the compound of Formula (I) or Compound 1 . 46. The lyophilized pharmaceutical composition of paragraph 43, wherein the composition includes:

[0271] (a) 97.2% ± 1% (w / w) of the mannitol;

[0272] (b) 0.3% ± 0.025% (w / w) of the ascorbic acid; and

[0273] (c) 2.5% ± 0.25% (w / w) of the compound of Formula (I) or Compound 1 .

[0274] 47. The lyophilized pharmaceutical composition of paragraph 43, wherein the composition includes:

[0275] (a) 97.3% ± 1% (w / w) of the mannitol;

[0276] (b) 0.3% ± 0.025% (w / w) of the ascorbic acid; and

[0277] (c) 2.4% ± 0.25% (w / w) of the compound of Formula (I) or Compound 1 .

[0278] 48. An aqueous solution prepared by reconstituting the lyophilized pharmaceutical composition of any one of paragraphs 1 to 47 with an aqueous carrier.

[0279] 49. The aqueous solution of paragraph 48, wherein the solution includes a pH of 3.5 to 7.5.

[0280] 50. The aqueous solution of paragraph 49, wherein the solution includes a pH of at least 4.

[0281] 51 . The aqueous solution of paragraph 50, wherein the pH is 4.4 to 5.5.

[0282] 52. The aqueous solution of paragraph 51 , wherein the pH is 4.4 to 4.6.

[0283] 53. The aqueous solution of paragraph 51 , wherein the pH is 4.6 to 4.8.

[0284] 54. The aqueous solution of paragraph 51 , wherein the pH is 4.8 to 5.1 .

[0285] 55. The aqueous solution of paragraph 51 , wherein the pH is 5.1 to 5.5.

[0286] 56. The aqueous solution of any one of paragraphs 48 to 55, wherein the aqueous carrier is water for injection (WFI).

[0287] 57. The aqueous solution of any one of paragraphs 48 to 56, wherein the aqueous solution is substantially free of saline.

[0288] 58. The lyophilized pharmaceutical composition of any one of paragraphs 1 to 47, or the aqueous solution of any one of paragraphs 48 to 57, wherein the composition or solution is stored in a container shielded from light, such as a sealed amber vial.

[0289] 59. A method of administering a compound of Formula (I) or Compound 1 to a subject in need thereof, including: (a) providing the lyophilized pharmaceutical composition according to any one of paragraphs 1 to

[0290] 47;

[0291] (b) reconstituting the composition of step (a) in an aqueous carrier to form a solution including the compound of Formula (I) or Compound 1 ; and

[0292] (c) within at least 5 minutes of completing step (b), administering to the subject the reconstituted solution of step (b).

[0293] 60. The method of paragraph 59, wherein the solution of step (c) is administered intravenously.

[0294] 61 . A method of treating a fungal infection in a subject, the method including administering to the subject an effective amount of the aqueous solution of any one of paragraphs 48 to 57.

[0295] 62. The method of paragraph 61 , wherein the route of administration is intravenous.

[0296] 63. A method of preparing the lyophilized composition of any one of paragraphs 1 to 47, including:

[0297] (a) dissolving the compound of Formula (I) or Compound 1 in an organic solvent;

[0298] (b) dissolving a cryoprotectant and a stabilizer and in water in vessel 2, followed by mixing;

[0299] (c) combining the mixtures of step (a) and step (b) into a single vessel, followed by mixing

[0300] (d) adjusting the pH of the mixture of step (c) between 4.4 to 5.5 to achieve a fully dissolved mixture;

[0301] (e) filtering the mixture of step (d);

[0302] (f) lyophilizing the mixture of step (e); and

[0303] (g) storing the lyophilized composition of step (f) at a temperature starting at least -15 °C.

[0304] 64. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 48 to 57 and a nonionic tonicity agent, wherein the nonionic tonicity agent is glucose.

[0305] 65. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 48 to 57 and a nonionic tonicity agent, wherein the nonionic tonicity agent is glycerin.

[0306] 66. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 48 to 57 and a nonionic tonicity agent, wherein the nonionic tonicity agent is mannitol.

[0307] 67. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 48 to 57 and a nonionic tonicity agent, wherein the nonionic tonicity agent is sucrose. 68. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 48 to 57 and a nonionic tonicity agent, wherein the nonionic tonicity agent is glycerol.

[0308] 69. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 48 to 57 and a nonionic tonicity agent, wherein the nonionic tonicity agent is sorbitol.

