Stable aviptadil formulations

Abstract

The present disclosure provides storage stable aviptadil formulations and uses thereof.

Description

STABLE AVIPTADIL FORMULATIONSBACKGROUND

[0001] Vasoactive intestinal peptide (also known as aviptadil) is a 28-residue amino acid peptide first characterized in 1970 that was initially isolated from porcine duodenum. A member of the secretin / glucagon hormone superfamily, aviptadil is evolutionarily well conserved with sequence similarity among fish, frogs, and humans. Sequence similarity among mammals is roughly 85%. Aviptadil has potent vasodilatory effects, and is widely distributed in the central and peripheral nervous system as well as in the digestive, respiratory, reproductive, and cardiovascular systems as a neurotransmitter and neuroendocrine releasing factor. These vasodilative effects contribute to an extensive range of physiological and pathological processes related to development, growth, and the control of neuronal, epithelial, and endocrine cell function. Aviptadil has also been implicated in the regulation of carcinogenesis, immune responses, and circadian rhythms.

[0002] Although aviptadil has therapeutic potential, it is difficult to formulate and rapidly degrades, limiting its delivery window and ultimately, its bioavailability. Accordingly, novel stable formulations comprising aviptadil and methods of formulating aviptadil to provide that stability are needed.BRIEF SUMMARY

[0003] The present disclosure is directed to storage stable formulations comprising aviptadil and uses thereof. In some embodiments, the storage stable aviptadil formulations are liquid aviptadil formulations. In some embodiments, the storage stable aviptadil formulations are powdered or lyophilized aviptadil formulations. The present disclosure also is directed to reconstituted liquid aviptadil formulations comprising a liquid and the powdered or lyophilized aviptadil formulations dissolved in the liquid.

[0004] In some embodiments, a powdered aviptadil formulation comprises: about 0.03 mg to about 0.4 mg of aviptadil acetate; about 3.8 mg to about 4 mg of L-histidine buffer salt; about 80 mg to about 200 mg of trehalose dihydrate; about 1.7 mg to about 5.6 mg of L-methionine; and about 0.1 mg to about 0.3 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C forat least 6 months and wherein the powdered formulation has a glass transition temperature of at least about 90 °C after storage at a temperature ranging from 2 °C to 25 °C for at least 6 months.

[0005] In some embodiments, a powdered aviptadil formulation comprises: about 0.05 mg to about 0.4 mg of aviptadil acetate; about 3.8 mg to about 4 mg of L-histidine buffer salt; about 80 mg to about 200 mg of trehalose dihydrate; about 1.7 mg to about 5.6 mg of L-methionine; and about 0.1 mg to about 0.3 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transition temperature of at least about 90 °C after storage at a temperature ranging from 2 °C to 25 °C for at least 6 months.

[0006] In some embodiments, a powdered aviptadil formulation comprises: about 0.1 mg to about 0.4 mg of aviptadil acetate; about 3.8 mg to about 4 mg of L-histidine buffer salt; about 80 mg to about 200 mg of trehalose dihydrate; about 1.7 mg to about 5.6 mg of L- methionine; and about 0.1 mg to about 0.3 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transition temperature of at least about 90 °C after storage at a temperature ranging from 2 °C to 25 °C for at least 6 months.

[0007] In some embodiments, a powdered aviptadil formulation comprises: about 0.1 mg to about 0.4 mg of aviptadil acetate; about 3.8 mg to about 4 mg of L-histidine buffer salt; about 80 mg to about 150 mg of trehalose dihydrate; about 1.7 mg to about 5.6 mg of L- methionine; and about 0.1 mg to about 0.3 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months.

[0008] In some embodiments, a powdered aviptadil formulation comprises: about 0.1 mg to about 0.4 mg of aviptadil acetate; about 3.8 mg to about 4 mg of L-histidine buffer salt; about 80 mg to about 120 mg of trehalose dihydrate; about 1.7 mg to about 5.6 mg of L- methionine; and about 0.1 mg to about 0.3 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transitiontemperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months.

[0009] In some embodiments, the powdered formulation comprises about 0.1 mg of aviptadil acetate.

[0010] In some embodiments, the powdered formulation comprises about 0.2 mg of aviptadil acetate.

[0011] In some embodiments, the powdered formulation comprises about 3.9 mg of L- histidine buffer.

[0012] In some embodiments, the L-histidine buffer salt comprises L-histidine anhydrous and L-histidine HC1 monohydrate.

[0013] In some embodiments, the L-histidine buffer salt comprises about 0.8 mg of L- histidine anhydrous and about 3.1 mg of L-histidine HC1 monohydrate.

[0014] In some embodiments, the powdered formulation comprises about 100 mg trehalose dihydrate.

[0015] In some embodiments, the powdered formulation comprises about 3.7 mg L- methionine.

[0016] In some embodiments, the powdered formulation comprises about 0.2 mg polysorbate 80.

[0017] In some embodiments, a powdered formulation consists essentially of: about 0.1 mg of aviptadil acetate; about 3.9 mg of a L-histidine buffer salt; about 100 mg of trehalose dihydrate; about 3.7 mg of L-m ethionine; and about 0.2 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months.

[0018] In some embodiments, a powdered formulation consisting essentially of: about 0.2 mg of aviptadil acetate; about 3.9 mg of a L-histidine buffer salt; about 100 mg of trehalose dihydrate; about 3.7 mg of L-m ethionine; and about 0.2 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months.

[0019] In some embodiments, a reconstituted liquid aviptadil formulation comprises a liquid and the powdered aviptadil formulation described herein dissolved in the liquid, wherein the reconstituted liquid aviptadil formulation has a pH ranging from about 5.3 to about 5.7.

[0020] In some embodiments, the reconstituted formulation has a pH that is about 5.4 to about 5.7.

[0021] In some embodiments, the reconstituted formulation has a pH that is about 5.4 to about 5.6.

[0022] In some embodiments, the reconstituted formulation comprises no more than about 4% of total impurities as measured by reversed phase ultra performance liquid chromatography (RP-UPLC).

[0023] In some embodiments, the reconstituted formulation comprises no more than about 3% of total impurities as measured by RP-UPLC.

[0024] In some embodiments, the reconstituted formulation comprises no more than about 2.5% of total impurities as measured by RP-UPLC.

[0025] In some embodiments, the reconstituted formulation comprises no more than about 1% of a methionine oxidation product (Met(O)) as measured by RP-UPLC.

[0026] In some embodiments, the reconstituted formulation comprises no more than about 0.7% of Met(O) as measured by RP-UPLC.

[0027] In some embodiments, the reconstituted formulation comprises no more than about 0.5% of Met(O) as measured by RP-UPLC.

[0028] Also described herein is a method of treating acute respiratory distress syndrome in a subject in need thereof, the method comprising administering to the subject an effective amount of the reconstituted formulation according to some embodiments of the present disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIGs. 1 A-1B are tables that show cumulative subvisible particle concentration (> 2,> 5, > 10, and > 25 pm in diameter) at TO for formulations F1-F24.

[0030] FIGs. 2A-2B are tables that show cumulative subvisible particle concentration (> 2,> 5, > 10, and > 25 pm in diameter) at TIOw and T14w at different storage conditions for formulations F12, F13, F15, F17, F18 and F19.

[0031] FIG. 3 is a table that shows cumulative subvisible particle concentration (> 2, > 5, > 10, and > 25 pm in diameter) at T6m at different storage conditions for formulations Fl 2, F13, F15, F17, F18 and F19.

[0032] FIG. 4 is a table showing cumulative subvisible particle concentration (> 2, > 5, > 10, and > 25 pm in diameter) at T9m at 2-8 °C for formulations F15, F17, and F19 and at T14m for formulations F12, F15, F17, and F19.

[0033] FIG. 5A-B are tables that show reconstitution time and foam levels for lyophilized formulations Fl-Lyo - F12-Lyo at different storage conditions.

[0034] FIG. 6A is a table that shows subvisible particle concentration (> 2 pm in diameter) for lyophilized formulations Fl-Lyo - F12-Lyo at different storage conditions.

[0035] FIG. 6B is a table that shows subvisible particle concentration (> 5 pm in diameter) for lyophilized formulations Fl-Lyo - F12-Lyo at different storage conditions.

[0036] FIG. 6C is a table that shows subvisible particle concentration (> 10 pm in diameter) for lyophilized formulations Fl-Lyo - F12-Lyo at different storage conditions.

[0037] FIG. 6D is a table that shows subvisible particle concentration (> 25 pm in diameter) for lyophilized formulations Fl-Lyo - F12-Lyo at different storage conditions.

[0038] FIG. 7 is a table that provides moisture content for lyophilized formulations F 1 -Lyo - F12-Lyo at different storage conditions.

[0039] FIG. 8A-8D shows a table with the relative content as measured by reverse phase high performance liquid chromatography (RP-UPLC) of the main peak area [%], methionine oxidation [%], and total impurities [%] for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl 1-Lyo, Fl 1- Lyo-A, Fl 1-Lyo- Aa, Fl 1-Lyo- Ab, Fl 1-Lyo-B and Fl 1-lyo-C.

[0040] FIG. 9A is a table that shows subvisible particle concentration (> 2 pm in diameter) for liquid formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5- Lyo-B, F5-Lyo-C, Fl 1-Lyo, Fl 1-Lyo- A, F 11-Lyo- Aa, Fl 1-Lyo- Ab, Fl 1-Lyo-B and Fl 1- lyo-C at different storage conditions.

[0041] FIG. 9B is a table that shows subvisible particle concentration (> 5 pm in diameter) for liquid formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5- Lyo-B, F5-Lyo-C, Fl 1-Lyo, Fl 1-Lyo- A, F 11-Lyo- Aa, Fl 1-Lyo- Ab, Fl 1-Lyo-B and Fl 1- lyo-C at different storage conditions.

[0042] FIG. 9C is a table that shows subvisible particle concentration (> 10 pm in diameter) for liquid formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fll-Lyo, Fll-Lyo-A, Fll-Lyo-Aa, Fll-Lyo-Ab, Fl l-Lyo-B and Fl 1- lyo-C at different storage conditions.

[0043] FIG. 9D is a table that shows subvisible particle concentration (> 25 pm in diameter) for liquid formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5- Lyo-B, F5-Lyo-C, Fl l-Lyo, Fl l-Lyo-A, Fll-Lyo-Aa, Fl l-Lyo-Ab, Fl l-Lyo-B and Fl 1- lyo-C at different storage conditions.

[0044] FIG. 10A is a table that shows subvisible particle concentration (> 2 pm in diameter) for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl l-Lyo, Fl l-Lyo-A, Fl l-Lyo-Aa, Fl l-Lyo-Ab, Fl l-Lyo-B and Fl 1-lyo-C at different storage conditions.

[0045] FIG. 10B is a table that shows subvisible particle concentration (> 5 pm in diameter) for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl l-Lyo, Fl l-Lyo-A, Fl l-Lyo-Aa, Fl l-Lyo-Ab, Fl l-Lyo-B and Fl 1-lyo-C at different storage conditions.

[0046] FIG. 10C is a table that shows subvisible particle concentration (> 10 pm in diameter) for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl l-Lyo, Fl l-Lyo-A, Fl l-Lyo-Aa, Fl l-Lyo-Ab, Fl l- Lyo-B and Fl 1-lyo-C at different storage conditions.

[0047] FIG. 10D is a table that shows subvisible particle concentration (> 25 pm in diameter) for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl l-Lyo, Fl l-Lyo-A, Fl l-Lyo-Aa, Fl l-Lyo-Ab, Fl l- Lyo-B and Fl 1-lyo-C at different storage conditions.

[0048] FIG. 11 is a table that provides moisture content for lyophilized formulations F2- Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl l-Lyo, Fl l-Lyo-A, Fl l-Lyo-Aa, Fl l-Lyo-Ab, Fl l-Lyo-B and Fl 1-lyo-C at different storage conditions.

[0049] FIG. 12A shows a table with the relative main peak areas as measured by RP-UPLC for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl l-Lyo, Fl l-Lyo-A, Fl l-Lyo-Aa, Fl l-Lyo-Ab, Fl l-Lyo-B and Fl 1-lyo-C.

[0050] FIG. 12B shows a table with the relative peak areas of methionine oxidation as measured by RP-UPLC for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl 1-Lyo, Fl 1-Lyo-A, Fl 1-Lyo-Aa, Fl 1- Lyo-Ab, Fl 1-Lyo-B and Fl 1-lyo-C.

[0051] FIG. 12C shows a table with the relative peak areas of degradation peak 1 as measured by RP-UPLC for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2- Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl 1-Lyo, Fl 1-Lyo-A, Fl 1-Lyo-Aa, Fl 1- Lyo-Ab, Fl 1-Lyo-B and Fl 1-lyo-C.

[0052] FIG. 12D shows a table with the relative peak areas of degradation peak 2 as measured by RP-UPLC for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2- Lyo-C, F5-Lyo, F5-Lyo-A, F5-Lyo-B, F5-Lyo-C, Fl 1-Lyo, Fl 1-Lyo-A, Fl 1-Lyo-Aa, Fl 1- Lyo-Ab, Fl 1-Lyo-B and Fl 1-lyo-C.

[0053] FIG. 12E shows a table with the total impurities as measured by RP-UPLC for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5- Lyo-B, F5-Lyo-C, Fl 1-Lyo, Fl 1-Lyo-A, Fl 1-Lyo-Aa, Fl 1-Lyo- Ab, Fl 1-Lyo-B and Fi lly o-C.

[0054] FIG. 12F shows a table with the total peak area as measured by RP-UPLC for lyophilized formulations F2-Lyo, F2-Lyo-A, F2-Lyo-B, F2-Lyo-C, F5-Lyo, F5-Lyo-A, F5- Lyo-B, F5-Lyo-C, Fl 1-Lyo, Fl 1-Lyo-A, Fl 1-Lyo-Aa, Fl 1-Lyo- Ab, Fl 1-Lyo-B and Fi lly o-C.DETAILED DESCRIPTION

[0055] The present disclosure is directed to storage stable formulations comprising aviptadil and uses thereof.Definitions

[0056] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0057] As used herein, the term “or” is a logical disjunction (i.e., and / or) and does not indicate an exclusive disjunction unless expressly indicated as such with the terms “either,” “unless,” “alternatively,” and words of similar effect.

[0058] As used herein, the term “about” refers to ±5% of the noted value, unless otherwise specified, and unless the upper bound of the range would exceed 100% of the composition, in which case the upper limit of the range is limited to 99.9%. Thus, and by way of example only, a composition including about 10 weight percent of a giveningredient could have from 9.5 to 10.5 weight percent of the compound. Similarly, a composition including about 95 weight percent of a given ingredient could have from 90.25 to 99.9 weight percent of the ingredient in the composition.

[0059] As used herein, the term “prevent” refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., Acute respiratory distress syndrome (ARDS)) resulting in a decrease in the probability that the subject will develop the condition.

[0060] The terms "treat," "treating," and "treatment," as used herein, refer to any type of intervention or process performed on, or administering an active agent to, a subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease or enhancing overall survival. Treatment can be of a subject having a disease or a subject who does not have a disease (e.g., for prophylaxis).

[0061] As used herein, "administering" refers to the physical introduction of aviptadil or an aviptadil composition described herein to a subject, using any of the various methods and delivery systems known to those skilled in the art. The different routes of administration for an aviptadil composition described herein include inhalative, intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, intratracheal, pulmonary, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraventricle, intravitreal, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. Alternatively, an aviptadil composition described herein can be administered via a non-parenteral route, such as a topical, epidermal, or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually, or topically. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0062] Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB BiochemicalNomenclature Commission. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation.

[0063] The term "therapeutically effective amount" or "effective dose" as used herein refers to an amount of aviptadil that is sufficient, when administered by a method of the disclosure, to efficaciously treat the condition or disease of interest to a subject in need thereof. In the case of acute respiratory distress syndrome (ARDS), and in some embodiments, the therapeutically effective amount of aviptadil can decrease shortness of breath, normalize breathing pattern, increase PaCh / FiCh ratio, decrease dizziness, or any combination of any of the foregoing.

[0064] Aviptadil consists of 28 amino acids and has the following sequence: HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 1).

[0065] Where “aviptadil” is being referred to, this includes both the free base form or any pharmaceutically acceptable salt thereof. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid (less preferred), hydroxyethanesulfonic acid, ethylenesulfonic acid, p- toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphersulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen- benzenesulfonic acid, picric acid, adipic acid, D-o-tolyltartaric acid, tartronic acid, a-toluic acid, (o, m, p)- toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. Alternatively, salts with bases or internal salts may be formed,Aqueous Aviptadil Formulations

[0066] The disclosure provides aqueous aviptadil formulations (also referred to as liquid aviptadil formulations) that are storage stable at a temperature ranging from about 2 °C to about 8 °C for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24months, at least about 30 months, or at least about 36 months without significant degradation of the aviptadil present in the formulations.

