Sustained-release peptide formulation

Abstract

The present disclosure relates, at least in part, to a pharmaceutical composition comprising: setomelanotide (also known as RM493); setomelanotide as the sole active pharmaceutical ingredient formulated for injection; setomelanotide as the sole active ingredient; setomelanotide as the active pharmaceutical ingredient; setomelanotide as the active pharmaceutical ingredient for injection; or another pharmaceutical composition having its primary mechanism of action as an agonist at the MC4 receptor (referred to herein as MC4RA P and / or a pharmaceutically acceptable carrier. The pharmaceutical compositions described herein provide for sustained release of setomelanotide or another pharmaceutical composition, which may result in a more desirable pharmacokinetic and pharmacodynamic profile upon administration.

Description

Technical Field

[0001] Claims of Priority This application claims the priority of U.S. Patent Application No. 62 / 586,643, filed on November 15, 2017, the entire content of which is incorporated herein by reference.

Background Art

[0002] Many biological compounds are rapidly released upon administration in standard formulations. Therefore, it is necessary to develop extended-release formulations that can extend the duration of compound circulation and provide desired pharmacokinetic and pharmacodynamic properties.

Summary of the Invention

Means for Solving the Problems

[0003] This disclosure relates, at least in part, to setmelanotide (also known as RM493); setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient formulated for injection; or another pharmaceutical composition having as its main mechanism of action an agonist at the MC4 receptor as the only active ingredient, as the only active ingredient formulated for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient formulated for injection (herein referred to as MC4RA PPharmaceuticals are provided that include an MC4 receptor agonist, such as BIM-22511 (also known as RM511), BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11, which includes SEQ ID NO: 11 disclosed in WO 2008 / 147556 pamphlet. The pharmaceuticals include a lipid excipient, alcohol, and a polar solvent, or combinations thereof, in different molar ratios. The pharmaceuticals may also include a pharmaceutically acceptable carrier. The pharmaceuticals described herein, for example, provide sustained release of setmelanotide (or MC4RA P ) having pharmacological activity, such as stepwise or extended release, compared to administration of setmelanotide (or MC4RA P ) alone. The pharmaceuticals also result in a more desirable pharmacokinetic and pharmacodynamic profile upon administration.

[0004] In one aspect, the disclosure provides a pharmaceutical comprising, as the only pharmaceutical active ingredient formulated for injection: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent, such as a buffer, optionally containing an antioxidant; and e) setmelanotide; setmelanotide as the only pharmaceutical active ingredient; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0005] In another aspect, the present disclosure provides a pharmaceutical comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, such as a buffer; and e) setomeranotide.

[0006] In another aspect, the present disclosure provides a pharmaceutical comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, such as a buffer; and e) setomeranotide as the sole active ingredient.

[0007] In another aspect, the present disclosure provides a pharmaceutical comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, such as a buffer; and e) setomeranotide as a pharmaceutical active ingredient.

[0008] In another aspect, the present disclosure provides a pharmaceutical comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, such as a buffer; and e) setomeranotide as a pharmaceutical active ingredient for injection.

[0009] In another aspect, the present disclosure provides a pharmaceutical comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, such as a buffer; and e) MC4RA P , such as BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11.

[0010] In another aspect, the present disclosure provides a pharmaceutical comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, such as a buffer; and e) MC4RA as the sole active ingredient P , for example, a pharmaceutical comprising BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11

[0011] In another aspect, the present disclosure provides a pharmaceutical for injection comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, such as a buffer; and e) MC4RA as the sole active ingredient P , for example, a pharmaceutical comprising BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11

[0012] In another aspect, the present disclosure provides a pharmaceutical comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, such as a buffer; and e) MC4RA as a pharmaceutical active ingredient P , for example, a pharmaceutical comprising BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent, such as a buffer, optionally containing an antioxidant; and e) an MC4RA as a pharmaceutical active ingredient for injection P , for example, a pharmaceutical comprising BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11.

[0014] In one embodiment, component a) of the composition comprises a neutral diacyl lipid. In an embodiment, the neutral diacyl lipid comprises a diacylglycerol. In one embodiment, the neutral diacyl lipid comprises glycerol dioleate (GDO).

[0015] In one embodiment, component b) of the composition comprises phosphatidylcholine. In another embodiment, the phospholipid comprises soy phosphatidylcholine.

[0016] In one embodiment, component c) of the composition comprises ethanol. In one embodiment, ethanol is provided in an amount sufficient to provide a solubility of at least 10 mg / g, 20 mg / g, or 30 mg / g of setmelanotide.