[0309] 70. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 48 to 57 and a nonionic tonicity, wherein the nonionic tonicity agent is agent trehalose.

[0310] 71 . The method of any one of paragraphs 64 to 70, wherein the isotonic solution is substantially free of saline.

[0311] 72. The method of any one of paragraphs 64 to 71 , wherein the injection is a bolus or an infusion.

[0312] 73. A lyophilized pharmaceutical composition including a stabilizer and a compound of Formula (I): or a pharmaceutically acceptable salt thereof.

[0313] 74. The lyophilized pharmaceutical composition of paragraph 73, wherein the compound is

[0314] Compound 1 :

[0315] Compound 1 , or a pharmaceutically acceptable salt thereof.

[0316] 75. The lyophilized pharmaceutical composition of paragraph 73 or 74, wherein the stabilizer is an antioxidant.

[0317] 76. The lyophilized pharmaceutical composition of paragraph 75, wherein the antioxidant is ascorbic acid.

[0318] 77. The lyophilized pharmaceutical composition of paragraph 75, wherein the antioxidant is sodium bisulfite.

[0319] 78. The lyophilized pharmaceutical composition of paragraph 75, wherein the antioxidant is sodium metabisulfite.

[0320] 79. The lyophilized pharmaceutical composition of paragraph 75, wherein the antioxidant is sodium thiosulfate.

[0321] 80. The lyophilized pharmaceutical composition of any one of paragraphs 73 to 79, wherein the composition includes 0.01% (w / w) to 2% (w / w) of the stabilizer.

[0322] 81 . The lyophilized pharmaceutical composition of paragraph 80, wherein the composition includes 0.01% (w / w) to 0.5% (w / w) of the stabilizer.

[0323] 82. The lyophilized pharmaceutical composition of paragraph 80, wherein the composition includes 0.5% (w / w) to 2% (w / w) of the stabilizer.

[0324] 83. The lyophilized pharmaceutical composition of any one of paragraphs 73 to 82, wherein the composition includes 0.1% (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1.

[0325] 84. The lyophilized pharmaceutical composition of paragraph 83, wherein the composition includes 0.1% (w / w) to 1% (w / w) of the compound of Formula (I) or Compound 1 .

[0326] 85. The lyophilized pharmaceutical composition of paragraph 83, wherein the composition includes 1% (w / w) to 4% (w / w) of the compound of Formula (I) or Compound 1 .

[0327] 86. The lyophilized pharmaceutical composition of paragraph 83, wherein the composition includes 4% (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

[0328] 87. The lyophilized pharmaceutical composition of any one of paragraphs 73 to 86, wherein the composition further includes a cryoprotectant. 88. The lyophilized pharmaceutical composition of paragraph 87, wherein the cryoprotectant is a saccharide.

[0329] 89. The lyophilized pharmaceutical composition of paragraph 87, wherein the cryoprotectant is a sugar alcohol.

[0330] 90. The lyophilized composition of paragraph 88, wherein the saccharide is glucose.

[0331] 91 . The lyophilized composition of paragraph 88, wherein the saccharide is mannose.

[0332] 92. The lyophilized composition of paragraph 88, wherein the saccharide is maltose.

[0333] 93. The lyophilized composition of paragraph 88, wherein the saccharide is lactose.

[0334] 94. The lyophilized composition of paragraph 88, wherein the saccharide is xylose.

[0335] 95. The lyophilized composition of paragraph 88, wherein the saccharide is sucrose.

[0336] 96. The lyophilized composition of paragraph 88, wherein the saccharide is trehalose.

[0337] 97. The lyophilized composition of paragraph 88, wherein the saccharide is erythrose.

[0338] 98. The lyophilized pharmaceutical composition of paragraph 89, wherein the sugar alcohol is mannitol.

[0339] 99. The lyophilized pharmaceutical composition of paragraph 89, wherein the sugar alcohol is sorbitol.

[0340] 100. The lyophilized pharmaceutical composition of paragraph 89, wherein the sugar alcohol is isomalt.

[0341] 101 . The lyophilized pharmaceutical composition of paragraph 89, wherein the sugar alcohol is maltitol.

[0342] 102. The lyophilized pharmaceutical composition of paragraph 89, wherein the sugar alcohol is lactitol.

[0343] 103. The lyophilized pharmaceutical composition of paragraph 89, wherein the sugar alcohol is xylitol.

[0344] 104. The lyophilized pharmaceutical composition of paragraph 89, wherein the sugar alcohol is erythritol. 105. The lyophilized pharmaceutical composition of any one of paragraphs 87 to 104, wherein the composition includes at least 80% (w / w) of the cryoprotectant.