[0067] In some embodiments, the aqueous aviptadil formulations can comprise about 0.01 mg / mL aviptadil to about 2 mg / mL aviptadil. In some embodiments, the aqueous aviptadil formulations can comprise about 0.02 mg / mL aviptadil to about 1.9 mg / mL aviptadil, about 0.03 mg / mL aviptadil to about 1.8 mg / mL aviptadil, about 0.04 mg / mL aviptadil to about 1.7 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 1.6 mg / mL aviptadil, about 0.06 mg / mL aviptadil to about 1.5 mg / mL aviptadil, aviptadil, about 0.06 mg / mL aviptadil to about 1.4 mg / mL aviptadil, about 0.07 mg / mL aviptadil to about 1.3 mg / mL aviptadil, about 0.08 mg / mL aviptadil to about 1.2 mg / mL aviptadil, about 0.09 mg / mL aviptadil to about 1.1 mg / mL aviptadil, about 0.1 mg / mL aviptadil to about 1 mg / mL aviptadil, about 0.1 mg / mL aviptadil to about 0.9 mg / mL aviptadil, about 0.1 mg / mL aviptadil to about 0.8 mg / mL aviptadil, about 0.1 mg / mL aviptadil to about 0.7 mg / mL aviptadil, about 0.1 mg / mL aviptadil to about 0.6 mg / mL aviptadil, about 0.1 mg / mL aviptadil to about 0.5 mg / mL aviptadil, about 0.1 mg / mL aviptadil to about 0.4 mg / mL aviptadil, about 0.1 mg / mL aviptadil to about 0.3 mg / mL aviptadil, or about 0.1 mg / mL aviptadil to about 0.2 mg / mL aviptadil.

[0068] In some embodiments, the aqueous aviptadil formulations can comprise about 0.05 mg / mL aviptadil to about 2 mg / mL aviptadil. In some embodiments, the aqueous aviptadil formulations can comprise about 0.05 mg / mL aviptadil to about 1.5 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 1 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 0.9 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 0.8 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 0.7 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 0.05 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 0.5 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 0.4 mg / mL aviptadil, about 0.05 mg / mL aviptadil to about 0.3 mg / mL aviptadil, or about 0.05 mg / mL aviptadil to about 0.2 mg / mL aviptadil.

[0069] In some embodiments, the aqueous aviptadil formulations can comprise about 0.01 mg / mL aviptadil, about 0.02 mg / mL aviptadil, about 0.03 mg / mL aviptadil, about 0.04 mg / mL aviptadil, about 0.05 mg / mL aviptadil, about 0.06 mg / mL aviptadil, about 0.07 mg / mL aviptadil, about 0.08 mg / mL aviptadil, about 0.09 mg / mL aviptadil, about 0.1 mg / mL aviptadil, about 0.2 mg / mL aviptadil, about 0.3 mg / mL aviptadil, about 0.4 mg / mL aviptadil, about 0.5 mg / mL aviptadil, about 0.6 mg / mL aviptadil, about 0.7mg / mL aviptadil, about 0.8 mg / mL aviptadil, about 0.9 mg / mL aviptadil, about 1.0 mg / mL aviptadil, about 1.1 mg / mL aviptadil, about 1.2 mg / mL aviptadil, about 1.3 mg / mL aviptadil, about 1.4 mg / mL aviptadil, about 1.5 mg / mL aviptadil, about 1.6 mg / mL aviptadil, about 1.7 mg / mL aviptadil, about 1.8 mg / mL aviptadil, about 1.9 mg / mL aviptadil, or about 2.0 mg / mL aviptadil. In certain embodiments, the aqueous aviptadil formulations can comprise about 0.05 mg / mL aviptadil, about 0.1 mg / mL aviptadil, or about 0.2 mg / mL aviptadil

[0070] In some embodiments, the aqueous aviptadil formulations described herein can comprise a buffer. In some embodiments, a buffer can be selected from the group consisting of formate (pKa=3.75), lactate (pKa=3.86), benzoic acid (pKa=4.2) oxalate (pKa=4.29), fumarate (pKa=4.38), aniline (pKa=4.63), acetate buffer (pKa=4.76), citric acid (pKa 2.79), citrate buffer (pKa2=4.76, pKa3=6.4), glutamate buffer (pKa=4.3), phosphate buffer (pKa=7.20), succinate (pkal=4.93; pKa2=5.62), pyridine (pKa=5.23), phthalate (pKa=5.41); histidine (pKa=6.04), MES (2-(N-morpholino)ethanesulphonic acid; pKa=6.15); maleic acid (pKa=6.26); cacodylate (dimethylarsinate, pKa=6.27), carbonic acid (pKa=6.35), ADA (N-(2-acetamido)imino-diacetic acid (pKa=6.62); PIPES (4-piperazinebis-(ethanesulfonic acid; BIS-TRIS-propane (1,3- bis[tris(hydroxymethyl)methylamino]-propane), pKa=6.80), ethylendiamine (pKa=6.85), ACES 2-[(2-amino-2-oxoethyl)amino]ethanesulphonic acid; pKa=6.9), imidazole (pKa=6.95), MOPS (3-(N-morphin)-propansulfonic acid; pKa=7.20), diethylmalonic acid (pKa=7.2), TES (2-[tris (hydroxymethyl)methyl]amino ethanesulphonic acid; pKa=7.50), trisodium citrate (pKa= 3.18, 4.76, and 6.4), HEPES (N-2-hydroxylethylpiperazin-N'-2- ethansulfonic acid; pKa=7.55) buffers, and combinations thereof.

[0071] In some embodiments, a buffer can comprise a carboxylic acid moiety (e.g., an acetate group). In some embodiments, a buffer can be an inorganic buffer. In some embodiments, the buffer can comprise an inorganic buffer, such as a phosphate buffer, a sulfate buffer, or a borate buffer. In some embodiments, the buffer can comprise an amino acid buffer, such as such as glycine, tyrosine, glutamic acid, glutamate, aspartic acid, aspartate, barbiturate, 5,5-diethylbarbiturate, methionine, arginine, alanine, tryptophan, lysine, serine and histidine. In certain embodiments, the buffer can be an acetate buffer, a citrate buffer, a histidine buffer, or a phosphate buffer.

[0072] In some embodiments, the aqueous aviptadil formulations can comprise about 1 mM to about 100 mM of the buffer. In some embodiments, the aqueous aviptadilformulations can comprise about 1 mM to about 90 mM, about 1 mM to about 80 mM, about 1 mM to about 70 mM, about 1 mM to about 60 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, or about 1 mM to about 20 mM of the buffer. In some embodiments, the aqueous aviptadil formulations can comprise about 5 mM to about 100 mM, about 5 mM to about 90 mM, about 5 mM to about 80 mM, about 5 mM to about 70 mM, about 5 mM to about 60 mM, about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, or about 5 mM to about 20 mM of the buffer. In some embodiments, the aqueous aviptadil formulations can comprise about 10 mM to about 100 mM, about 10 mM to about 90 mM, about 10 mM to about 80 mM, about 10 mM to about 70 mM, about 10 mM to about 60 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, about 10 mM to about 30 mM, or about 10 mM to about 20 mM of the buffer. In some embodiments, the aqueous aviptadil formulations can comprise about 15 mM to about 100 mM, about 15 mM to about 90 mM, about 15 mM to about 80 mM, about 15 mM to about 70 mM, about 15 mM to about 60 mM, about 15 mM to about 50 mM, about 15 mM to about 40 mM, about 15 mM to about 30 mM, or about 15 mM to about 25 mM of the buffer.

[0073] In certain embodiments, the aqueous aviptadil formulations can comprise about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM of the buffer. In certain embodiments, the aqueous aviptadil formulations can comprise about 20 mM of the buffer.

[0074] In certain embodiments, the aqueous aviptadil formulations can comprise about 20 mM of an acetate buffer. In certain embodiments, the aqueous aviptadil formulations can comprise about 20 mM of a citrate buffer. In certain embodiments, the aqueous aviptadil formulations can comprise about 20 mM of a histidine buffer. In certain embodiments, the aqueous aviptadil formulations can comprise about 20 mM of a phosphate buffer.

[0075] In some embodiments, the aqueous aviptadil formulations can comprise a carbohydrate, a polyhydric alcohol, or a combination of a carbohydrate and a polyhydric alcohol. In some embodiments, the polyhydric alcohol can include such compounds as sorbitol, mannitol, glycerol, inositol, xylitol, and polypropylene / ethylene glycol copolymer, as well as various polyethylene glycols (PEGs) of molecular weights 200, 400, 1450, 3350, 4000, 6000, and 8000. In some embodiments, the carbohydrate caninclude such compounds as sucrose, mannose, ribose, trehalose, maltose inositol, erythritol and lactose. In certain embodiments, the aqueous aviptadil formulations can comprise sucrose, trehalose, lactose, sorbitol, mannitol, or combinations thereof.

[0076] In some embodiments, the aqueous aviptadil formulations can comprise about 1% (w / v) to about 20% (w / v) of a carbohydrate, a polyhydric alcohol, or a combination of a carbohydrate and a polyhydric alcohol. In some embodiments, the aqueous aviptadil formulations can comprise about 2% (w / v) to about 19% (w / v), about 3% (w / v) to about 18% (w / v), about 4% (w / v) to about 17% (w / v), about 5% (w / v) to about 16% (w / v), about 5% (w / v) to about 15% (w / v), about 6% (w / v) to about 14% (w / v), about 7% (w / v) to about 13% (w / v), about 8% (w / v) to about 12% (w / v), or about 9% (w / v) to about 11% (w / v). In certain embodiments, the aqueous aviptadil formulations can comprise about 1% (w / v), about 2% (w / v), about 3% (w / v), about 4% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), about 10% (w / v), about 11% (w / v), about 12% (w / v), about 13% (w / v), about 14% (w / v), about 15% (w / v), about 16% (w / v), about 17% (w / v), about 18% (w / v), about 19% (w / v), or about 20% (w / v) of a carbohydrate, a polyhydric alcohol, or a combination of a carbohydrate and a polyhydric alcohol.

[0077] In certain embodiments, the aqueous aviptadil formulations can comprise about 10% (w / v) of a carbohydrate, a polyhydric alcohol, or a combination of a carbohydrate and a polyhydric alcohol. In certain embodiments, the aqueous aviptadil formulations can comprise about 10% (w / v) of sucrose. In certain embodiments, the aqueous aviptadil formulations can comprise about 10% (w / v) of trehalose. In certain embodiments, the aqueous aviptadil formulations can comprise about 10% (w / v) of sorbitol. In certain embodiments, the aqueous aviptadil formulations can comprise about 10% (w / v) of mannitol. In certain embodiments, the aqueous aviptadil formulations can comprise about 5% (w / v) of sucrose and about 5% (w / v) of mannitol.

[0078] In some embodiments, the aqueous aviptadil formulations can comprise a pharmaceutically acceptable antioxidant. In some embodiments, the pharmaceutically acceptable antioxidant can delay or inhibit aviptadil oxidation. In some embodiments, the antioxidant can include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite (SMB), potassium metabisulfite (KMB), propyl gallate (PG), cysteine, ascorbic acid, tocopherol (vitamin E), sesamol, guaiac resin, methionine, arginine, citric acid, tartaric acid, phosphoric acid, and combinations thereof. In someembodiments, the aqueous aviptadil composition can be free of antioxidants. In certain embodiments, the aqueous aviptadil formulations can comprise methionine.

[0079] In some embodiments, the aqueous aviptadil formulations can comprise about 1 mM to about 100 mM of the antioxidant. In some embodiments, the aqueous aviptadil formulations can comprise about 1 mM to about 80 mM, about 1 mM to about 60 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to about 30 mM, or about 1 mM to about 25 mM of the antioxidant. In some embodiments, the aqueous aviptadil formulations can comprise about 5 mM to about 100 mM, about 5 mM to about 80 mM, about 5 mM to about 60 mM, about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, or about 5 mM to about 25 mM of the antioxidant. In some embodiments, the aqueous aviptadil formulations can comprise about 10 mM to about 100 mM, about 10 mM to about 80 mM, about 10 mM to about 60 mM, about 10 mM to about 50 mM, about 10 mM to about 40 mM, or about 10 mM to about 30 mM of the antioxidant. In some embodiments, the aqueous aviptadil formulations can comprise about 15 mM to about 100 mM, about 15 mM to about 80 mM, about 15 mM to about 60 mM, about 15 mM to about 50 mM, about 15 mM to about 40 mM, or about 15 mM to about 30 mM of the antioxidant. In some embodiments, the aqueous aviptadil formulations can comprise about 20 mM to about 100 mM, about 20 mM to about 80 mM, about 20 mM to about 60 mM, about 20 mM to about 50 mM, or about 20 mM to about 40 mM of the antioxidant. In some embodiments, the aqueous aviptadil formulations can comprise about 25 mM to about 100 mM, about 25 mM to about 80 mM, about 25 mM to about 60 mM, or about 25 mM to about 50 mM of the antioxidant.

[0080] In some embodiments, the aqueous aviptadil formulations can comprise about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, or about 100 mM of the antioxidant. In certain embodiments, the aqueous aviptadil formulations can comprise about 25 mM of the antioxidant. In certain embodiments, the aqueous aviptadil formulations can comprise about 50 mM of the antioxidant. In certain embodiments, the aqueous aviptadil formulations can comprise about 25 mM of methionine. In certain embodiments, the aqueous aviptadil formulations can comprise about 50 mM of arginine.

[0081] In some embodiments, the aqueous aviptadil composition can comprise a surfactant. In some embodiments, the aqueous aviptadil composition can be free of surfactants. In some embodiments, the composition can comprise one or more surfactants. In some embodiments, the surfactant can be anionic, cationic, zwitterionic, or nonionic. In some embodiments, the one or more surfactants can be selected from the group consisting of polysorbate 80 (i.e., polyoxyethylene (20) sorbitan monooleate; Tween 80), 3 -[(3 -Cholamidopropyl)dimethylammonio]-1 -propanesulfonate, polyoxyethylene lauryl ether, poloxamer 88, lecithin, sucrose monoester of palmitic acid, dioctyl sodium sulfosuccinate, chemically modified food starch from waxy maize, polysorbate 20, polysorbate 40, polysorbate 60, tri thy 1 ammonium bromide, cetylpyridinium chloride, polyethoxylated tallow amine, benzalkonium chloride, dodecyl betaine, cocamidopropyl betaine, coco ampho glycinate, poly (alkyl ene-oxide) block copolymer (e.g., PEO-PPO- PEO), oligomeric alkyl-ethylene oxides (e.g., Brij, Tergitol), alkyl-phenol poly-ethylenes (e.g., Triton), alkyl polyglucosides (e.g., octyl glucoside, decyl maltoside), fatty alcohols (e.g., cetyl alcohol, oleyl alcohol, stearyl alcohol, palmityl alcohol), cocamide MEA sorbitan esters (e.g., Tween, Span), perfluorooctanoate (PFOA or PFO), perfluorooctanesulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, sodium lauryl ether sulfate, alkyl benzene sulfonate, fatty acids (e.g., oleate, stearate, palmitate, etc.), and combinations thereof. In certain embodiments, the surfactant can be polysorbate 80 or poloxamer 88.

[0082] In some embodiments, the formulations can comprise from about 0.001% (w / v) to about 1.0% (w / v) of a surfactant. In some embodiments, the formulations can comprise from about 0.005% (w / v) to about 1.0% (w / v) or about 0.01% (w / v) to about 1.0% (w / v) of a surfactant. In some embodiments, the formulations can comprise from about 0.01% (w / v) to about 0.9% (w / v), about 0.01% (w / v) to about 0.8% (w / v), about 0.01% (w / v) to about 0.7% (w / v), about 0.01% (w / v) to about 0.6% (w / v), about 0.01% (w / v) to about 0.5% (w / v), about 0.01% (w / v) to about 0.4% (w / v), about 0.01% (w / v) to about 0.3% (w / v), about 0.01% (w / v) to about 0.2% (w / v), or about 0.01% (w / v) to about 0.1% (w / v) of a surfactant. In some embodiments, the formulations comprise about 0.01% (w / v) to about 0.09% (w / v), about 0.01% (w / v) to about 0.08% (w / v), about 0.01% (w / v) to about 0.08% (w / v), about 0.01% (w / v) to about 0.08% (w / v), about 0.01% (w / v) to about 0.07% (w / v), about 0.01% (w / v) to about 0.06% (w / v), about 0.01% (w / v) to about 0.05% (w / v),about 0.01% (w / v) to about 0.04% (w / v), or about 0.01% (w / v) to about 0.03% (w / v) of a surfactant.