[0017] In one embodiment, component d) of the composition comprises a polar solvent, such as a buffer, for example, a citrate buffer optionally having a pH of 6.4. In one embodiment, the polar solvent, such as the buffer, comprises citrate acid monohydrate. In another embodiment, the polar solvent, such as the buffer, comprises an additional component, such as an antioxidant or a chemical or physical stabilizer. In one embodiment, the antioxidant is EDTA. In one embodiment, the polar solvent, such as the buffer, comprises citrate monohydrate, disodium EDTA, and water.

[0018] In one embodiment, component e) of the composition is setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; or MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). In one embodiment, component e) of the composition comprises setomeranotide.

[0019] In one embodiment, component e) provides setomeranotide as the only active ingredient.

[0020] In one embodiment, component e) provides setomeranotide as a pharmaceutical active ingredient.

[0021] In one embodiment, component e) provides setomeranotide as a pharmaceutical active ingredient for injection.

[0022] In one embodiment, component e) is MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as the only active ingredient.

[0023] In one embodiment, component e) is MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as the only active ingredient for injection.

[0024] In one embodiment, component e) is MC4RA PProvide (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as an active pharmaceutical ingredient.

[0025] In one embodiment, component e) is MC4RA P Provide (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as an active pharmaceutical ingredient for injection.

[0026] In one embodiment, the composition comprises a neutral diacyl lipid containing glycerol dioleate; a phospholipid containing phosphatidylcholine; an alcohol containing ethanol; a polar solvent, for example, a buffer containing EDTA and, for example, a citrate buffer at pH 6.4; and cetomelatonin.

[0027] In one embodiment, the composition comprises, per milliliter of the composition, 419.8 mg of glycerol dioleate (GDO); 419.8 mg of soy phosphatidylcholine; 105 mg of ethanol; 20 mg of citrate buffer; and 30 mg of cetomelatonin.

[0028] In another aspect, the present disclosure provides a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent optionally containing an antioxidant, for example, a buffer; and e) cetomelatonin or MC4RA P Provide an injectable pharmaceutical comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0029] In one embodiment, component e) provides setomeranotide as the sole active ingredient.

[0030] In one embodiment, component e) provides setomeranotide as a pharmaceutical active ingredient.

[0031] In one embodiment, component e) provides setomeranotide as an injectable pharmaceutical active ingredient.

[0032] In one embodiment, component e) is MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as the sole active ingredient.

[0033] In one embodiment, component e) is MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as the sole injectable active ingredient.

[0034] In one embodiment, component e) is MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as a pharmaceutical active ingredient.

[0035] In one embodiment, component e) is MC4RA P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is provided as an active ingredient of an injectable pharmaceutical product.

[0036] In one embodiment, component a) of the composition comprises a neutral diacyl lipid. In an embodiment, the neutral diacyl lipid comprises diacylglycerol. In one embodiment, the neutral diacyl lipid comprises glycerol dioleate (GDO).

[0037] In one embodiment, component b) of the composition comprises phosphatidylcholine. In an embodiment, the phospholipid comprises soybean phosphatidylcholine.

[0038] In one embodiment, component c) of the composition comprises ethanol. In an embodiment, ethanol is provided in an amount sufficient to provide a solubility of at least 10 mg / g, 20 mg / g, or 30 mg / g of setomelanotide.

[0039] In one embodiment, component d) of the composition comprises a polar solvent, such as a buffer solution, such as a citrate buffer solution, optionally with a pH of 6.4 for the buffer solution. In an embodiment, the polar solvent, such as the buffer solution, comprises citrate hydrochloride monohydrate. In one embodiment, the polar solvent, such as the buffer solution, comprises additional components, such as an antioxidant or a chemical or physical stabilizer. In an embodiment, the antioxidant is EDTA. In one embodiment, the polar solvent, such as the buffer solution, comprises citric acid monohydrate, disodium EDTA, and water.

[0040] In one embodiment, component e) is setomelanotide. In an embodiment, component e) is MC4RA P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0041] In one embodiment, component e) provides setomeranotide as the sole active ingredient.

[0042] In one embodiment, component e) provides setomeranotide as a pharmaceutical active ingredient.

[0043] In one embodiment, component e) provides setomeranotide as an injectable pharmaceutical active ingredient.

[0044] In one embodiment, component e) is MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) and provides it as the sole active ingredient.

[0045] In one embodiment, component e) is MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) and provides it as the sole injectable active ingredient.

[0046] In one embodiment, component e) is MC4RA P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is provided as an active pharmaceutical ingredient.

[0047] In one embodiment, component e) is MC4RA P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is provided as an active pharmaceutical ingredient for injection.