[0345] 106. The lyophilized pharmaceutical composition of paragraph 105, wherein the composition includes 90% (w / w) to 99.9% (w / w) of the cryoprotectant.

[0346] 107. The lyophilized pharmaceutical composition of paragraph 105, wherein the composition includes 90% (w / w) to 95% (w / w) of the cryoprotectant.

[0347] 108. The lyophilized pharmaceutical composition of paragraph 105, wherein the composition includes 95% (w / w) to 99.9% (w / w) of the cryoprotectant.

[0348] 109. The lyophilized pharmaceutical composition of any one of paragraphs 73 to 108, wherein the compound of Formula (I) or Compound 1 is in a pharmaceutically acceptable salt.

[0349] 110. The lyophilized pharmaceutical composition of any one of paragraphs 73 to 108, wherein the composition further includes an acetate buffer.

[0350] 111. The lyophilized pharmaceutical composition of any one of paragraphs 73 to 110, wherein the compound is in substantially amorphous form.

[0351] 112. An aqueous solution prepared by reconstituting the lyophilized pharmaceutical composition of any one of paragraphs 73 to 111 with an aqueous carrier.

[0352] 113. The aqueous solution of paragraph 112, wherein the solution includes a pH of 3.5 to 7.5.

[0353] 114. The aqueous solution of paragraph 113, wherein the solution includes a pH of at least 4.

[0354] 115. The aqueous solution of paragraph 114, wherein the pH is 4.4 to 5.5.

[0355] 116. The aqueous solution of paragraph 115, wherein the pH is 4.4 to 4.6.

[0356] 117. The aqueous solution of paragraph 115, wherein the pH is 4.6 to 4.8.

[0357] 118. The aqueous solution of paragraph 115, wherein the pH is 4.8 to 5.1 .

[0358] 119. The aqueous solution of paragraph 115, wherein the pH is 5.1 to 5.5.

[0359] 120. The aqueous solution of any one of paragraphs 112 to 119, wherein the aqueous carrier is water for injection (WFI). 121. The aqueous solution of any one of paragraphs 112 to 120, wherein the aqueous solution is substantially free of saline.

[0360] 122. The lyophilized pharmaceutical composition of any one of paragraphs 73 to 111 , or the aqueous solution of any one of paragraphs 112 to 121 , wherein the composition or solution is stored in a container shielded from light, such as sealed amber vial.

[0361] 123. A method of administering a compound of Formula (I) or Compound 1 to a subject in need thereof, including:

[0362] (a) providing the lyophilized pharmaceutical composition according to any one of paragraphs 73 to 111 ;

[0363] (b) reconstituting the composition of step (a) in an aqueous carrier to form a solution including the compound of Formula (I) or Compound 1 ; and

[0364] (c) within at least 5 minutes of completing step (b), administering to the subject the reconstituted solution of step (b).

[0365] 124. The method of paragraph 123, wherein the solution of step (c) is administered intravenously.

[0366] 125. A method of treating a fungal infection in a subject, the method including administering to the subject an effective amount of the aqueous solution of any one of paragraphs 112 to 121.

[0367] 126. The method of paragraph 125, wherein the route of administration is intravenous.

[0368] 127. A method of preparing the lyophilized composition of any one of paragraphs 73 to 111 , including:

[0369] (a) dissolving the compound of Formula (I) or Compound 1 in an organic solvent;

[0370] (b) dissolving a cryoprotectant and a stabilizer and in water in vessel 2, followed by mixing;

[0371] (c) combining the mixtures of step (a) and step (b) into a single vessel, followed by mixing, to achieve a fully dissolved mixture;

[0372] (d) adjusting the pH of the mixture of step (c) between 4.4 to 5.5;

[0373] (e) filtering the mixture of step (d);

[0374] (f) lyophilizing the mixture of step (e); and

[0375] (g) storing the lyophilized composition of step (f) at a temperature starting at least -15 °C.

[0376] 128. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 112 to 121 and a nonionic tonicity agent, wherein the nonionic tonicity agent is glucose.

[0377] 129. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 112 to 121 and a nonionic tonicity agent, wherein the nonionic tonicity agent is glycerin. 130. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 112 to 121 and a nonionic tonicity agent, wherein the nonionic tonicity agent is mannitol.

[0378] 131. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 112 to 121 and a nonionic tonicity agent, wherein the nonionic tonicity agent is sucrose.