[0083] In some embodiments, the formulations can comprise from about 0.001% (w / v), 0.005% (w / v), about 0.01% (w / v), about 0.02% (w / v), about 0.03% (w / v), about 0.04% (w / v), about 0.05% (w / v), about 0.06% (w / v), about 0.07% (w / v), about 0.08% (w / v) about 0.09% (w / v), about 0.1% (w / v), about 0.2% (w / v), about 0.3% (w / v), about 0.4% (w / v), about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v), about 0.8% (w / v), about 0.9% (w / v), or about 1% (w / v) of a surfactant. In certain embodiments, the formulations can comprise about 0.02% (w / v) of polysorbate 80. In certain embodiments, the formulations can comprise about 0.02% (w / v) of poloxamer 88.

[0084] In some embodiments, the aqueous aviptadil formulations can comprise a chelating agent. In some embodiments, the stabilizer can be ethylenediaminetetraacetic acid (EDTA). In some embodiments, the stabilizer can be ethylene glycol tetraacetic acid (EGTA). In some embodiments, the formulations can be free of stabilizers.

[0085] In some embodiments, the aqueous aviptadil formulations can comprise about 0.1 mM to about 10 mM of a chelating agent. In some embodiments, the aqueous aviptadil formulations can comprise about 0.1 mM to about 9 mM, about 0.1 mM to about 8 mM, about 0.1 mM to about 7 mM, about 0.1 mM to about 6 mM, about 0.1 mM to about 5 mM, about 0.1 mM to about 4 mM, about 0.1 mM to about 3 mM, about 0.1 mM to about 2 mM, or about 0.1 mM to about 1 mM of a chelating agent. In some embodiments, the aqueous aviptadil formulations can comprise about 0.5 mM to about 10 mM, about 0.5 mM to about 9 mM, about 0.5 mM to about 8 mM, about 0.5 mM to about 7 mM, about 0.5 mM to about 6 mM, about 0.5 mM to about 5 mM, about 0.5 mM to about 4 mM, about 0.5 mM to about 3 mM, about 0.5 mM to about 2.5 mM, about 0.5 mM to about 2 mM, about 0.5 mM to about 1.5 mM, or about 0.5 mM to about 1 mM of a chelating agent. In certain embodiments, the aqueous aviptadil formulations can comprise about 1 mM of EDTA.

[0086] In some embodiments, the aqueous aviptadil formulations can comprise a tonicity modifier. In some embodiments, the tonicity modifier can be selected from the group consisting of dextrose, glycerin, mannitol, potassium chloride, sodium chloride, and combinations thereof. In some embodiments, the tonicity modifier can be sodium acetate, sodium aspartate, sodium benzenesulfonate, sodium benzoate, sodium bicarbonate, sodium bitartrate, sodium bromide, sodium camsylate, sodium carbonate, sodiumchloride, sodium citrate, sodium decanoate, sodium edetate, sodium esylate, sodium fumarate, sodium gluceptate, sodium gluconate, sodium glutamate, sodium glycolate, sodium hexaonate, sodium hydroxynaphthoate, sodium iodide, sodium isethionate, sodium lactate, sodium lactobionate, sodium malate, sodium maleate, sodium mandelate, sodium mesylate, sodium methyl sulfate, sodium mucate, sodium napsylate, sodium nitrate, sodium octanoate, sodium pamoate, sodium pantothenate, phosphate, sodium polygalacturonate, sodium propionate, sodium salicylate, sodium stearate, sodium succinate, sodium suflate, sodium tartrate, sodium teoclate, sodium tosylate, and combinations thereof. In certain embodiments, the tonicity modifier can be sodium chloride.

[0087] In some embodiments, the aqueous aviptadil formulations can comprise about 1 mM to about 500 mM of a tonicity modifier. In some embodiments, the aqueous aviptadil formulations can comprise about 10 mM to about 500 mM, about 25 mM to about 500 mM, about 50 mM to about 500 mM, about 75 mM to about 500 mM, about 100 mM to about 500 mM, about 100 mM to about 400 mM, about 100 mM to about 300 mM, about 100 mM to about 250 mM, about 100 mM to about 200 mM, about 110 mM to about 190 mM, about 120 mM to about 180 mM, about 130 mM to about 170 mM, or about 140 mM to about 160 mM a tonicity modifier. In some embodiments, the aqueous aviptadil formulations can comprise about 150 mM of a tonicity modifier. In certain embodiments, the aqueous aviptadil formulations can comprise about 150 mM of sodium chloride as a tonicity modifier.

[0088] In some embodiments, the aqueous aviptadil formulations can further comprise one or more pharmaceutically acceptable solvents. In some embodiments, the one or more pharmaceutically acceptable solvents can be selected from the group consisting of ethanol, butanol, 2-ethylhexanol, isobutanol, propanol, propylene glycol, dimethyl sulfoxide, ethyl acetate, N,N-dimethylformamide, and combinations thereof. In some embodiments, the aqueous aviptadil composition can be free of the one or more pharmaceutically acceptable solvents.

[0089] In some embodiments, the aqueous aviptadil formulations can comprise a pharmaceutically acceptable preservative. In some embodiments, the formulations can comprise from about 0.001% (w / v) to about 1% (w / v) of the pharmaceutically acceptable preservative. In some embodiments, the pharmaceutically acceptable preservative can be selected from the group consisting of benzyl alcohol, m-cresol, methyl-, ethyl-, propyl-,or butyl-parabens, and combinations thereof. In some embodiments, the pharmaceutically acceptable preservative can be selected from the group consisting of chlorobutanol, 2- ethoxyethanol, sorbic acid, chlorhexidine, phenol, 4-chloroxylenol, thimerosal, phenylmercurate salts, imidurea, cetylpyridinium bromide, or domiphen bromide, or combinations thereof. In some embodiments, the aqueous aviptadil composition can be free of pharmaceutically acceptable preservatives.

[0090] In some embodiments, the aqueous aviptadil formulations can comprise an emulsifier. In some embodiments, the emulsifier can be selected from the group consisting of cetrimide, macrohol esters, sorbitan esters, glycine esters oleic acid, sorbitan tristearate, ethylene glycol monostearate, glycerol monostearate, sorbitan monostearate, sorbitan monopalmitate, PEG-4 dilaurate, sucrose dipalmitate, PEG-4 monooleate, PEG-4 monolaurate, polysorbate 85, PEG-8 monooleate, and combinations thereof.

[0091] In some embodiments, the aqueous aviptadil formulations can have a pH from about 4.5 to about 7. In some embodiments, the aqueous aviptadil formulations can have a pH from about 5 to about 7, from about 5.5 to about 7, from about 6 to about 7, from about 4.5 to about 6.5, from about 4.5 to about 6, from about 4.5 to about 5.5, from about 4.5 to about 5, from about 5 to about 6.5, from about 5 to about 6, or from about 5 to about 5.5. In some embodiments, the aqueous aviptadil formulations can have a pH from about 5 to about 6, from about 5 to about 5.9, from about 5 to about 5.8, from about 5 to about 5.7, from about 5 to about 5.6, from about 5 to about 5.5, from about 5.1 to about 6, from about 5.1 to about 5.9, from about 5.1 to about 5.8, from about 5.1 to about 5.7, from about 5.1 to about 5.6, from about 5.1 to about 5.5, from about 5.2 to about 6, from about 5.2 to about 5.9, from about 5.2 to about 5.8, from about 5.2 to about 5.7, from about 5.2 to about 5.6, from about 5.2 to about 5.5, from about 5.3 to about 6, from about 5.3 to about 5.9, from about 5.3 to about 5.8, from about 5.3 to about 5.7, from about 5.3 to about 5.6, from about 5.3 to about 5.5, from about 5.4 to about 6, from about 5.4 to about 5.9, from about 5.4 to about 5.8, from about 5.4 to about 5.7, from about 5.4 to about 5.6, from about 5.5 to about 6, from about 5.5 to about 5.9, from about 5.5 to about 5.8, from about 5.5 to about 5.7, from about 5.5 to about 5.6, from about 5.6 to about 6, from about 5.6 to about 5.9, from about 5.6 to about 5.8, from about 5.6 to about 5.7, from about 5.7 to about 6, from about 5.7 to about 5.9, from about 5.7 to about 5.8, from about 5.8 to about 6, from about 5.8 to about 5.9, from about 5.9 to about 6. In certain embodiments, the aqueous aviptadil formulations can have a pH from about 5 to about 6,from about 5.1 to about 5.9, from about 5.2 to about 5.8, from about 5.3 to about 5.7, or from about 5.4 to about 5.6. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.5.

[0092] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 150 mM of NaCl, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 150 mM of NaCl, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 150 mM of NaCl, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about 5.6 or about 5.5.

[0093] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 4.8 to about 5.2 and can comprise 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 150 mM of NaCl, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 4.8 to about 5.2 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 150 mM of NaCl, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 4.8 to about 5.2 and consists of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 150 mM of NaCl, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about 5.6 or about 5.5.

[0094] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certainembodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0095] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.2 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.2 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.2 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0096] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and comprises 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0097] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.8 to about 6.2 and can comprise 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.8 to about 6.2 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.8 to about 6.2 and consists of 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certainembodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0098] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sorbitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sorbitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.1 mg / mL of aviptadil, 20 mM of acetate buffer, 10% (w / v) of sorbitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0099] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists of 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0100] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists essentially of 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists of 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certainembodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0101] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists essentially of 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists of 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0102] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists essentially of 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists of 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of trehalose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0103] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists of 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certainembodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0104] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists essentially of 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists of 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0105] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists essentially of 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists of 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about5.6 or about 5.5.

[0106] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists essentially of 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about5.3 to about 5.7 and consists of 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 10% (w / v) of sucrose, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certainembodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about 5.6 or about 5.5.

[0107] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, v25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.1 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about 5.6 or about 5.5.

[0108] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L- methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.2 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about 5.6 or about 5.5.

[0109] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L- methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.3 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about 5.6 or about 5.5.

[0110] In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and can comprise 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists essentially of 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L- methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, the aqueous aviptadil formulations can have a pH of about 5.3 to about 5.7 and consists of 0.4 mg / mL of aviptadil, 20 mM of histidine buffer, 5% (w / v) of sucrose, 5% (w / v) of mannitol, 25 mM of L-methionine, and 0.02% (w / v) of polysorbate 80. In certain embodiments, these aqueous aviptadil formulations can have a pH of about 5.4 to about 5.6 or about 5.5.[OHl] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 weeks. Measurements by RP-UPLC are taken based on the protocol described in Example 1. In some embodiments, the formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 weeks.

[0112] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months. In some embodiments, the formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months.

[0113] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months. In some embodiments, the formulationscan comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months.

[0114] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months. In some embodiments, the formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months.

[0115] In some embodiments, the formulations can comprise no more than about 3% of a methionine oxidation product (Met(O)), e. g., methionine sulfoxide or methionine sulfone, as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 weeks. In some embodiments, the formulations comprise no more than about 2.5%, about 2%, about 1.5%, or about 1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 weeks. In certain embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 weeks.

[0116] In some embodiments, the formulations can comprise no more than about 3% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months. In some embodiments, the formulations can comprise no more than about 2.5%, about 2%, about 1.5%, or about 1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months. In certain embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months.

[0117] In some embodiments, the formulations can comprise no more than about 3% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months. In some embodiments, the formulations can comprise no more than about 2.5%, about 2%, about 1.5%, or about 1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months. In certain embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months.

[0118] In some embodiments, the formulations can comprise no more than about 3% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months. In some embodiments, the formulations can comprise no more than about 2.5%, about 2%, about 1.5%, or about 1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months. In certain embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months.

[0119] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by high performance size-exclusion chromatography (HP-SEC) after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months. Measurements by HP-SEC are taken based on the protocol described in Example 6. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months.

[0120] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%,about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months.

[0121] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months.

[0122] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months.

[0123] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 months. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 months.

[0124] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of high molecular weight (BMW) species as measured by HP-SECafter storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months.

[0125] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months.

[0126] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months.

[0127] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months.

[0128] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 months. In someembodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 months.

[0129] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of low molecular weight (LMW) species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months.

[0130] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months.

[0131] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months.

[0132] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%,about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months.

[0133] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 14 months.

[0134] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage at about 25 °C for at least 3 months. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage at about 25 °C for at least 3 months.

[0135] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage at about 25 °C for at least 6 months. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage at about 25 °C for at least 6 months.

[0136] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage at about 25 °C for at least 3 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%,about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage at about 25 °C for at least 3 months.

[0137] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage at about 25 °C for at least 6 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage at about 25 °C for at least 6 months.

[0138] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage at about 25 °C for at least 3 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at about 25 °C for at least 3 months.

[0139] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage at about 25 °C for at least 6 months. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at about 25 °C for at least 6 months.Powdered Aviptadil Formulations

[0140] The disclosure provides powdered aviptadil formulations (also referred herein as lyophilized aviptadil formulations) that are storage stable at a temperature ranging from about 2 °C to about 40 °C for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months without significant degradation of the aviptadil present in the formulations. In some embodiments, the powdered aviptadil formulations are storage stable at a temperature ranging from about 2 °C to about 25 °C for at least about 1 month, at least about 3months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months without significant degradation of the aviptadil present in the formulations. In some embodiments, the storage stable powdered aviptadil formulations are prepared by lyophilizing the aqueous aviptadil formulations described herein.

[0141] In some embodiments, the powdered aviptadil formulations can comprise about 0.01 mg aviptadil to about 2 mg aviptadil. In some embodiments, the powdered aviptadil formulations can comprise about 0.01 mg aviptadil to about 1.5 mg aviptadil, about 0.01 mg aviptadil to about 1 mg aviptadil, about 0.01 mg aviptadil to about 0.9 mg aviptadil, about 0.01 mg aviptadil to about 0.8 mg aviptadil, about 0.01 mg aviptadil to about 0.7 mg aviptadil, about 0.01 mg aviptadil to about 0.6 mg aviptadil, about 0.01 mg aviptadil to about 0.5 mg aviptadil, about 0.01 mg aviptadil to about 0.4 mg aviptadil, about 0.01 mg aviptadil to about 0.3 mg aviptadil, or about 0.01 mg aviptadil to about 0.2 mg aviptadil. In some embodiments, the powdered aviptadil formulations can comprise about 0.02 mg aviptadil to about 1.9 mg aviptadil, about 0.03 mg aviptadil to about 1.8 mg aviptadil, about 0.04 mg aviptadil to about 1.7 mg aviptadil, about 0.05 mg aviptadil to about 1.6 mg aviptadil, about 0.06 mg aviptadil to about 1.5 mg aviptadil, aviptadil, about 0.06 mg aviptadil to about 1.4 mg aviptadil, about 0.07 mg aviptadil to about 1.3 mg aviptadil, about 0.08 mg aviptadil to about 1.2 mg aviptadil, about 0.09 mg aviptadil to about 1.1 mg aviptadil, about 0.1 mg aviptadil to about 1 mg aviptadil, about 0.1 mg aviptadil to about 0.9 mg aviptadil, about 0.1 mg aviptadil to about 0.8 mg aviptadil, about 0.1 mg aviptadil to about 0.7 mg aviptadil, about 0.1 mg aviptadil to about 0.6 mg aviptadil, about 0.1 mg aviptadil to about 0.5 mg aviptadil, about 0.1 mg aviptadil to about 0.4 mg aviptadil, about 0.1 mg aviptadil to about 0.3 mg aviptadil, or about 0.1 mg aviptadil to about 0.2 mg aviptadil.

[0142] In some embodiments, the powdered aviptadil formulations can comprise about 0.03 mg aviptadil to about 2 mg aviptadil. In some embodiments, the powdered aviptadil formulations can comprise about 0.03 mg aviptadil to about 1.5 mg aviptadil, about 0.03 mg aviptadil to about 1 mg aviptadil, about 0.03 mg aviptadil to about 0.9 mg aviptadil, about 0.03 mg aviptadil to about 0.8 mg aviptadil, about 0.03 mg aviptadil to about 0.7 mg aviptadil, about 0.03 mg aviptadil to about 0.6 mg aviptadil, about 0.03 mg aviptadil to about 0.5 mg aviptadil, about 0.03 mg aviptadil to about 0.4 mg aviptadil, about 0.03mg aviptadil to about 0.3 mg aviptadil, or about 0.03 mg aviptadil to about 0.2 mg aviptadil.

[0143] In some embodiments, the powdered aviptadil formulations can comprise about 0.05 mg aviptadil to about 2 mg aviptadil. In some embodiments, the powdered aviptadil formulations can comprise about 0.05 mg aviptadil to about 1.5 mg aviptadil, about 0.05 mg aviptadil to about 1 mg aviptadil, about 0.05 mg aviptadil to about 0.9 mg aviptadil, about 0.05 mg aviptadil to about 0.8 mg aviptadil, about 0.05 mg aviptadil to about 0.7 mg aviptadil, about 0.05 mg aviptadil to about 0.6 mg aviptadil, about 0.05 mg aviptadil to about 0.5 mg aviptadil, about 0.05 mg aviptadil to about 0.4 mg aviptadil, about 0.05 mg aviptadil to about 0.3 mg aviptadil, or about 0.05 mg aviptadil to about 0.2 mg aviptadil.