[0048] In one embodiment, the injectable pharmaceutical contains setomelanotide as the active pharmaceutical ingredient. In one embodiment, the injectable pharmaceutical contains a neutral diacyl lipid containing glycerol dioleate; a phospholipid containing phosphatidylcholine; an alcohol containing ethanol; a polar solvent, for example, a buffer containing EDTA and, for example, a citrate buffer at pH 6.4; and setomelanotide.

[0049] In one embodiment, the injectable pharmaceutical contains 419.8 mg of glycerol dioleate (GDO); 419.8 mg of soy phosphatidylcholine; 105 mg of ethanol; 20 mg of citrate buffer; and 30 mg of setomelanotide per milliliter of the composition.

[0050] In another aspect, the present disclosure relates to setomelanotide; setomelanotide as the only active pharmaceutical ingredient formulated for injection; setomelanotide as the only active ingredient; setomelanotide as an active pharmaceutical ingredient; setomelanotide as an active pharmaceutical ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, an active pharmaceutical ingredient, or an active pharmaceutical ingredient for injection PA method for producing a formulation or composition, such as a pharmaceutical composition, for example a formulation or composition having a controlled level of EtOH, comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), i) Setomelotide; Setomelotide as the only pharmaceutical active ingredient formulated for injection; or MC4RA P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), a first amount of EtOH, and one or more of the following components: a) Neutral diacyl lipid and / or tocopherol; b) Phospholipid; c) Alcohol; and d) Polar solvent, such as buffer providing a mixture of; and ii) adding a second amount of EtOH, thereby providing a method for producing a formulation or composition, such as a pharmaceutical composition, comprising setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; or MC4RA P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0051] In one embodiment, the pharmaceutical comprises setomelotide.

[0052] In one embodiment, the method is setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); producing a mixture comprising EtOH, a neutral diacyl lipid and / or tocopherol, and a phospholipid, wherein one or both of the neutral diacyl lipid and / or tocopherol and the phospholipid is setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is added after being combined with EtOH, thereby, setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) To produce a composition or formulation, e.g., a pharmaceutical further comprising.

[0053] In another aspect, setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); A method for producing a pharmaceutical comprising component a, component b, component d, and a predetermined amount of alcohol is (in any order) setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); providing a mixture by combining component a, component b, component d, and alcohol, and comparing the value of the alcohol content in the mixture with the reference value of the alcohol content Thereby, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Manufacturing a formulation of (for example, BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11), component a, component b, component d, and a predetermined amount of alcohol comprising.

[0054] In one embodiment, the pharmaceutical comprises setmelanotide.

[0055] In one embodiment, the method further comprises increasing or decreasing the amount of alcohol in the mixture in response to a value or comparison to provide a formulation having a predetermined amount of alcohol. In one embodiment, the method comprises adding an addition amount of alcohol to the mixture.

[0056] In another aspect, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PA method for manufacturing a pharmaceutical product containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), component a (for example, GDO), component b (for example, soy PC), component d (for example, a polar solvent, for example, a buffer, for example, a citrate buffer at pH 6.4), and a predetermined amount of alcohol is setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection, in any order P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); combining component a (for example, GDO), component b (for example, soy PC), component d (for example, a polar solvent, for example, a buffer, for example, a citrate buffer at pH 6.4) and alcohol to provide a mixture, and comparing the value of the alcohol content in the mixture with a reference value of the alcohol content, thereby, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection, in any order PManufacturing a pharmaceutical product comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), component a (for example, GDO), component b (for example, soy PC), component d (for example, a polar solvent, for example, a buffer, for example, a citrate buffer at pH 6.4), and a predetermined amount of alcohol comprising.

[0057] In one embodiment, the pharmaceutical product comprises setomelotide.

[0058] In one embodiment, the method further comprises adding an amount of alcohol to the mixture. In one embodiment, the amount of alcohol added is more than the predetermined amount of alcohol.

[0059] In one aspect, setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A method for manufacturing a pharmaceutical product comprising component e) comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is (i) setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PComponent e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11)) and a mixture containing alcohol (component e)-alcohol mixture), for example, contacting with alcohol, for example ethanol, for example, cetomelotide dissolved or dispersed therein; cetomelotide as the only pharmaceutical active ingredient formulated for injection; cetomelotide as the only active ingredient; cetomelotide as a pharmaceutical active ingredient; cetomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P Providing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); and (ii) Combining the component e)-alcohol mixture with an amount of component a, for example GDO, component b, for example soy PC, and component d, for example citrate buffer at pH 6.4, or all of components a, b, and d is included.

[0060] In one embodiment, the method further includes performing step (i), (ii), or (i) and (ii) in a sealed container.