[0379] 132. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 112 to 121 and a nonionic tonicity agent, wherein the nonionic tonicity agent is glycerol.

[0380] 133. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 112 to 121 and a nonionic tonicity agent, wherein the nonionic tonicity agent is sorbitol.

[0381] 134. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, including the aqueous solution according to any one of paragraphs 112 to 121 and a nonionic tonicity, wherein the nonionic tonicity agent is agent trehalose.

[0382] 135. The method of paragraph 134, wherein the isotonic solution is substantially free of saline.

[0383] 136. The method of paragraph 134 or 135, wherein the injection is a bolus or an infusion.

[0384] Other embodiments are within the following claims.

[0385] What is claimed is:

Claims

CLAIMS1 . A lyophilized pharmaceutical composition comprising a cryoprotectant and a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

2. The lyophilized pharmaceutical composition of claim 1 , wherein the compound is Compound 1 :Compound 1 , or a pharmaceutically acceptable salt thereof.

3. The lyophilized pharmaceutical composition of claim 1 or 2, wherein the cryoprotectant is a saccharide.

4. The lyophilized pharmaceutical composition of claim 1 or 2, wherein the cryoprotectant is a sugar alcohol.

5. The lyophilized composition of claim 3, wherein the saccharide is mannose, maltose, lactose, xylose, sucrose, trehalose, or erythrose.

6. The lyophilized pharmaceutical composition of claim 4, wherein the sugar alcohol is mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol.

7. The lyophilized pharmaceutical composition of any one of claims 1 to 6, wherein the composition comprises at least 80% (w / w) of the cryoprotectant.

8. The lyophilized pharmaceutical composition of claim 7, wherein the composition comprises 90% (w / w) to 99.9% (w / w) of the cryoprotectant.

9. The lyophilized pharmaceutical composition of any one of claims 1 to 8, wherein the composition further comprises a stabilizer.

10. The lyophilized pharmaceutical composition of claim 9, wherein the stabilizer is an antioxidant.11 . The lyophilized pharmaceutical composition of claim 10, wherein the antioxidant is ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate.

12. The lyophilized pharmaceutical composition of any one of claims 9 to 11 , wherein the composition comprises 0.01 % (w / w) to 2% (w / w) of the stabilizer.

13. The lyophilized pharmaceutical composition of any one of claims 1 to 12, wherein the composition comprises 0.1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

14. The lyophilized pharmaceutical composition of any one of claims 1 to 13, wherein the compound of Formula (I) or Compound 1 is in a pharmaceutically acceptable salt.

15. The lyophilized pharmaceutical composition of any one of claims 1 to 14, wherein the composition further comprises an acetate buffer.

16. The lyophilized pharmaceutical composition of any one of claims 1 to 15, wherein the compound is in substantially amorphous form.

17. The lyophilized pharmaceutical composition of any one of claims 1 to 16, wherein the composition comprises:(a) 90% (w / w) to 99% (w / w) of the cryoprotectant;(b) 0.05% (w / w) to 2% (w / w) of the stabilizer; and(c) 1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1.

18. The lyophilized pharmaceutical composition of claim 17, wherein the composition comprises:(a) 90% (w / w) to 99% (w / w) of the cryoprotectant, wherein the cryoprotectant is selected from mannose, maltose, lactose, xylose, sucrose, trehalose, erythrose, mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol;(b) 0.05% (w / w) to 2% (w / w) of the stabilizer, wherein the stabilizer is selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; and(c) 1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

19. The lyophilized composition of claim 17, wherein the composition comprises:(a) 95% (w / w) to 98% (w / w) of the cryoprotectant;(b) 0.1% (w / w) to 1% (w / w) of the stabilizer; and(c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 .

20. The lyophilized composition of claim 19, wherein the composition comprises:(a) 95% (w / w) to 98% (w / w) of the cryoprotectant, wherein the cryoprotectant is selected from mannose, maltose, lactose, xylose, sucrose, trehalose, erythrose, mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol;(b) 0.1% (w / w) to 1% (w / w) of the stabilizer, wherein the stabilizer is selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; and(c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 .21 . The lyophilized pharmaceutical composition of any one of claims 17 to 20, wherein the stabilizer is ascorbic acid and the composition comprises 0.25% ± 0.05% (w / w) of ascorbic acid.

22. An aqueous solution prepared by reconstituting the lyophilized pharmaceutical composition of any one of claims 1 to 21 with an aqueous carrier.