[0144] In some embodiments, the powdered aviptadil formulations can comprise about 0.01 mg aviptadil, about 0.02 mg aviptadil, about 0.03 mg aviptadil, about 0.04 mg aviptadil, about 0.05 mg aviptadil, about 0.06 mg aviptadil, about 0.07 mg aviptadil, about 0.08 mg aviptadil, about 0.09 mg aviptadil, about 0.1 mg aviptadil, about 0.2 mg aviptadil, about 0.3 mg aviptadil, about 0.4 mg aviptadil, about 0.5 mg aviptadil, about 0.6 mg aviptadil, about 0.7 mg aviptadil, about 0.8 mg aviptadil, about 0.9 mg aviptadil, about 1.0 mg aviptadil, about 1.1 mg aviptadil, about 1.2 mg aviptadil, about 1.3 mg aviptadil, about 1.4 mg aviptadil, about 1.5 mg aviptadil, about 1.6 mg aviptadil, about 1.7 mg aviptadil, about 1.8 mg aviptadil, about 1.9 mg aviptadil, or about 2.0 mg aviptadil. In certain embodiments, the powdered aviptadil formulations can comprise about 0.05 mg aviptadil, about 0.1 mg aviptadil, or about 0.2 mg aviptadil.

[0145] In some embodiments, the powdered aviptadil formulations described herein can comprise a buffer salt. In some embodiments, a buffer salt can be selected from the group consisting of salts of formate (pKa=3.75), lactate (pKa=3.86), benzoic acid (pKa=4.2) oxalate (pKa=4.29), fumarate (pKa=4.38), aniline (pKa=4.63), acetate buffer (pKa=4.76), citric acid (pKa 2.79), citrate buffer (pKa2=4.76, pKa3=6.4), glutamate buffer (pKa=4.3), phosphate buffer (pKa=7.20), succinate (pkal=4.93; pKa2=5.62), pyridine (pKa=5.23), phthalate (pKa=5.41); histidine (pKa=6.04), MES (2-(N-morpholino)ethanesulphonic acid; pKa=6.15); maleic acid (pKa=6.26); cacodylate (dimethylarsinate, pKa=6.27), carbonic acid (pKa=6.35), ADA (N-(2-acetamido)imino-diacetic acid (pKa=6.62); PIPES (4-piperazinebis-(ethanesulfonic acid; BIS-TRIS-propane (1,3- bis[tris(hydroxymethyl)methylamino]-propane), pKa=6.80), ethylendiamine (pKa=6.85),ACES 2-[(2-amino-2-oxoethyl)amino]ethanesulphonic acid; pKa=6.9), imidazole (pKa=6.95), MOPS (3-(N-morphin)-propansulfonic acid; pKa=7.20), diethylmalonic acid (pKa=7.2), TES (2-[tris (hydroxymethyl)methyl]amino ethanesulphonic acid; pKa=7.50), trisodium citrate (pKa= 3.18, 4.76, and 6.4), HEPES (N-2-hydroxylethylpiperazin-N'-2- ethansulfonic acid; pKa=7.55) buffers, and combinations thereof.

[0146] In some embodiments, a buffer salt can comprise a carboxylic acid moiety (e.g., an acetate group). In some embodiments, a buffer salt can be an inorganic buffer salt. In some embodiments, the buffer salt can comprise an inorganic buffer salt, such as a phosphate buffer salt, a sulfate buffer salt, or a borate buffer salt. In some embodiments, the buffer salt can comprise an amino acid buffer salt, such as salts of glycine, tyrosine, glutamic acid, glutamate, aspartic acid, aspartate, barbiturate, 5,5-diethylbarbiturate, methionine, arginine, alanine, tryptophan, lysine, serine, and histidine. In certain embodiments, the buffer salt can be an acetate buffer salt, a citrate buffer salt, a histidine buffer salt, or a phosphate buffer salt.

[0147] In some embodiments, the powdered aviptadil formulations can comprise about 1 mg to about 100 mg of the buffer salt. In some embodiments, the powdered aviptadil formulations can comprise about 1 mg to about 80 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, or about 1 mg to about 5 mg of the buffer salt. In some embodiments, the powdered aviptadil formulations can comprise about 2 mg to about 100 mg, about 2 mg to about 80 mg, about 2 mg to about 60 mg, about 2 mg to about 50 mg, about 2 mg to about 40 mg, about 2 mg to about 20 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, or about 2 mg to about 5 mg of the buffer salt. In some embodiments, the powdered aviptadil formulations can comprise about 3 mg to about 100 mg, about 3 mg to about 80 mg, about 3 mg to about 60 mg, about 3 mg to about 50 mg, about 3 mg to about 40 mg, about 3 mg to about 20 mM, about 3 mg to about 10 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, or about 3 mg to about 5 mg of the buffer salt.

[0148] In certain embodiments, the powdered aviptadil formulations can comprise about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg. about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg,about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10 mg of the buffer salt.

[0149] In certain embodiments, the powdered aviptadil formulations can comprise about 3.9 mg of a histidine buffer salt. In certain embodiments, the powdered aviptadil formulations can comprise about 3.1 mg of an L-histidine HC1 monohydrate and about 0.8 mg of an L-histidine anhydrous.

[0150] In certain embodiments, the powdered aviptadil formulations can comprise about5.3 mg of a citrate buffer salt. In certain embodiments, the powdered aviptadil formulations can comprise about 4.3 mg of a tri-sodium citrate dihydrate and about 1 mg of a citric acid anhydrous.

[0151] In certain embodiments, the powdered aviptadil formulations can comprise about 8.1 mg of a citrate buffer salt. In certain embodiments, the powdered aviptadil formulations can comprise about 6.7 to about 6.8 mg of a tri-sodium citrate dihydrate and about 1.3 to about 1.4 mg of a citric acid anhydrous.

[0152] In certain embodiments, the powdered aviptadil formulations can comprise about 13.7 mg of a citrate buffer salt. In certain embodiments, the powdered aviptadil formulations can comprise about 11.7 mg of a tri-sodium citrate dihydrate and about 2 mg of a citric acid anhydrous.

[0153] In some embodiments, the powdered aviptadil formulations can comprise a carbohydrate, a polyhydric alcohol, or a combination of a carbohydrate and a polyhydric alcohol. In some embodiments, the polyhydric alcohol can include such compounds as sorbitol, mannitol, glycerol, inositol, xylitol, and polypropylene / ethylene glycol copolymer, as well as various polyethylene glycols (PEGs) of molecular weights 200, 400, 1450, 3350, 4000, 6000, and 8000. In some embodiments, the carbohydrate can include such compounds as sucrose, mannose, ribose, trehalose, maltose inositol,erythritol and lactose. In certain embodiments, the powdered aviptadil formulations can comprise sucrose, trehalose, lactose, sorbitol, mannitol, or combinations thereof. In certain embodiments, the powdered aviptadil formulations can sucrose, trehalose dihydrate, lactose monohydrate, sorbitol, mannitol, or combinations thereof.

[0154] In some embodiments, the powdered aviptadil formulations can comprise about 10 mg to about 200 mg of a carbohydrate, a polyhydric alcohol, or a combination of a carbohydrate and a polyhydric alcohol. In some embodiments, the powdered aviptadil formulations can comprise about 20 mg to about 190 mg, about 30 mg to about 180 mg, about 40 mg to about 170 mg, about 50 mg to about 160 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 200 mg, about 80 mg to about 150 mg, about 80 mg to about 120 mg, or about 90 mg to about 110 mg. In certain embodiments, the powdered aviptadil formulations can comprise about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of a carbohydrate, a polyhydric alcohol, or a combination of a carbohydrate and a polyhydric alcohol.

[0155] In certain embodiments, the powdered aviptadil formulations can comprise about 100 mg of a carbohydrate, a polyhydric alcohol, or a combination of a carbohydrate and a polyhydric alcohol. In certain embodiments, the powdered aviptadil formulations can comprise about 100 mg of sucrose. In certain embodiments, the powdered aviptadil formulations can comprise about 100 mg of trehalose (in the form of trehalose dehydrate). In certain embodiments, the powdered aviptadil formulations can comprise about 100 mg of sorbitol. In certain embodiments, the powdered aviptadil formulations can comprise about 100 mg of mannitol. In certain embodiments, the powdered aviptadil formulations can comprise about 80 mg of mannitol and about 20 mg of trehalose (in the form of trehalose dehydrate). In certain embodiments, the powdered aviptadil formulations can comprise about 50 mg of mannitol and about 50 mg of trehalose (in the form of trehalose dehydrate). In certain embodiments, the powdered aviptadil formulations can comprise about 50 mg of mannitol and about 50 mg of sucrose. In certain embodiments, the powdered aviptadil formulations can comprise about 100 mg of lactose (in the form of lactose monohydrate).

[0156] In some embodiments, the powdered aviptadil formulations can comprise a pharmaceutically acceptable antioxidant. In some embodiments, the pharmaceutically acceptable antioxidant can delay or inhibit methionine oxidation in aviptadil. In some embodiments, the antioxidant can include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite (SMB), potassium metabisulfite (KMB), propyl gallate (PG), cysteine, ascorbic acid, tocopherol (vitamin E), sesamol, guaiac resin, methionine, arginine, citric acid, tartaric acid, phosphoric acid, and combinations thereof. In some embodiments, the powdered aviptadil composition can be free of antioxidants. In certain embodiments, the powdered aviptadil formulations can comprise methionine.

[0157] In some embodiments, the powdered aviptadil formulations can comprise about 1 mg to about 10 mg of the antioxidant. In some embodiments, the powdered aviptadil formulations can comprise about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, or about 1 mg to about 2 mg of the antioxidant. In some embodiments, the powdered aviptadil formulations can comprise about 2 mg to about 10 mg, 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, or about 2 mg to about 3 mg of the antioxidant. In some embodiments, the powdered aviptadil formulations can comprise about 3 mg to about 10 mg, 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, or about 3 mg to about 4 mg of the antioxidant.

[0158] In certain embodiments, the powdered aviptadil formulations can comprise about 1.8 mg, about 3.7 mg, or about 5.5 mg of the antioxidant. In certain embodiments, the powdered aviptadil formulations can comprise about 1.8 mg, about 3.7 mg, or about 5.5 mg of methionine.

[0159] In some embodiments, the powdered aviptadil composition can comprise a surfactant. In some embodiments, the powdered aviptadil composition can be free of surfactants. In some embodiments, the composition can comprise one or more surfactants. In some embodiments, the surfactant can be anionic, cationic, zwitterionic, or nonionic. In some embodiments, the one or more surfactants can be selected from the group consisting of polysorbate 80 (i.e., polyoxyethylene (20) sorbitan monooleate; Tween 80), 3 -[(3 -Cholamidopropyl)dimethylammonio]-1 -propanesulfonate, polyoxyethylene laurylether, poloxamer 88, lecithin, sucrose monoester of palmitic acid, dioctyl sodium sulfosuccinate, chemically modified food starch from waxy maize, polysorbate 20, polysorbate 40, polysorbate 60, tri thy 1 ammonium bromide, cetylpyridinium chloride, polyethoxylated tallow amine, benzalkonium chloride, dodecyl betaine, cocamidopropyl betaine, coco ampho glycinate, poly (alkyl ene-oxide) block copolymer (e.g., PEO-PPO- PEO), oligomeric alkyl-ethylene oxides (e.g., Brij, Tergitol), alkyl-phenol poly-ethylenes (e.g., Triton), alkyl polyglucosides (e.g., octyl glucoside, decyl maltoside), fatty alcohols (e.g., cetyl alcohol, oleyl alcohol, stearyl alcohol, palmityl alcohol), cocamide MEA sorbitan esters (e.g., Tween, Span), perfluorooctanoate (PFOA or PFO), perfluorooctanesulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, sodium lauryl ether sulfate, alkyl benzene sulfonate, fatty acids (e.g., oleate, stearate, palmitate, etc.), and combinations thereof. In certain embodiments, the surfactant can be polysorbate 80 or poloxamer 88.

[0160] In some embodiments, the powdered aviptadil formulations can comprise about 0.01 mg to about 1 mg of the surfactant. In some embodiments, the powdered aviptadil formulations can comprise about 0.01 mg to about 0.9 mg, about 0.01 mg to about 0.8 mg, about 0.01 mg to about 0.7 mg, about 0.01 mg to about 0.6 mg, about 0.01 mg to about 0.5 mg, about 0.01 mg to about 0.4 mg, about 0.01 mg to about 0.3 mg, or about 0.01 mg to about 0.2 mg of the surfactant. In some embodiments, the powdered aviptadil formulations can comprise about 0.05 mg to about 1 mg of the antioxidant. In some embodiments, the powdered aviptadil formulations can comprise about 0.05 mg to about 0.9 mg, about 0.05 mg to about 0.8 mg, about 0.05 mg to about 0.7 mg, about 0.05 mg to about 0.6 mg, about 0.05 mg to about 0.5 mg, about 0.05 mg to about 0.4 mg, about 0.05 mg to about 0.3 mg, or about 0.05 mg to about 0.2 mg of the surfactant. In some embodiments, the powdered aviptadil formulations can comprise about 0.1 mg to about 1 mg of the antioxidant. In some embodiments, the powdered aviptadil formulations can comprise about 0.1 mg to about 0.9 mg, about 0.1 mg to about 0.8 mg, about 0.1 mg to about 0.7 mg, about 0.1 mg to about 0.6 mg, about 0.1 mg to about 0.5 mg, about 0.1 mg to about 0.4 mg, about 0.1 mg to about 0.3 mg, or about 0.1 mg to about 0.2 mg of the surfactant. In certain embodiments, the powdered aviptadil formulations can comprise about 0.2 mg of the surfactant. In certain embodiments, the powdered aviptadil formulations can comprise about 0.2 mg of polysorbate 80.

[0161] In some embodiments, the powdered aviptadil formulations can comprise a chelating agent. In some embodiments, the stabilizer can be ethylenediaminetetraacetic acid (EDTA). In some embodiments, the stabilizer can be ethylene glycol tetraacetic acid (EGTA). In some embodiments, the formulations can be free of stabilizers.

[0162] In some embodiments, the powdered aviptadil formulations can comprise a tonicity modifier. In some embodiments, the tonicity modifier can be selected from the group consisting of dextrose, glycerin, mannitol, potassium chloride, sodium chloride, and combinations thereof. In some embodiments, the tonicity modifier can be sodium acetate, sodium aspartate, sodium benzenesulfonate, sodium benzoate, sodium bicarbonate, sodium bitartrate, sodium bromide, sodium camsylate, sodium carbonate, sodium chloride, sodium citrate, sodium decanoate, sodium edetate, sodium esylate, sodium fumarate, sodium gluceptate, sodium gluconate, sodium glutamate, sodium glycolate, sodium hexaonate, sodium hydroxynaphthoate, sodium iodide, sodium isethionate, sodium lactate, sodium lactobionate, sodium malate, sodium maleate, sodium mandelate, sodium mesylate, sodium methylsulfate, sodium mucate, sodium napsylate, sodium nitrate, sodium octanoate, sodium pamoate, sodium pantothenate, phosphate, sodium polygalacturonate, sodium propionate, sodium salicylate, sodium stearate, sodium succinate, sodium suflate, sodium tartrate, sodium teoclate, sodium tosylate, and combinations thereof. In certain embodiments, the tonicity modifier can be sodium chloride.

[0163] In some embodiments, the powdered aviptadil formulations can comprise a pharmaceutically acceptable preservative. In some embodiments, the pharmaceutically acceptable preservative can be selected from the group consisting of benzyl alcohol, m- cresol, methyl-, ethyl-, propyl-, or butyl-parabens, and combinations thereof. In some embodiments, the pharmaceutically acceptable preservative can be selected from the group consisting of chlorobutanol, 2-ethoxyethanol, sorbic acid, chlorhexidine, phenol, 4- chloroxylenol, thimerosal, phenylmercurate salts, imidurea, cetylpyridinium bromide, or domiphen bromide, or combinations thereof. In some embodiments, the powdered aviptadil composition can be free of pharmaceutically acceptable preservatives.

[0164] In some embodiments, the powdered aviptadil formulations can comprise an emulsifier. In some embodiments, the emulsifier can be selected from the group consisting of cetrimide, macrohol esters, sorbitan esters, glycine esters oleic acid, sorbitan tristearate, ethylene glycol monostearate, glycerol monostearate, sorbitan monostearate,sorbitan monopalmitate, PEG-4 dilaurate, sucrose dipalmitate, PEG-4 monooleate, PEG-4 monolaurate, polysorbate 85, PEG-8 monooleate, and combinations thereof.

[0165] In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 91 °C, about 92 °C, about 93 °C, about 94 °C, about 95 °C, about 96 °C, about 97 °C, about 98 °C, about 99 °C, about 100 °C after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months.

[0166] In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 40 °C for at least 3 months. In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 91 °C, about 92 °C, about 93 °C, about 94 °C, about 95 °C, about 96 °C, about 97 °C, about 98 °C, about 99 °C, or about 100 °C after storage at a temperature ranging from about 2 °C to about 40 °C for at least 3 months.

[0167] In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months. In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 91 °C, about 92 °C, about 93 °C, about 94 °C, about 95 °C, about 96 °C, about 97 °C, about 98 °C, about 99 °C, or about 100 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months.

[0168] In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 9 months. In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 91 °C, about 92 °C, about 93 °C, about 94 °C, about 95 °C, about 96 °C, about 97 °C, about 98 °C, about 99 °C, or about 100 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 9 months.

[0169] In some embodiments, the powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 12 months. In some embodiments, the powderedaviptadil formulations can have a glass transition temperature of at least about 91 °C, about 92 °C, about 93 °C, about 94 °C, about 95 °C, about 96 °C, about 97 °C, about 98 °C, about 99 °C, or about 100 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 12 months.

[0170] In some embodiments, the powdered aviptadil formulations can have a reconstitution time of 2 minutes or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, the formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, the powdered aviptadil formulations can have a reconstitution time of 2 minutes or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months, 3 months, 6 months, or 12 months. In some embodiments, the formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months, 3 months, 6 months, or 12 months.

[0171] In certain embodiments, the powdered aviptadil formulations can comprise about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months, 9 months, or 12 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months. 3 months, 6 months, or 12 months.

[0172] In certain embodiments, the powdered aviptadil formulations can comprise about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months, 9 months, or 12 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months. 3 months, 6 months, or 12 months.

[0173] In certain embodiments, the powdered aviptadil formulations can comprise about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months, 9 months, or 12 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or lessafter storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months. 3 months, 6 months, or 12 months.

[0174] In certain embodiments, the powdered aviptadil formulations can comprise about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of trehalose dehydrate, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months, 9 months, or 12 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months. 3 months, 6 months, or 12 months.

[0175] In certain embodiments, the powdered aviptadil formulations can comprise about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, these formulations can have a reconstitution time of 1minute or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months. 3 months, 6 months, or 12 months.

[0176] In certain embodiments, the powdered aviptadil formulations can comprise about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months. 3 months, 6 months, or 12 months.

[0177] In certain embodiments, the powdered aviptadil formulations can comprise about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, these formulations can have a reconstitution time of 1minute or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months. 3 months, 6 months, or 12 months.

[0178] In certain embodiments, the powdered aviptadil formulations can comprise about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 100 mg of sucrose, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months. In some embodiments, these formulations can have a reconstitution time of 1 minute or less after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months. 3 months, 6 months, or 12 months.

[0179] In certain embodiments, the powdered aviptadil formulations can comprise about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.1 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 45 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months.

[0180] In certain embodiments, the powdered aviptadil formulations can comprise about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.2 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 45 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months.

[0181] In certain embodiments, the powdered aviptadil formulations can comprise about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.3 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 45 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months.

[0182] In certain embodiments, the powdered aviptadil formulations can comprise about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg ofpolysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist essentially of about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In certain embodiments, the powdered aviptadil formulations can consist of about 0.4 mg aviptadil (acetate salt), about 3.9 mg of histidine buffer, about 3.7 mg of methionine, about 50 mg of sucrose, about 50 mg of mannitol, and about 0.2 mg of polysorbate 80. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. In some embodiments, these powdered aviptadil formulations can have a glass transition temperature of about 45 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months.Reconstituted Aviptadil Formulations

[0183] The disclosure further provides reconstituted liquid aviptadil formulations comprising a liquid and one of the powdered aviptadil formulations described herein dissolved in the liquid. In some embodiments, the liquid to reconstitute the powdered aviptadil formulations can be water, an NaCl solution (e.g., 0.9% NaCl solution), or an aqueous buffer solution. In some embodiments, the aqueous buffer solution can be a buffer as previously described with releation to aqueous aviptadil formulations. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7.

[0184] In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7 after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7 after storage at a temperature ranging from about 2 °C to about 40 °C for at least 3 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7 after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7 after storage at a temperature ranging from about 2 °C to about 25 °C for at least 9 months prior to reconstitution. In someembodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7 after storage at a temperature ranging from about 2 °C to about 25 °C for at least 12 months prior to reconstitution.

[0185] In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about 5.5 to about 5.7 after storage at a temperature ranging from about 2 °C to about 8 °C for at least 2 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about5.6, or from about 5.5 to about 5.7 after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about5.7, from about 5.4 to about 5.6, or from about 5.5 to about 5.7 after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about 5.5 to about 5.7 after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution.

[0186] In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about 5.5 to about 5.7 after storage at a temperature of about 25 °C for at least 2 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature of about 25 °C for at least 3 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature of about 25 °C for at least 6 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature of about 25 °C for at least 9 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations canhave a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature of about 25 °C for at least 12 months prior to reconstitution.

[0187] In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about 5.5 to about 5.7 after storage at a temperature of about 40 °C for at least 2 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature of about 40 °C for at least 3 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature of about 40 °C for at least 6 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature of about 40 °C for at least 9 months prior to reconstitution. In some embodiments, the reconstituted liquid aviptadil formulations can have a pH ranging from about 5.3 to about 5.7, from about 5.4 to about 5.6, or from about5.5 to about 5.7 after storage at a temperature of about 40 °C for at least 12 months prior to reconstitution.

[0188] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months, 3 months, 6 months, or 12 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP- UPLC after storage at a temperature ranging from about 2 °C to about 25 °C for at least 2 months, 3 months, 6 months, or 12 months prior to reconstitution.

[0189] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months or 3 months prior to reconstitution.

[0190] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months, 3 months, 6 months, or 12 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP- UPLC after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months, 3 months, 6 months, or 12 months prior to reconstitution.

[0191] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 2 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 2 months prior to reconstitution.

[0192] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months prior to reconstitution. Measurements by RP-UPLC are taken based on the protocol described in Examples 2-4. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months prior to reconstitution.

[0193] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperatureranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution.

[0194] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution.

[0195] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution.

[0196] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at about 25 °C for at least 2 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at about 25 °C for at least 2 months prior to reconstitution.

[0197] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at about 25 °C for at least 3 months prior to reconstitution. In some embodiments, the reconstitutedformulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at about 25 °C for at least 3 months prior to reconstitution.

[0198] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage as powdered formulations at about 25 °C for at least 6 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage as powdered formulations at about 25 °C for at least 6 months prior to reconstitution.

[0199] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage as powdered formulations at about 25 °C for at least 9 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage as powdered formulations at about 25 °C for at least 9 months prior to reconstitution.

[0200] In some embodiments, the reconstituted formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage as powdered formulations at about 25 °C for at least 12 months prior to reconstitution. In some embodiments, the reconstituted formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage as powdered formulations at about 25 °C for at least 12 months prior to reconstitution.

[0201] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 2 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 2 months prior to reconstitution.

[0202] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 3 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 3 months prior to reconstitution.

[0203] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 6 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 6 months prior to reconstitution.

[0204] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 9 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 9 months prior to reconstitution.

[0205] In some embodiments, the formulations can comprise no more than about 10% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 12 months prior to reconstitution. In some embodiments, the formulations comprise no more than about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by RP-UPLC after storage at about 40 °C for at least 12 months prior to reconstitution.

[0206] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%,about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 2 months prior to reconstitution.

[0207] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months prior to reconstitution.

[0208] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution.

[0209] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution.

[0210] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution.

[0211] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 25 °C for at least 2 months prior to reconstitution.

[0212] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 25 °C for at least 3 months prior to reconstitution.

[0213] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%,about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 25 °C for at least 6 months prior to reconstitution.

[0214] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 25 °C for at least 9 months prior to reconstitution.

[0215] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 25 °C at least 12 months prior to reconstitution.

[0216] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 40 °C for at least 2 months prior to reconstitution.

[0217] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 40 °C for at least 3 months prior to reconstitution.

[0218] In some embodiments, the formulations comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 40 °C for at least 6 months prior to reconstitution.

[0219] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 40 °C for at least 9 months prior to reconstitution.

[0220] In some embodiments, the formulations can comprise no more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Met(O) as measured by RP-UPLC after storage at about 40 °C at least 12 months prior to reconstitution.

[0221] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least3 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 3 months prior to reconstitution.

[0222] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution.

[0223] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution.

[0224] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%,about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution.

[0225] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 3 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 3 months prior to reconstitution.

[0226] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution.

[0227] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution.

[0228] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage aspowdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution.

[0229] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage as powdered formulations a at a temperature ranging from about 2 °C to about 8 °C for at least 3 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at a temperature ranging from about 2 °C to about 8 °C for at least 3 months.

[0230] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 6 months prior to reconstitution.

[0231] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 9 months prior to reconstitution.

[0232] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage as powdered formulations at a temperature ranging from about 2 °C to about 8 °C for at least 12 months prior to reconstitution.

[0233] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 3 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 3 months prior to reconstitution.

[0234] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 6 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 6 months prior to reconstitution.

[0235] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 9 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%,about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 9 months prior to reconstitution.

[0236] In some embodiments, the formulations can comprise a detectable amount, but no more than about 15% of total impurities as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 12 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of total impurities as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 12 months prior to reconstitution.

[0237] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 3 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 3 months prior to reconstitution.

[0238] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 6 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 6 months prior to reconstitution.

[0239] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 9 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%,about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 9 months prior to reconstitution.

[0240] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of HMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 12 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of HMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 12 months prior to reconstitution.

[0241] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 3 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage at about 25 °C for at least 3 months.

[0242] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 6 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 6 months prior to reconstitution.

[0243] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 9 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1%of LMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 9 months prior to reconstitution.

[0244] In some embodiments, the formulations can comprise a detectable amount, but no more than about 10% of LMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 12 months prior to reconstitution. In some embodiments, the formulations can comprise no more than about about 9%, about 8.5%, about 8%, about 7.5%, about 7%, about 6.5%, about 6%, about 5.5%, about 5%, about 4.5%, about 4%, about 3.5%, about 3%, about 2.5%, about 2%, about 1.5%, or about 1% of LMW species as measured by HP-SEC after storage as powdered formulations at about 25 °C for at least 12 months prior to reconstitution.Methods of Treatment

[0245] The disclosure further provides a method of treating acute respiratory distress syndrome in a subject in need thereof by administering to the subject an effective amount of one of the reconstituted liquid aviptadil formulations described herein. In some embodiments, the effective amount of the reconstituted liquid aviptadil formulation can be administered intravenously or by inhalation.

[0246] The disclosure further provides a method of treating pulmonary sarcoidosis in a subject in need thereof by administering to the subject an effective amount of one of the reconstituted liquid aviptadil formulations described herein. In some embodiments, the effective amount of the reconstituted liquid aviptadil formulation can be administered intravenously or by inhalation.

[0247] The disclosure further provides a method of treating berylliosis in a subject in need thereof by administering to the subject an effective amount of one of the reconstituted liquid aviptadil formulations described herein. In some embodiments, the effective amount of the reconstituted liquid aviptadil formulation can be administered intravenously or by inhalation.

[0248] The disclosure further provides a method of treating checkpoint inhibitor-induced pneumonitis (CIP) in a subject in need thereof by administering to the subject an effective amount of one of the reconstituted liquid aviptadil formulations described herein. In some embodiments, the effective amount of the reconstituted liquid aviptadil formulation can be administered intravenously or by inhalation.EXAMPLES

[0249] These examples are provided for the purpose of illustration only and the embodiments described herein should in no way be construed as being limited to these examples. Rather, the embodiments should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.Example 1: Liquid formulations preparation and stability

[0250] Liquid aviptadil formulations and their preparation are exemplified below.Preparation

[0251] The aviptadil used in the preparation of the liquid formulations are shown in Table 1. The API was provided as solid acetate salt and in solution. Upon receipt, the drug substance (DS) was stored protected from light at -20 °C (aviptadil acetate salt) or 2 - 8 °C (GMP batch) until further use.

[0252] Table 1 : Description of starting aviptadil material.

[0253] 24 exemplary liquid aviptadil formulations are shown in Table 2. For formulation buffer (FB) preparation, all excipients except the surfactant were weighed into a beaker and completely dissolved in water (final volume: 200 ml) under gently stirring. pH was checked and adjusted with 1 M sodium hydroxide (NaOH) or 1 M hydrogen chloride (HC1). FBs were then transferred to volumetric flasks and filled to the final volume. After homogenization, all FBs were filtered through a bottleneck filter unit (0.22-pmpolyvinylidene fluoride (PVDF) membrane filter) and either stored at 2-8 °C for up to 2 weeks or frozen at -20 °C for use at later time points. The required amount of surfactant was added for each formulation buffer before freezing at -20 °C. The formulation buffers used to dissolve aviptadil did not contain any surfactant.

[0254] Table 2: Exemplary Formulations

[0255] For formulations F2 and F4-F24, 12.30 mg of aviptadil acetate salt was weighed and transferred (light-protected) into a beaker. The amount of aviptadil for formulations Fl and F3 were 6.13 mg and 24.54 mg, respectively. The DS was directly dissolved in pre-chilled formulation buffers (without surfactant) under gently swirling and covered with N2 as well. The target concentration for aviptadil in all the formulations besides Fl and F3 were 100 pg / ml (0.1 mg / ml) in a final volume of 100 ml per formulation. The pH of the formulations was checked, and no pH adjustment was necessary after complete dissolution of aviptadil.

[0256] The weight of the aviptadil acetate salt mDS was calculated as follows: cf = [NPC% x (Purity% / 100] / 100 m Aviptadil=CAviptadil X Vfinal cf = correction factor NPC%= net peptide content determined (82.4%) Purity% = purity determined by HPLC (system I) (98.9%) CAviptadil = final concentration of Aviptadil mAviptadii = mass of Aviptadil Vfinai = final volume

[0257] Under laminar air-flow conditions (LAF), the prepared formulations were filtered by using a 0.22-pm bottle top PVDF filter unit (Millex-GP, Millipore). Pre-filtered surfactants (through 0.22-pm syringe PVDF filter) were spiked into the appropriate formulations: 10% (v / v) PS80 stock solution) 20% (v / v) or pol oxamer 188 (PX188) stock solution were used for spiking. Subsequently, 2.5 ml of filtered DP (final formulation)was filled into 30 washed and sterilized 2R glass vials per formulation. The vials were carefully covered with N2, sealed with washed and sterilized rubber stoppers under LAF conditions and closed manually with aluminum caps.

[0258] The analytical time points and associated analytical methods to characterize stability of samples are summarized in Table 3. All 24 exemplary liquid formulations were characterized and stability was evaluated up to 6 weeks of storage at 2-8 °C, 25 °C, and 40 °C. The results of the stability study indicated promising results for peptide stability in 6 formulations. These formulation candidates were further investigated up to 6 months using analytical methods mentioned in Table 3. The letter “w” is used as an abbreviation for weeks and the letter “m” is used as an abbreviation for months.

[0259] Table 3: Overview of sampling time points, stress conditions and analytical methods.Visual Inspection

[0260] The vials of the exemplary liquid formulations were inspected for the presence or absence of visible particles under gentle, manual, radial agitation for 5 sec in front of a white background and for 5 sec in front of a black background according to the European Pharmacopoeia (10th edition; monograph 2.9.20) at 2,000 - 3,750 lux. The inspection was performed independently by two trained examiners. To classify the observed visible particles, a number score based on the “Deutscher Arzneimittel-Codex” (DAC 2006) was used, as listed in Table 4. Fiber-like structures and particles that are likely non-inherent to the product were not accounted for the number score used. The definition of “inherent particles” follows thereby the suggestions of USP chapter <1787>. Fiber-like structures, particles that are likely non-inherent, and additional sample attributes were documented.