23. The aqueous solution of claim 22, wherein the solution comprises a pH of 3.5 to 7.5.

24. The aqueous solution of claim 23, wherein the solution comprises a pH of at least 4.

25. The aqueous solution of claim 23, wherein the pH is 4.4 to 5.5.

26. The aqueous solution of claim 23, wherein the pH is 5.0 ± 0.3.

27. The aqueous solution of any one of claims 22 to 26, wherein the aqueous carrier is water for injection (WFI).

28. The aqueous solution of any one of claims 22 to 27, wherein the aqueous solution is substantially free of saline.

29. The lyophilized pharmaceutical composition of any one of claims 1 to 21 , or the aqueous solution of any one of claims 22 to 28, wherein the composition or solution is stored in a container shielded from light, such as a sealed amber vial.

30. A method of administering a compound of Formula (I) or Compound 1 to a subject in need thereof, comprising:(a) providing the lyophilized pharmaceutical composition according to any one of claims 1 to 21 ;(b) reconstituting the composition of step (a) in an aqueous carrier to form a solution comprising the compound of Formula (I) or Compound 1 ; and(c) within at least 5 minutes of completing step (b), administering to the subject the reconstituted solution of step (b).31 . The method of claim 30, wherein the solution of step (c) is administered intravenously.

32. A method of treating a fungal infection in a subject, the method comprising administering to the subject an effective amount of the aqueous solution of any one of claims 22 to 28.

33. The method of claim 32, wherein the route of administration is intravenous.

34. A method of preparing the lyophilized composition of any one of claims 1 to 21 , comprising:(a) dissolving the compound of Formula (I) or Compound 1 in an organic solvent;(b) dissolving a cryoprotectant and a stabilizer and in water in vessel 2, followed by mixing;(c) combining the mixtures of step (a) and step (b) into a single vessel, followed by mixing(d) adjusting the pH of the mixture of step (c) between 4.4 to 5.5 to achieve a fully dissolved mixture;(e) filtering the mixture of step (d);(f) lyophilizing the mixture of step (e); and(g) storing the lyophilized composition of step (f) at a temperature starting at least -15 °C.

35. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, comprising the aqueous solution according to any one of claims 22 to 28 and a nonionic tonicity agent selected from glucose, glycerin, mannitol, sucrose, glycerol, sorbitol, and trehalose.

36. The method of claim 35, wherein the isotonic solution is substantially free of saline.

37. The method of claim 35 or 36, wherein the injection is a bolus or an infusion.

38. A lyophilized pharmaceutical composition comprising a stabilizer and a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

39. The lyophilized pharmaceutical composition of claim 38, wherein the compound is Compound 1 :Compound 1 , or a pharmaceutically acceptable salt thereof.

40. The lyophilized pharmaceutical composition of claim 38 or 39, wherein the stabilizer is an antioxidant.41 . The lyophilized pharmaceutical composition of claim 40, wherein the antioxidant is ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate.

42. The lyophilized pharmaceutical composition of any one of claims 38 to 41 , wherein the composition comprises 0.01% (w / w) to 2% (w / w) of the stabilizer.

43. The lyophilized pharmaceutical composition of any one of claims 38 to 42, wherein the composition comprises 0.1% (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

44. The lyophilized pharmaceutical composition of any one of claims 38 to 43, wherein the composition further comprises a cryoprotectant.

45. The lyophilized pharmaceutical composition of claim 44, wherein the cryoprotectant is a saccharide.

46. The lyophilized pharmaceutical composition of claim 44, wherein the cryoprotectant is a sugar alcohol.

47. The lyophilized composition of claim 45, wherein the saccharide is mannose, maltose, lactose, xylose, sucrose, trehalose, or erythrose.

48. The lyophilized pharmaceutical composition of claim 46, wherein the sugar alcohol is mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol.

49. The lyophilized pharmaceutical composition of any one of claims 44 to 48, wherein the composition comprises at least 80% (w / w) of the cryoprotectant.

50. The lyophilized pharmaceutical composition of claim 49, wherein the composition comprises 90% (w / w) to 99.9% (w / w) of the cryoprotectant.51 . The lyophilized pharmaceutical composition of any one of claims 38 to 50, wherein the compound of Formula (I) or Compound 1 is in a pharmaceutically acceptable salt.

52. The lyophilized pharmaceutical composition of any one of claims 38 to 51 , wherein the composition further comprises an acetate buffer.

53. The lyophilized pharmaceutical composition of any one of claims 38 to 52, wherein the compound is in substantially amorphous form.