[0261] Formulations at time=0 (TO) and up to 6 months (T6m) of storage at 2-8 °C, 25 °C, and 40 °C were visually inspected as discussed above. At TO, F1-F4, F8-F9, F13-F15, F18-F20, and F23-F24 contained no to few visible particles. Formulations F3, F13, and F14 showed an extrinsic, sporadic fiber. The follow-up observations up to 6 weeks of storage at 2-8 °C, 25 °C, and 40 °C revealed slight increase in visible particles in some of the formulations (F4, F7, Fl 8, and F22). After 14 weeks of storage at 2-8 °C and 25 °C, F12, F13, F15, F17, and F18 showed no further increase in visible particles. One visual inspector indicated that F 19 (stored at 2-8 °C) had a slight increase in visible particles. At T6m, F12, F13, F15, F17, F18, and F19 showed no further increase in visible particles. After 14 months of storage at 2-8 °C, F15, F17, F18, and F19 had low levels of visible particles. After 14 months of storage at 2-8 °C, F12 had medium levels of visible particles.Digital camera inspection (DCI)

[0262] Formulations in the vials were inspected in a setup with a camera and two LED light sources, one providing light from underneath (bottom light picture) and the other one light from behind (back light picture) the formulation. Formulations were turned and swirled gently in front of the camera and in total two pictures were taken, one photo with each light source switched on in turn. The following camera parameters were defined for the final setup:- Shutter time: 1 / 100 s- Aperature: F16- ISO: 100

[0263] DCI observations corresponded well to visual inspection results. No to low levels of visible particles were observed in Formulations F12, F13, F15, and F17 - F19 after 6 months of storage at 2-8 °C. Similarly, no to low levels of visible particles were observed in Formulation F15, F17, and F19 after 9 months of storage at 2-8 °C. Low to medium levels of visible particles were observed in F12, F15, F17, and F19 after 14 months of storage at 2-8 °C.Micro-Flow Imaging (MFI)

[0264] MFI measurements were conducted with an MFI-5200 particle analyzer system (ProteinSimple) equipped with a silane-coated high-resolution 100-pm SP3 flow cell.Particle concentrations per ml for sizes >2 pm, >5 pm, >10 pm, >25 pm were reported. The system was flushed with 2,000 pl water at a speed of 1 ml / min and the background illumination was subsequently optimized using formulation buffer.

[0265] All aviptadil samples were analyzed undiluted. A pre-run volume of 0.33 ml was followed by a sample run of 0.30 ml. Approximately 1,100 images were taken per sample. Between the measurements, the flow cell was cleaned with 5 ml water at a speed of 1 ml / min. MFI View System Software (MVSS) version 2-R2-6.1.20.1915 was used to perform the measurements and MFI View Analysis Suite (MVAS) software version 1.3.0.1007 was used to analyze the samples.

[0266] MFI was measured for all 24 formulations at TO and 6 weeks of storage at 2-8 °C, 25 °C, and 40 °C. At TO, low numbers of subvisible particles were detected in all analyzed formulations. Marginally higher level of subvisible particles (> 2 and > 5 pm in size) were observed in formulations F9 and F 12. Apart from F7 (T6w_40 °C) and F15 (T6w_2-8 °C), low levels of subvisible particles (> 2, > 5, > 10, and > 25 pm in diameter) were detected in all formulations independent of storage conditions. Cumulative subvisible particle concentrations [# / ml] of formulations F1-F24 stored at TO are shown in FIGs. 1A-1B.

[0267] Further MFI measurements were taken for formulations F12, F13, F15, F17, F18, and F19. Cumulative subvisible particle concentrations [# / ml] of formulations F12, F13, F15, F17, F18 stored at different storage conditions for 10 weeks, 14 weeks and 6 months are shown in FIGs. 2A-2B and 3. Formulations F12, F13, F15, F17, F18, and F19 showed a low level of subvisible particles (> 2, > 5, > 10, and > 25 pm in diameter) after storage at 2-8 °C and 25 °C for up to 6 months.

[0268] MFI measurements were taken for formulations F15, F17, and F19 after storage at 2-8 °C for 9 months and for formulations F12, F15, F17, and F19 after storage at 2-8 °C for 14 months. The results of these MFI measurements are shown in FIG. 4. Formulations F12, F15, F17, and F19 showed a low level of subvisible particles (> 2, > 5, > 10, and > 25 pm in diameter) after storage at 2-8 °C for up to 14 months.PH

[0269] The pH values of the formulations were measured with a calibrated pH meter (SevenEasy®, Mettler Toledo AG, Schwerzenbach, Switzerland) by using a normal ionic strength electrode (InLab® Micro) with temperature sensor. pH measurements wereperformed at room temperature. 200 pl of formulations were transferred into a 1.5-ml polypropylene tube for each measurement. The probe was thoroughly rinsed with water prior to every measurement.

[0270] All formulations met their target pH (± 0.1) at TO and up to 6 weeks of storage at 2-8 °C, 25 °C, and 40 °C, except for formulation F16. F16 had a pH of a 6.2, which was outside of its target range (6± 0.1), after storage at 40 °C for 6 weeks. The results of the pH measurements are shown in Table 4 and Table 5. Further pH measurements were obtained for F12, F13, F15, F17, F18, and F19 after storage for 10 weeks, 14 weeks, and 6 months at 2-8 °C and 25 °C. These pH measurements are presented in Table 6 - Table 8. No substantial changes in pH were detected after 6 months irrespective of storage conditions and all selected formulations met their target pH.

[0271] pH measurements were obtained for F15, 17, and F19 after 9 months of storage at 2-8 °C and for F12, F15, F17, and F19 after 14 months of storage at 2-8 °C. No distinguishing changes in pH were detected after 14 months of storage and all selected formulations met their target pH.

[0272] Table 4: pH values of formulations Fl - F24 at TO and storage at different storage conditions for 2 weeks.

[0273] Table 5: pH values of formulations Fl - F24 at TO and storage at different storage conditions for 6 weeks.

[0274] Table 6: pH values of selected formulation candidates at TO and at different storage condition for 10 weeks.

[0275] Table 7: pH values of selected formulation candidates at TO and at different storage condition for 14 weeks.

[0276] Table 8: pH values of selected formulation candidates at TO and at different storage condition for 14 months.Osmolality

[0277] Osmolality of the samples was measured by method of freezing-point depression using a Gonotec Osmomat 3000 (Gonotec). 50 pl samples were transferred into a 0.5-ml polypropylene tube (Eppendorf) and directly measured. Osmolality was measured at TO for all 24 formulations. Osmolality was measured for F12, F13, F15, F17, F18, and F19 after 6 months of storage at 2-8 °C and 25 °C.

[0278] No target osmolality range was defined for the formulations. At TO, the measured osmolality values of formulations Fl to F18 were within a range of 307-400 mOsmol / kg (Table 9). Formulations F19 to F22 showed a higher osmolality at around 670 mOsmol / kg due to the high concentration of 10% mannitol or 10% sorbitol. Osmolality values of formulations F23 and F24 were 132 and 133 mOsmol / kg, respectively. Osmolality values of F12, F13, F15, F17, F18, and F19 after 6 months of storage at 2-8 °C and 25 °C are shown in Table 10. Osmolality values of Fl 5, Fl 7, and F19 after 9 months of storage at 2-8 °C and osmolality values of F12, F15, F17, and F19 after 14 months of storage at 2-8 °C are also shown in Table 10. Regardless of storage conditions, no major differences in osmolality values were observed compared to TO.

[0279] Table 9: Osmolality [mOsmol / kg] of formulations Fl - F24 at TO.

[0280] Table 10: Osmolality [mOsmol / kg] of F12, F13, F15, F17, F18, and F19 after storage at different storage conditions after up to 14 months.Reverse phase high performance liquid chromatography (RP-UPLC)

[0281] RP-UPLC was performed on the formulations using the following parameters and gradient as shown in Table 11 :■ Instrument: Water Acquity UPLC Lclass plus Bio system■ Column: Hypersil Gold C18, 2.1 x 10 mm, 1.9 pm, 175 A■ Flow rate: 0.50 ml / min■ Mobile phases: Mobile phase A: 95% (v / v) water, 5% (v / v) acetonitrile (ACN) + 0.02% (v / v) trifluoroacetic acid (TFA); Mobile phase B: 80% (v / v) ACN, 20% (v / v) water + 0.02% (v / v) TFA; Purge: 50% (v / v) water, 50% (v / v) ACN; Needle wash: 50% (v / v) water, 50% (v / v) ACN■ Detection: UV at 215 nm■ Data rate: 40 Hz■ Column oven: 55 °C■ Sample cooling: 8 ± 3 °C■ Injection volume: 20 pl■ Analysis time: 30 min■ Expected RT: 8.16 min■ Integration range: 5 - 11 min

[0282] Table 11 : Gradient setting of the mobile phases for RP-UPLC.

[0283] The mobile phase was prepared as follows: one liter mobile phase A was prepared by mixing 50 ml of ACN with 950 ml of water and 200 pl of TFA. One liter mobile phase B was prepared by mixing 800 ml of ACN with 200 ml of water and 200 pl TFA. 200 pl of polysorbate 80 was dissolved in 1,000 ml of water. Prior to sample analysis, the performance of the RP-UPLC column was tested with VIP reference standard (GMP batch) which was prepared with the formulations and was stored at -80 °C.

[0284] The RP-UPLC method was performed to quantify impurities and degradation products of the aviptadil peptide in different formulations. The relative main peak areas as measured by RP-UPLC of all formulations showed slight decrease after storage for up to 6 weeks at 2-8 °C, while the highest relative main peak areas (> 97.5 %) were obtained in Fl, F2, F3, F6, F7, F9, F12, F15, F17, and F19. However, substantial reduction in relative main peak areas was observed for all formulations after storage up to 6 weeks at 25 °C and 40 °C.

[0285] Formulations without 25 mM methionine (F1-F5, F8, F9, F23, and F24) showed increased values of methionine oxidation and formulations with histidine buffer (F4, F8,Fl 1, F16, F20, F22) or EDTA (F8, F9, F23, F24) also showed increased values of methionine oxidation. Relative main peak areas and relative peak areas of methionine oxidation, degradation peak 1, and degradation peak 2 for all formulations after storage for up to 6 weeks are presented in Table 12. Degradation peaks 1 and 2 could not be resolved in samples stored at 40 °C. Relative content of total impurities of all formulations also are presented in Table 12.

[0286] Table 12: Summary of RP-UPLC results for formulation F1-F24 at different storage conditions for storage up to 6 weeks.

[0287] Formulations F12, F13, F15, F17, F18, and F19 with highest relative main peak areas, as measured in RP-UPLC, after storage for up to 6 weeks were further evaluated up to 6 months of storage at 2-8 °C and 25 °C. Fl 5, F 17 and F19 showed the highest relative main peak areas (> 95%), after storage at 2-8 °C for up to 6 months. F18 revealed a significant reduction in relative main peak area (49%), as determined by the relative main peak areas measured in RP-UPLC, upon storage at 25 °C for up to 6 months. F17 showed the highest relative main peak area (> 95%) after 14 months of storage at 2-8 °C. Relative peak areas of methionine oxidation, degradation peak 1 and degradation peak 2 for the selected formulations at 6 months, 9 months, and 14 months of storage are presented in Table 13. Relative content of total impurities of the selected formulations are also presented in Table 13.

[0288] Table 13: Summary of RP-UPLC results for formulation F12, F13, F15, F17, F18, and F 19 at different storage conditions for storage up to 14 months.Example 2: Lyophilized aviptadil formulations and sample characterization

[0289] Exemplary lyophilized aviptadil formulations and their preparation are shown below. The composition of the exemplary formulations are shown in Table 14-25. All formulations prior to lyophilization were prepared according to the methods described in Example 1.

[0290] Table 14: Fl-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0291] Table 15: F2-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0292] Table 16: F3-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0293] Table 17: F4-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0294] Table 18: F5-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0295] Table 19: F6-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0296] Table 20: F7-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0297] Table 21 : F8-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0298] Table 22: F9-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0299] Table 23: FlO-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0300] Table 24: Fl 1-Lyo Formulation.* Prior to lyophilization** Overfill not included

[0301] Table 25: F12-Lyo Formulation.* Prior to lyophilization** Overfill not includedLyophilization

[0302] Lyophilization of these formulations was performed with and without annealing steps according to the processes described in Tables 26 and 27.

[0303] Table 26: Lyophilization process with annealing.*Approximate time

[0304] Table 27: Lyophilization process without annealing.* Approximate time

[0305] Primary drying (PD) was finished after approximately 55 hours for Formulations 1-12 with the exception for F8 (Table 28). Product temperature roughly 20 hours into PD was below critical temperature for all formulations with the exception of F8-F10.

[0306] Table 28: Product and Glass Transition temperature after Primary Drying step of Lyophilization.

[0307] The analytical time points and associated analytical methods to characterize stability of samples are summarized in Table 29 and performed as described in Example 1. All formulations were characterized and stability was evaluated up to 2 months of storage at 2-8 °C, 25 °C and 40 °C. 4 formulations were further evaluated up to 6 months of storage at 2-8 °C, 25 °C and 40 °C and discussed in Example 3.

[0308] Table 29: Overview of sampling time points, storage conditions and analytical methods* 1: Sample aliquots will be stored at < -70 °C and analyzed in a common sequence at the T-Lyo-2m time point (if the SEC method is operational at T-Lyo-2m).Visual Inspection

[0309] Visual inspection was conducted at TO for Fl-Lyo - F12-Lyo before and after lyophilization. Visual inspection was performed as described in Example 1. Fl-Lyo, F3- Lyo, F5-F7-Lyo, and F9-F12-Lyo contained no visible particles prior to lyophilization. F2-Lyo, F4-Lyo, and F8-Lyo contained a few particles. The lyophilized formulations at T=0 were reconstituted in 0.9% NaCl. Fl-Lyo, F3-Lyo, F5-Lyo-F7-LYo, F9-Lyo-F12- Lyo contained no or few visible particles. The first reconstituted vials of F2-Lyo and F8- Lyo at T=0 Lyo had a small number of visible particles, whereas, the second reconstituted vials of F2 and F8 only contained a few visible particles. The lyophilized formulations stored at 2-8 °C were reconstituted in 0.9% NaCl. F2-Lyo, F3-Lyo, F4-Lyo, F7-Lyo, F10- Lyo and F12-Lyo contained no visible particles. Fl-Lyo, F5-Lyo, F6-Lyo, F8-Lyo, F9- Lyo and Fl 1-Lyo contained few visible particles. The lyophilized formulations stored at 25 °C were reconstituted in 0.9% NaCl. F2-Lyo, F3-Lyo, F5-Lyo, F7-Lyo, F9-Lyo, and F12-Lyo contained no visible particles. Fl-Lyo, F4-Lyo, F6-Lyo, FlO-Lyo and Fl 1-Lyo contained few visible particles. The lyophilized formulations stored at 40 °C were reconstituted in 0.9% NaCl. All formulations with the exception of FlO-Lyo contained no visible particles. FlO-Lyo contained few visible particles.Optical Appearance

[0310] In addition to the analytical methods described in Table 29, optical appearance of each lyophilized formulation was observed. Lyophilized formulations had overall good optical appearance, cylindrical shape, white color and had a dense structure. Adherence to the vial wall and bottom of the vial was observed for F8-Lyo. Minor shrinkage was observed in all formulations (Table 30). Formulations F4-Lyo and F6-Lyo also showedshrinkage at the bottom of the vials. Minor dents were observed at the vial bottom for formulations, Fl-Lyo, F4-Lyo, Fl 1-Lyo, and F12-Lyo. F5-Lyo had small dents at the surface and F2-Lyo, F8-Lyo and FlO-Lyo had minor dents at the surface.

[0311] Table 30: Shrinkage of lyophilized formulations Fl-F12-Lyo.Differential scanning calorimetry (DSC)

[0312] The glass transition temperatures for the lyophilized formulations were measured by differential scanning calorimetry (DSC). Samples were immediately cooled from 25 °C to 0 °C at a rate of -10 K / min, held at 0 °C for 5 minutes, heated from 0 °C to 110 °C at 10 K / min, cooled from 110 °C to 0 °C at -10 K / min, held at 0 °C for 5 minutes, and then heated from 0 °C to 180 °C at 10 K / min. The glass transition temperatures for the lyophilized formulations were measured after a 2ndheating scan. Tg < 62 °C was observed for sucrose- and mannitol-containing formulations. Tg of - 100 °C was observed for formulations containing single sugar moiety of trehalose or lactose (Table 31). At T2m, Tg < 62 °C was observed for sucrose- and mannitol-containing formulations and Tg of - 100 °C was observed for formulations containing a single sugar moiety of trehalose or lactose at all storage conditions (Table 31).

[0313] Table 31: DSC solid glass transition temperatures.MFI

[0314] Low levels of subvisible particles were detected in all 12 formulations at T=0 Liq and T=0 Lyo. Results are presented in FIGs. 6A-6D. Subvisible particle levels at T=0 Liq were in the following ranges: > 2 pm: 15 - 251 # / ml, > 5 pm: 0 - 73 # / ml, > 10 pm: 0 - 39 # / ml and > 25 pm: 0 - 27 # / ml. Subvisible particle levels at T=0 Lyo were in the following ranges: > 2 pm: 148 - 736 # / ml, > 5 pm: 15 - 142 # / ml, > 10 pm: 0 - 30 # / ml and > 25 pm: 0 - 6 # / ml. Subvisible particle levels at T=Lyo 2m 2-8 °C were in the following ranges: > 2 pm: 276 - 1645 # / ml, > 5 pm: 25 - 276 # / ml, > 10 pm: 4 - 19 # / ml and > 25 pm: 0 - 4 # / ml. Subvisible particle levels at T=Lyo Im 25 °C were in the following ranges: > 2 pm: 73 - 545 # / ml, > 5 pm: 3 - 82 # / ml, > 10 pm: 0 - 27 # / ml and > 25 pm: 0 - 4 # / ml. Subvisible particle levels at T=Lyo 2m 25 °C were in the following ranges: > 2 pm: 191 - 1064 # / ml, > 5 pm: 10 - 134 # / ml, > 10 pm: 0 - 58 # / ml and > 25 pm: 0 - 7 # / ml. Subvisible particle levels at T=Lyo Im 40 °C were in the following ranges: > 2 pm: 76 - 345 # / ml, > 5 pm: 0 - 36 # / ml, > 10 pm: 0 - 18 # / ml and > 25 pm: 0 - 6 # / ml. Subvisible particle levels at T=Lyo 2m 40 °C were in the following ranges: > 2 pm: 173 - 879 # / ml, > 5 pm: 13 - 97 # / ml, > 10 pm: 0 - 16 # / ml and > 25 pm: 0 - 7 # / ml.Reconstitution time and foam levels

[0315] Formulations were reconstituted with 2 mL of 0.9% NaCl solution. Reconstitution times less than 1 minute were observed for Fl-Lyo - F7-Lyo and Fl 1-12-Lyo with moderate foaming at T-Lyo-0. Formulations F8-Lyo - FlO-Lyo had a reconstitution timegreater than 4 minutes and no foam was observed at T-Lyo-0. FIGs. 5A-5B show the reconstitution time and foam levels at different storage conditions.Moisture Content

[0316] Moisture content was determined using Karl -Fischer’s test which directly measured the water in a sample. The measurement temperature was determined by a temperature ramp from 50 °C to 175 °C. All formulations were measured at 120 °C with the exception of F6-Lyo and F7-Lyo, which were measured at 110 °C. The highest levels of moisture content was observed in F9-Lyo and FlO-Lyo at TO with over 1.2%. FIG. 7 shows the moisture content of the exemplary formulations as measured using Karl- Fischer’s test. pH measurements

[0317] pH measurements were conducted as discussed in Example 1 with the lyophilized formulations reconstituted in 2 mL of 0.9% NaCl solution. With the exception of F5 and F9 in the T=0 liq, which had pH values above the target range of 5.5 ± 0.1, the rest of the formulations were within the target range. At T=0 Lyo, pH values of all formulations were within the target range. The pH was higher in histidine-containing formulations Fl- Lyo, F2-Lyo, F3-Lyo, F4-Lyo, F6-Lyo, F7-Lyo, F8-Lyo and F9-Lyo and lower for the citrate-containing formulations Fl 1-Lyo and F12-Lyo (Table 32). After 2 months of storage, lyophilization formulations Fl -Lyo - F12-Lyo had comparable pH measurements to T=0 Lyo (Table 33).

[0318] Table 32: Comparison of the pH of the lyophilized formulations at different storage conditions for storage up to 2 months.

[0319] Table 33: Comparison of the pH of the lyophilized formulations for storage up to2 months at 40 °C.RP-UPLC

[0320] RP-UPLC was performed on the Waters Acquity UPLC I-class plus Bio system using the following parameters:- PDA detector with analytical cell (UV detection at 215 nm) Column: Hypersil Gold C18, 2.1 x 10 mm, 1.9 pm, 175 A 50 pl sample loopInjection volume: 20 pl (0.05 mg / ml for T=0 Liqu / SST samples and 0.03 mg / ml for T=0 Lyo samples)Flow rate: 0.5 ml / min- Mobile phase A: 95% (v / v) water, 5% (v / v) acetonitrile (ACN) + 0.1% (v / v) trifluoroacetic acid (TFA)- Mobile phase B: 80% (v / v) ACN, 20% (v / v) water + 0.1% (v / v) TFA- Purge: 50% ACN- Needle wash: 50% ACNSeal wash: 10% MeOHIntegration: 5.0 -11.0 min

[0321] VIP purity, as determined by the relative main peak areas measured by RP-UPLC, was greater than 98% for all T=0 Liq and T=0 Lyo samples except for F4 and F 12 at T=0 Lyo (Table 34). Highest levels of methionine oxidation of greater than 0.4% were observed in F4 at T=0 Lyo and F12 at and T=0 Lyo (Table 34). No clear changes in levels of degradation peak 1 and peak 2 were observed for all formulations between T=0 Lyo and T=0 Liq. Total content of impurities was comparable in all formulations except F7- lyo at 40 °C which had increased to 24% after 1 month and 33% after 2 months (Table 35).

[0322] Table 34: Comparison of the relative main peak areas as measured by RP-UPLC in the lyophilized formulations.

[0323] Table 35: Comparison of the relative peak areas of methionine oxidation as measured by RP-UPLC in the lyophilized formulations.

[0324] Table 36: Comparison of a total content of impurities including degradation peaks in the lyophilized formulations as measured by RP-UPLC.Example 3: Sample characterization of select lyophilized formulations after 3-6 months in storage.

[0325] Formulations Fl-Lyo, F2-Lyo, F5-Lyo and Fl 1-Lyo of Example 2 were further characterized after 3 months (T3m) and 6 months (T6m) of storage. Measurements and characterization were all conducted as described in Examples 1 and 2.Visual Inspection

[0326] Visual inspection was conducted on reconstituted lyophilized formulations Fl- Lyo, F2-Lyo, F5-Lyo, and Fl 1-Lyo at T6m_2-8 °C and T6m_25 °C as previously described. There were no to low levels of visible particles observed at T3m independent of formulation composition and storage condition. No distinguishable changes of visible particles was observed for all formulations at T3m compared to previous time points. There was an increase in visible particles observed for Fl-Lyo and F5-Lyo at T6m_2-8 °C. No distinguishable changes of visible particles was observed for F2-Lyo and Fl 1-Lyo compared to previous time points.Optical Appearance

[0327] Lyophilized formulations had overall good optical appearance, cylindrical shape, white color and had a dense structure at T6m_2-8 °C and T6m_25 °C. No adherence to the vial wall and bottom of the vial was observed. Minor shrinkage was observed in all formulations. Cracks were observed for Fl-Lyo T6m_25 °C.Differential scanning calorimetry (DSC)

[0328] The glass transition temperatures of the lyophilized formulations were also determined by differential scanning calorimetry (DSC). Tg values between approximately 99-106 °C were observed at T3m after storage at 2-8 °C, with slightly lower Tg values observed at elevated temperatures (Table 37).

[0329] Table 37: DSC solid glass transition temperatures.MFI

[0330] MFI was measured for all reconstituted lyophilized formulations Fl-Lyo, F2-Lyo, F5-Lyo and Fl 1-Lyo after 3 months and 6 months of storage at 2-8 °C, 25 °C, and 40 °C (FIGs. 6A-6D). Overall low subvisible particle levels observed after 3 months, irrespective of formulation composition and storage conditions. Increase in subvisible particles was observed in all formulations at 6m at 2-8 and 25 °C.Reconstitution time

[0331] Formulations were reconstituted with 2 mL of 0.9% NaCl solution. All formulations had fast reconstitution time less than 40 seconds at T6m (Table 38). No distinguished changes of reconstitution time observed at elevated temperatures and compared to previous time points (Table 38).

[0332] Table 38: Reconstitution time and foam levels for lyophilized formulations Fl- Lyo, F2-Lyo, F5-Lyo and Fl 1-Lyo at T6m_2-8 °C and T6m_25 °C.Moisture Content

[0333] Moisture content was determined using Karl -Fischer’s test and ranged between 0.28% and 0.77% at T3m_2-8 °C, 0.51% and 1.01% at T3m_25 °C, 0.87% and 1.41% at T3m_40 °C, 0.5% and 1.0% at T6m_2-8 °C and between 0.80% and 1.20% at T6m_25 °C. Moisture content increased at elevated temperatures. The highest levels of moisture content was observed in the citrate-containing formulation, Fl 1-Lyo, at T6m_25 °C and T3m_40 °C which was over 1.1% (FIG. 7).PH

[0334] Target pH value of 5.5 ± 0.1 was met by F5-Lyo at T6m. F 1-Lyo and F2-Lyo stored at 2-8 °C were exceeding the target range. The pH values of Fl 1-Lyo at different storage conditions were below target range (Table 39).

[0335] Table 39: pH values of lyophilized formulations Fl-Lyo, F2-Lyo, F5-Lyo and Fl 1-Lyo at different storage conditions at 6 weeks.RP-UPLC

[0336] Relative main peak areas of > 97% as measured by RP-UPLC were observed for all formulations after storage up to 6 months, with the exception of Fl-Lyo (Table 40). A slight temperature and time-dependent decrease of peptide relative main peak areas (measured by RP-UPLC) was observed for all formulations after 6 months of storage as compared to after 3 months.

[0337] Table 40: Relative main peak area [%] comparison in the lyophilized formulations.

[0338] A temperature and time dependent increase in methionine oxidation was also observed in all formulations (Table 41).

[0339] Table 41 : Methionine oxidation peak area [%] in the lyophilized formulations.

[0340] Fl-Lyo (at 2-8 °C and 25 °C) and Fl 1-Lyo (at 2-8 °C) had higher values of total impurities (Table 42). There were no distinguished changes observed in other formulations between 3 and 6 months.

[0341] Table 42: Relative content of total impurities [%] in the lyophilized formulations.Example 4: Lyophilization of selected formulations and sample characterization

[0342] Variants of formulations F2-Lyo, F5-Lyo, and Fl 1-Lyo were prepared prior to lyophilization according to the methods described in Example 1 and lyophilized according to the methods described in Example 2. The composition of the variants of formulations F2-Lyo, F5-Lyo, and Fl 1-Lyo are provided in Tables 43-53. The following quality parameters were tested:• Optical appearance• Moisture content by Karl-Fischer• Reconstitution time• Visual inspection (particulate matter after reconstitution)• pH• Osmolality• Subvisible particles• Aviptadil (VIP) purity• Relative main peak area by RP-UPLC• Methionine oxidation product (Met(O))• Total Impurities

[0343] Critical quality attributes for storage stable formulations are:• Purity• Degradation• Absence of visible particles• Absence of non-visible particles• Reconstitution time• Stability in solution• Absence of aggregates and truncation (no information available to date, due to unavailability of a suitable analytical method)• Water content• Glass transition temperature

[0344] Table 43 : F2-Lyo-A Formulation.* Prior to lyophilization** Overfill not included

[0345] Table 44: F2-Lyo-B Formulation.* Prior to lyophilization** Overfill not included

[0346] Table 45: F2-Lyo-C Formulation.* Prior to lyophilization** Overfill not included

[0347] Table 46: F5-Lyo-A Formulation.* Prior to lyophilization** Overfill not included

[0348] Table 47: F5-Lyo-B Formulation.* Prior to lyophilization** Overfill not included

[0349] Table 48: F5-Lyo-C Formulation.* Prior to lyophilization** Overfill not included

[0350] Table 49: Fl 1-Lyo-A Formulation.* Prior to lyophilization** Overfill not included

[0351] Table 50: Fl 1-Lyo-Aa Formulation.* Prior to lyophilization** Overfill not included

[0352] Table 51 : Fl l-Lyo-Ab Formulation.* Prior to lyophilization** Overfill not included

[0353] Table 52: Fl 1-Lyo-B Formulation.* Prior to lyophilization** Overfill not included

[0354] Table 53: Fl 1-Lyo-C Formulation.* Prior to lyophilization** Overfill not included

[0355] Tests that demonstrated differences between the formulation variants include reconstitution times, visual inspection, moisture content, micro-flow imaging, relative main peak area as measured by RP-UPLC, and stability in solution. Results are discussed below.Visual inspection

[0356] Visual inspection was performed on the formulations as part of the liquid stability studies (up to 3 months at 2-8°C and 25°C / 60%RH). Low to medium levels of visible particles were observed at the 2 months’ time point in most formulations. After storage for 2 months at 2-8°C, high levels of visible particles were observed in F2-Lyo-B, F2- Lyo-C, Fl 1-Lyo-A, and Fl 1-Lyo-C. After storage at 2 months 25°C / 60%RH, high levels of visible particles were observed in F5-Lyo-B, Fl 1-Lyo-A, Fl 1-Lyo-Aa and Fl 1-lyo-C. Similar results were observed at the 3 months’ time point. The results provide an- I l l - indication that the citrate buffered (Fl 1) solutions have an increased tendency of particle formation.Optical appearance

[0357] The optical appearance of all formulations after 3 months of stability at 2-8°C and 25°C / 60%RH was determined. Lyophilized formulations had overall good optical appearance, cylindrical shape, white color and had a dense structure. Minor shrinkage observed for all formulations at T-Lyo-2m, irrespective of storage conditions. Cracks and minor dents observed for some formulations. Optical cake appearance was retained at T- Lyo-3m irrespective of the storage conditions. At 25°C, minor shrinkage was observed for all formulations, except for F2-Lyo-B and F2-Lyo-C. No distinguishable differences were observed between different formulation variants and storage conditions.Differential scanning calorimetry (DSC)

[0358] Glass transition temperature (Tg) was determined by differential scanning calorimetry (DSC). Tg ranging between 76 °C - 115 °C was observed at T-Lyo-2m across all storage conditions and Tg values ranging between 85 °C - 113 °C were observed at T- Lyo-3m across all storage conditions (Table 54). High and comparable Tg values were observed for formulation variants of F2-Lyo and F5-Lyo, except for F2-Lyo-A after 2 months of storage at 40 °C. Lower Tg was observed for citrate-containing formulation variants of Fl 1-Lyo. Across all formulations, there was a general temperature dependent decrease of Tg (Table 54).

[0359] Table 54: DSC solid glass transition temperatures.MFI

[0360] Low levels of subvisible particles were observed for almost all formulation variants at T-Liq-3m, except formulation Fl 1-Lyo-C. Results are presented in FIG. 10A- D.Reconstitution time

[0361] Results of reconstitution time testing are provided in Tables 55 and 56.

[0362] Table 55: Reconstitution times for the variants of lyophilized formulations F2, F5, and Fl 1 at different storage conditions.

[0363] Table 56: Reconstitution times for the variants of lyophilized formulations F2, F5, and Fl 1 after 3 months at different storage conditions.Moisture Content

[0364] Moisture content was determined using Karl -Fischer’s test which directly measured water in a sample. The measurement temperature was determined by a temperature ramp from 50 °C to 175 °C. All formulations were measured at 120 °C. The highest levels of moisture content was observed in Fl 1-Lyo variants. FIG. 11 shows the moisture content of the exemplary formulations as measured using Karl -Fischer’s test.RP-VPLC

[0365] The formulations all had relative main peak areas of greater than 96% across all storage conditions with the exception of Fl 1-Lyo- A, which had roughly 93% across all storage conditions, tabulated results are presented in FIGs. 8A-8D and 12A-12F. Less than 1% methionine oxidation was observed in all reconstituted formulations except for Fl 1-Lyo-A. Fl 1-Lyo- A also had the most total impurities ranging from 6-10% (FIGs. 8C and 12E).Stability in solution Results

[0366] Stability of the variants of F2, F5 and Fl 1 as liquids (non-lyophilized products) was also evaluated based on the relative main peak areas measured by RP-UPLC. The results are provided in Tables 57-61. The results demonstrated that the non-buffered F5 formulations are not as stable as the other formulations. The Fl 1 formulations Fl 1-Lyo- Aa, Fl 1-Lyo- Ab, and Fl 1-Lyo-B, demonstrated comparable solution stability as F2-Lyo- A and F2-Lyo-B. The 200pg / ml product Fl 1-Lyo-C has decreased stability compared to the 200pg / ml product F2-Lyo-C.

[0367] Table 57: Percent relative main peak area in samples of formulations containing lyophilization excipients kept in liquid state.

[0368] Table 58: Percent relative content of total impurities in samples of formulations containing lyophilization excipients kept in liquid state

[0369] Table 59: Percent methionine oxidation in samples of formulations containing lyophilization excipients kept in liquid state

[0370] Table 60: Percent of degradation 1 peak in samples of formulations containing lyophilization excipients kept in liquid state

[0371] Table 61 : Percent of degradation 2 peak in samples of formulations containing lyophilization excipients kept in liquid stateExample 5: Additional lyophilized aviptadil formulations

[0372] Additional exemplary lyophilized aviptadil formulations were prepared prior to lyophilization according to the methods described in Example 1 and lyophilized according to the methods described in Example 2. The composition of the exemplary formulations are shown in Tables 62-63. The same exemplary formulations were also made with only water for reconstitution instead of a saline solution. All formulations were prepared according to the methods described in Examples 1 and 2.