54. The lyophilized pharmaceutical composition of any one of claims 38 to 53, wherein the composition comprises:(a) 90% (w / w) to 99% (w / w) of the cryoprotectant;(b) 0.05% (w / w) to 2% (w / w) of the stabilizer; and(c) 1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1.

55. The lyophilized pharmaceutical composition of claim 54, wherein the composition comprises:(a) 90% (w / w) to 99% (w / w) of the cryoprotectant, wherein the cryoprotectant is selected from mannose, maltose, lactose, xylose, sucrose, trehalose, erythrose, mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol;(b) 0.05% (w / w) to 2% (w / w) of the stabilizer, wherein the stabilizer is selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; and(c) 1 % (w / w) to 7.5% (w / w) of the compound of Formula (I) or Compound 1 .

56. The lyophilized composition of claim 54, wherein the composition comprises:(a) 95% (w / w) to 98% (w / w) of the cryoprotectant;(b) 0.1 % (w / w) to 1 % (w / w) of the stabilizer; and(c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 .

57. The lyophilized composition of claim 56, wherein the composition comprises:(a) 95% (w / w) to 98% (w / w) of the cryoprotectant, wherein the cryoprotectant is selected from mannose, maltose, lactose, xylose, sucrose, trehalose, erythrose, mannitol, sorbitol, isomalt, maltitol, lactitol, xylitol, or erythritol;(b) 0.1% (w / w) to 1% (w / w) of the stabilizer, wherein the stabilizer is selected from ascorbic acid, sodium bisulfite, sodium metabisulfite, or sodium thiosulfate; and(c) 1 .5% (w / w) to 5% (w / w) of the compound of Formula (I) or Compound 1 .

58. The lyophilized pharmaceutical composition of any one of claims 54 to 57, wherein the stabilizer is ascorbic acid and the composition comprises 0.25% ± 0.05% (w / w) of ascorbic acid.

59. An aqueous solution prepared by reconstituting the lyophilized pharmaceutical composition of any one of claims 38 to 58 with an aqueous carrier.

60. The aqueous solution of claim 59, wherein the solution comprises a pH of 3.5 to 7.5.61 . The aqueous solution of claim 60, wherein the solution comprises a pH of at least 4.

62. The aqueous solution of claim 60, wherein the pH is 4.4 to 5.5.

63. The aqueous solution of claim 60, wherein the pH is 5.0 ± 0.3.

64. The aqueous solution of any one of claims 59 to 63, wherein the aqueous carrier is water for injection (WFI).

65. The aqueous solution of any one of claims 59 to 64, wherein the aqueous solution is substantially free of saline.

66. The lyophilized pharmaceutical composition of any one of claims 38 to 58, or the aqueous solution of any one of claims 59 to 65, wherein the composition or solution is stored in a container shielded from light, such as sealed amber vial.

67. A method of administering a compound of Formula (I) or Compound 1 to a subject in need thereof, comprising:(a) providing the lyophilized pharmaceutical composition according to any one of claims 38 to 58;(b) reconstituting the composition of step (a) in an aqueous carrier to form a solution comprising the compound of Formula (I) or Compound 1 ; and(c) within at least 5 minutes of completing step (b), administering to the subject the reconstituted solution of step (b).

68. The method of claim 67, wherein the solution of step (c) is administered intravenously.

69. A method of treating a fungal infection in a subject, the method comprising administering to the subject an effective amount of the aqueous solution of any one of claims 59 to 65.

70. The method of claim 69, wherein the route of administration is intravenous.71 . A method of preparing the lyophilized composition of any one of claims 38 to 58, comprising:(a) dissolving the compound of Formula (I) or Compound 1 in an organic solvent;(b) dissolving a cryoprotectant and a stabilizer and in water in vessel 2, followed by mixing;(c) combining the mixtures of step (a) and step (b) into a single vessel, followed by mixing, to achieve a fully dissolved mixture;(d) adjusting the pH of the mixture of step (c) between 4.4 to 5.5;(e) filtering the mixture of step (d);(f) lyophilizing the mixture of step (e); and(g) storing the lyophilized composition of step (f) at a temperature starting at least -15 °C.

72. A method of injecting an isotonic solution that is isotonic with body fluids to a subject in need thereof, comprising the aqueous solution according to any one of claims 59 to 65 and a nonionic tonicity agent selected from glucose, glycerin, mannitol, sucrose, glycerol, sorbitol, and trehalose.

73. The method of claim 72, wherein the isotonic solution is substantially free of saline.

74. The method of claim 72 or 73, wherein the injection is a bolus or an infusion.

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