[0373] Reconstitution of formulations with 300 pg / ml and 400 pg / ml of Aviptadil with 2.5 ml of 0.9% NaCl resulted in the formation of fibers rendering these formulations unsuitable for use. Fiber formation was reduced when formulations with 300 pg / ml and 400 pg / ml of Aviptadil were reconstituted with 5 ml of 0.9% NaCl. Surprisingly, when formulations with 300 pg / ml and 400 pg / ml of Aviptadil were reconstituted with water instead, these fibers were formed to a lesser extent.

[0374] For administration by nebulization, formulations were reconstituted with 2 mL of 0.9% NaCl solution or water. Reconstitution of formulations with 300 pg / ml and 400 pg / ml of Aviptadil with 2 mL of 0.9% NaCl resulted in the formation of fibers rendering these formulations unsuitable for use. Surprisingly, formulations with increased Aviptadil concentration of 300 pg / ml and 400 pg / ml that were reconstituted with water formed fibers to a lesser extent.

[0375] Table 62: F2-Lyo-D Formulation.* Prior to lyophilization** Overfill not included

[0376] Table 63: F2-Lyo-E formulation.* Prior to lyophilization** Overfill not included

[0377] Formulations F2-Lyo-D and F2-Lyo-E were further characterized based on the protocols described in Examples 1 and 2.Visual Inspection

[0378] Visual inspection was conducted on formulations F2-Lyo-D and F2-Lyo-E at TO as previously described. There were no to low levels of visible particles observed at T- Liq-0 (prior to lyophilization). There were low levels of visible particles observed at T- Lyo-0 (after lyophilization). There were no to low levels of visible particles observed after reconstitution (TO) at 2-8 °C and 25 °C. No distinguishable changes of visible particles was observed for F2-Lyo-D after storage at 2-8 °C and 25 °C for 24 hours. Medium levels of visible particles were observed for F2-Lyo-E after storage for 24 hours.

[0379] No visible particles were observed at T-Lyo-6w. Phase separation was observed for both formulation variants by one visual inspector.Optical Appearance

[0380] Lyophilized formulations had overall good optical appearance, cylindrical shape, white color and had a dense structure at TO and T-Lyo-6w. No adherence to the vial wall and bottom of the vial was observed. Minor shrinkage was observed in both formulations.Differential scanning calorimetry (DSC)

[0381] The glass transition temperatures of the lyophilized formulations were also determined by differential scanning calorimetry (DSC). The glass transition temperatures are shown in Table 64.

[0382] Table 64: DSC solid glass transition temperatures.MFI

[0383] MFI was measured at T-Liq-0, T-Lyo-0, and T-Lyo-6w at 25 °C. Overall low subvisible particle levels observed for both formulations before and after lyophilization as shown in Tables 65-68.

[0384] Table 65: MFI subvisible particle size > 2 pm [# / ml]

[0385] Table 66: MFI subvisible particle size > 5 pm [# / ml]

[0386] Table 67: MFI subvisible particle size > 10 pm [# / ml]

[0387] Table 68: MFI subvisible particle size > 10 pm [# / ml]Reconstitution time

[0388] Formulations were reconstituted with 2 mL of 0.9% NaCl solution. All formulations had fast reconstitution time and moderating foaming at T-Lyo-0 and T-Lyo- 6w as shown in Table 69.

[0389] Table 69: Reconstitution time and foam levels for lyophilized formulations F2- Lyo-D and F2-Lyo-E at T-Lyo-0 and T-Lyo-6w.Moisture Content

[0390] Moisture content was determined using Karl -Fischer’s test. Residual moisture content was 0.2% or lower for both F2-Lyo-D and F2-Lyo-E at T-Lyo-0 as shown in Table 70. Residual moisture content was 0.3% for both F2-Lyo-D and F2-Lyo-E at T- Lyo-6w at 25 °C as shown in Table 70.

[0391] Table 70: Residual moisture content for lyophilized formulations at T-Lyo-0.PH

[0392] Target pH value of 5.5 ± 0.1 was met by F2-Lyo-D and F2-Lyo-E formulations before lyophilization. After lyophilization, F2-Lyo-D and F2-Lyo-E formulations had a pH of 5.7 as shown in Table 71.

[0393] Table 71 : pH values of F2-Lyo-D and F2-Lyo-E formulations at TO.Osmolality

[0394] No target osmolality range was defined for the formulations. At T-Liq-0, the measured osmolality values of formulations F2-Lyo-D and F2-Lyo-E were 358 mOsmol / kg and 357 mOsmol / kg, respectively. Higher osmolality values at T-Lyo-0 were observed due to the reconstitution medium (0.9% NaCl) as shown in Table 72.

[0395] Table 72: Osmolality [mOsmol / kg] of F2-Lyo-D and F2-Lyo-E formulations at TO.RP-UPLC

[0396] Relative main peak areas of > 97% as measured by RP-UPLC were observed for both F2-Lyo-D and F2-Lyo-E formulations at T-Liq-0 and T-Lyo-0 as shown in Table 73. Highest relative Met(O) peak area of 0.58% was observed in F2-Lyo-D at T-Lyo-0. No distinguished changes in level of degradation peaks 1 and 2 were observed after lyophilization compared to before lyophilization.

[0397] Relative main peak areas and relative peak areas of methionine oxidation, degradation peak 1 and degradation peak 2 for F2-Lyo-D and F2-Lyo-E formulations at TO are presented in Table 73. Relative content of total impurities of the selected formulations are also presented in Table 73.

[0398] Table 73: Summary of RP-UPLC results for formulations F2-Lyo-D and F2-Lyo- E at TO and T-Lyo-6w_25°C.Example 6: Additional characterization of select formulations

[0399] Select exemplary aqueous and lyophilized aviptadil formulations were further characterized. The select exemplary lyophilized formulations were reconstituted with a saline solution. All formulations were prepared according to the methods described in Examples 1 and 2.

[0400] High performance size-exclusion chromatography (HP-SEC) was performed on the formulations using the following parameters:

[0401] Instrument: Dionex 3000 bio-inert with Ultimate 3000 UV Detector VWD

[0402] Loop: 100 pl

[0403] Column: Cytiva Superdex 30 increase 10 / 300 GL

[0404] Detection: UV absorption at 215 nm, 280 nm

[0405] Column temperature: n.a.

[0406] Sample cooling: 5±3 °C

[0407] Flow rate: 0.5 ml / min

[0408] Run time: 50 min

[0409] Detection: UV at 215 nm

[0410] Mobile phase: 40 mM sodium phosphate, 160 mM sodium sulphate, pH 6.8, 20% ACN

[0411] Needle wash: 20% MeOH

[0412] Seal wash: 20 % EtOH

[0413] Sample concentration: from 0.1 to 0.4 mg / ml VIP

[0414] Injection volume: from 25 to 100 pl (10 pg of VIP injected)

[0415] HP-SEC data for select F2, F5, and Fl 1 formulations, incl. variants is shown inTables 74-79 below. F2-Lyo-C demonstrated both liquid and lyophilized stability. F5- Lyo-C also demonstrated good stability after storage at 25 °C for 6 months. Fl 1-Lyo-A, both in liquid and lyophilized form, exhibited the highest relative area for high and low molecular weight species. Without being bound to any particular theory, it is believed that solubility of the VIP was an issue as the main peak was low in these formulations.

[0416] Table 74: Relative main peak areas (%) as measured by HP-SEC

[0417] Table 75: Relative HMW species peak areas (%)

[0418] Table 76: Relative LMW species peak areas (%)

[0419] Table 77: Absolute main peak areas [m AU* sec] as measured by HP- SEC

[0420] Table 78: Absolute HMW species peak areas [mAU*sec]

[0421] Table 79: Absolute LMW species peak areas [mAU*sec]

[0422] HP-SEC data for F2-Lyo-D and F2-Lyo-E formulations is shown below in Tables 80-85. F2-Lyo-D and F2-Lyo-E both show good stability with no significant increase in HMW species and LMW species after storage at 25 °C for 6 weeks.

[0423] Table 80: Relative main peak areas (%) as measured by HP-SEC

[0424] Table 81 : Relative HMW species peak areas (%)

[0425] Table 82: Relative LMW species peak areas (%)

[0426] Table 83: Absolute main peak areas s measured by HP-SEC

[0427] Table 84: Absolute HMW species peak areas [mAU*sec]

[0428] Table 85: Absolute LMW species peak areas [mAU*sec]

[0429] HP-SEC data for F12, F15, F17, F19 formulations after storage at 2-8 °C for 14 months is shown below in Tables 86-91. Fl 5 exhibited the best stability profile out of the tested formulations, with a relative main peak area of 94%. F17 exhibited the lowest absolute main peak area.

[0430] Table 86: Relative main peak areas (%) as measured by HP-SEC

[0431] Table 87: Relative HMW species peak areas (%)

[0432] Table 88: Relative LMW species peak areas (%)

[0433] Table 89: Absolute main peak areas [mAU*sec] as measured by HP-SEC

[0434] Table 90: Absolute HMW species peak areas [mAU*sec]

[0435] Table 91 : Absolute LMW species peak areas [mAU*sec]Example 7: Additional characterization of select formulations

[0436] Select exemplary lyophilized aviptadil formulations were further characterized. The composition of the select exemplary formulations are described in the previous Examples. All formulations were prepared according to the methods described in Examples 1 and 2. The select exemplary lyophilized formulations were reconstituted with a saline solution.

[0437] HP-SEC was performed on Fl-Lyo, F2-Lyo, F6-Lyo, FlO-Lyo, and F2-Lyo-C formulations using the parameters described in Example 6. Fl-Lyo had the lowest relative main peak area and highest relative HMW species peak area at TO. After storage for 12 months at 2-8 °C, the relative main peak area of Fl-Lyo decreased compared to the relative main peak area at TO. The relative main peak area of Fl-Lyo also decreased after storage for 12 months at 25 °C compared to the relative main peak area at TO.

[0438] The relative main peak areas of F2-Lyo decreased after storage for 12 months at 2-8 °C and 25 °C compared to the relative main peak area at TO. The relative main peak areas of F6-Lyo decreased after storage for 12 months at 2-8 °C and 25 °C compared to the relative main peak area at TO. FlO-Lyo did not show a decrease in the relative main peak area after storage for 12 months at 2-8 °C and 25 °C compared to the relative main peak area at TO. Compared to the relative main peak area at TO, the relative main peak areas for F2-Lyo-C were stable after storage for 12 months at 2-8 °C and 25 °C. HP-SEC data for Fl-Lyo, F2-Lyo, F6-Lyo, FlO-Lyo, and F2-Lyo-C formulations at various time points and storage temperatures is shown below in Tables 92-94.

[0439] Table 92: Relative main peak areas (%) as measured by HP-SEC

[0440] Table 93: Relative HMW species peak areas (%)

[0441] Table 94: Relative LMW species peak areas (%)Example 8: Additional characterization of select formulations

[0442] Select exemplary lyophilized aviptadil formulations were further characterized to compare the effect of aviptadil concentration on the formation of fragments and aggregates. The composition of the select exemplary formulations are described in the previous Examples. All formulations were prepared according to the methods described in Examples 1 and 2. The select exemplary lyophilized formulations were reconstituted with a saline solution.

[0443] HP-SEC was performed on Fl-Lyo, F2-Lyo, F2-Lyo-C, and F2-Lyo-E formulations using the parameters described in Example 6. Fl-Lyo had the lowest relative main peak areas and highest relative HMW species and LMW species peak areas after storage for 12 months at 2-8 °C and 25 °C. F2-Lyo-C had the highest relative main peakareas and lowest relative HMW species and LMW species peak areas after storage for 12 months at 2-8 °C and 25 °C. HP-SEC data is shown in Tables 95-97.

[0444] Table 95: Relative main peak areas (%) as measured by HP-SEC

[0445] Table 96: Relative HMW species peak areas (%)

[0446] Table 97: Relative LMW species peak areas (%)Example 9: Additional characterization of select formulations

[0447] Select exemplary lyophilized aviptadil formulations were further characterized. The composition of the select exemplary formulations are described in the previous Examples. All formulations were prepared according to the methods described in Examples 1 and 2. The select exemplary lyophilized formulations were reconstituted with a saline solution.

[0448] RP-UPLC was performed on Fl-Lyo, F2-Lyo, F6-Lyo, FlO-Lyo, and F2-Lyo-C formulations using the parameters described in Example 1. F6-Lyo had the highest relative main peak area after storage for 12 months at 25 °C. FlO-Lyo had the lowest relative main peak area after storage for 12 months at 25 °C. RP-UPLC data is shown in Tables 98-99.

[0449] Table 98: Summary of RP-UPLC results

[0450] Table 99: Summary of RP-UPLC results

[0451] Although the invention has been described in conjunction with specific aspects thereof, it is evident that many alternatives, modifications, and variations will be apparent to those of skill in the art. Accordingly, it is entitled to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A powdered aviptadil formulation comprising: about 0.1 mg to about 0.4 mg of aviptadil acetate; about 3.8 mg to about 4 mg of L-histidine buffer salt; about 80 mg to about 200 mg of trehalose dihydrate; about 1.7 mg to about 5.6 mg of L-methionine; and about 0.1 mg to about 0.3 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transition temperature of at least about 90 °C after storage at a temperature ranging from about 2 °C to about 25 °C for at least 6 months.

2. The powdered aviptadil formulation of claim 1, wherein the formulation comprises about 0.1 mg of aviptadil acetate.

3. The powdered formulation of claim 1, wherein the formulation comprises about 0.2 mg of aviptadil acetate.

4. The powdered formulation of claim 1, wherein the formulation comprises about 3.9 mg of L-histidine buffer.

5. The powdered formulation of claim 1, wherein the L-histidine buffer salt comprises L- histidine anhydrous and L-histidine HC1 monohydrate.

6. The powdered formulation of claim 1, wherein the L-histidine buffer salt comprises about 0.8 mg of L-histidine anhydrous and about 3.1 mg of L-histidine HC1 monohydrate.

7. The powdered formulation of claim 1, wherein the formulation comprises about 100 mg trehalose dihydrate.The powdered formulation of claim 1, wherein the formulation comprises about 3.7 mg L-methionine. The powdered formulation of claim 1, wherein the formulation comprises about 0.2 mg polysorbate 80. The powdered formulation of claim 1, wherein the formulation consists essentially of: about 0.1 mg of aviptadil acetate; about 3.9 mg of L-histidine buffer salt; about 100 mg of trehalose dihydrate; about 3.7 mg of L-methionine; and about 0.2 mg of polysorbate 80. The powdered formulation of claim 1, wherein the formulation consists essentially of: about 0.2 mg of aviptadil acetate; about 3.9 mg of L-histidine buffer salt; about 100 mg of trehalose dihydrate; about 3.7 mg of L-methionine; and about 0.2 mg of polysorbate 80. A powdered formulation consisting essentially of: about 0.1 mg of aviptadil acetate; about 3.9 mg of L-histidine buffer salt; about 100 mg of sucrose; about 3.7 mg of L-methionine; and about 0.2 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. A powdered formulation consisting essentially of:about 0.2 mg of aviptadil acetate; about 3.9 mg of L-histidine buffer salt; about 100 mg of sucrose; about 3.7 mg of L-methionine; and about 0.2 mg of polysorbate 80, wherein the powdered formulation is storage stable at a temperature ranging from about 2 °C to about 25 °C for at least 6 months and wherein the powdered formulation has a glass transition temperature of about 62 °C or less after storage at a temperature ranging from about 2 °C to about 40 °C for at least 2 months. A reconstituted liquid aviptadil formulation comprising a liquid and the powdered aviptadil formulation of claim 1 dissolved in the liquid, wherein the reconstituted liquid aviptadil formulation has a pH ranging from about 5.3 to about 5.

7. The reconstituted formulation of claim 14, wherein the pH is about 5.4 to about 5.

7. The reconstituted formulation of claim 14, wherein the pH is about 5.4 to about 5.

6. The reconstituted formulation of claim 14, wherein the formulation comprises no more than about 4% of total impurities as measured by reversed phase ultra performance liquid chromatography (RP-UPLC). The reconstituted formulation of claim 14, wherein the formulation comprises no more than about 3% of total impurities as measured by RP-UPLC. The reconstituted formulation of claim 14, wherein the formulation comprises no more than about 2.5% of total impurities as measured by RP-UPLC. The reconstituted formulation of claim 14, wherein the formulation comprises no more than about 1% of methionine sulfoxide (Met(O)) as measured by RP-UPLC.The reconstituted formulation of claim 14, wherein the formulation comprises no more than about 0.7% of Met(O) as measured by RP-UPLC. The reconstituted formulation of claim 14, wherein the formulation comprises no more than about 0.5% of Met(O) as measured by RP-UPLC. A method of treating acute respiratory distress syndrome in a subject in need thereof, the method comprising administering to the subject an effective amount of the reconstituted formulation of claim 14.

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