[0061] In one aspect, the present disclosure relates to cetomelotide; cetomelotide as the only pharmaceutical active ingredient formulated for injection; cetomelotide as the only active ingredient; cetomelotide as a pharmaceutical active ingredient; cetomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection PA method of manufacturing a formulation of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), or a method of evaluating a candidate formulation for, for example, quality control or shipping specifications, comprising: Setomelanotide; setomelanotide as the only pharmaceutical active ingredient formulated for injection; setomelanotide as the only active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Providing a value of the amount of EtOH in a candidate formulation of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); and Comparing the value with a reference value of the amount of EtOH; Thereby, setomelanotide; setomelanotide as the only pharmaceutical active ingredient formulated for injection; setomelanotide as the only active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Providing a method of manufacturing a formulation of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0062] In one embodiment, the pharmaceutical comprises setomelanotide.

[0063] In one aspect, setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (such as BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), a composition or formulation, for example, a method of manufacturing a pharmaceutical, Setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (such as BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); producing a mixture comprising EtOH, neutral diacyl lipid and / or tocopherol, and a phospholipid, wherein one or both of the neutral diacyl lipid and / or tocopherol and the phospholipid is setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is added after being combined with EtOH, whereby setomelanotide; setomelanotide as the only pharmaceutical active ingredient formulated for injection; setomelanotide as the only active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) composition or formulation, for example, to manufacture a pharmaceutical A method comprising the same is provided herein.

[0064] In one embodiment, one or both of neutral diacyl lipid and / or tocopherol and phospholipid is setomelanotide; setomelanotide as the only pharmaceutical active ingredient formulated for injection; setomelanotide as the only active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is added after at least 10%, 25%, 50%, 75%, or all of it has been dissolved.

[0065] In one embodiment, the order of formation of the mixture is i) Setomeranotide; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as the only active ingredient; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is contacted with EtOH (and optionally water or buffer); ii) A phospholipid is added to the mixture resulting from i); iii) A neutral diacyl lipid and / or tocopherol is added to the mixture resulting from ii) is.

[0066] In one embodiment, the pharmaceutical comprises setomeranotide.

[0067] In another aspect, Setomeranotide; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as the only active ingredient; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A method for manufacturing a pharmaceutical of component (e) comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) comprises the following steps: (i) Setomeranotide; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as the only active ingredient; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) and a mixture containing alcohol (component (e)-alcohol mixture), e.g., alcohol, e.g., ethanol, in contact with, e.g., dissolved or dispersed therein, Setomeranotide; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as the only active ingredient; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) to provide; and (ii) combining the component (e)-alcohol mixture with an amount of component a (e.g., GDO), component b (e.g., soy PC), and component d (e.g., citrate buffer at pH 6.4), or an amount of all components a, b, and d (in that order); Thereby, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P A pharmaceutical (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), for example, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection, containing a predetermined amount of alcohol, for example, 10% by weight of alcohol, for example, ethanol P Including manufacturing a pharmaceutical (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0068] In one embodiment, the pharmaceutical contains setmelanotide.

[0069] In one aspect, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection PA method for manufacturing a pharmaceutical product of component (e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) comprises the following steps: (i) Setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); a mixture (component (e)-alcohol-buffer mixture) containing alcohol and component d, for example, a polar solvent, for example, a buffer solution, for example, a citrate buffer solution at pH 6.4, for example, alcohol, for example, ethanol and a citrate buffer solution at pH 6.4, with setomelotide dissolved or dispersed therein; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is provided; and (ii) Combine the component (e)-alcohol-buffer mixture with an amount of component a (e.g., GDO) and component b (e.g., soy PC), or with an amount of all components a and b. Contain them in sequence; Thereby, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A pharmaceutical (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), for example, containing a predetermined amount of alcohol, such as 10 wt% alcohol, such as ethanol, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection (for injection) P Including manufacturing a pharmaceutical (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0070] In one embodiment, the pharmaceutical contains setomeranotide.

[0071] In yet another aspect, a method for manufacturing a pharmaceutical containing setomeranotide, component a, component b, component d, and a predetermined amount of alcohol is comprising combining, in the order indicated, setomeranotide, component a, component b, component d, and an amount of alcohol that provides a predetermined amount of alcohol in the pharmaceutical, wherein the order indicated is the following steps: (i) providing a mixture comprising setomeranotide and an amount of alcohol (setomeranotide-alcohol mixture), for example, alcohol such as ethanol, in contact with, for example, dissolved or dispersed therein setomeranotide; and (ii) combining the setomeranotide-alcohol mixture with an amount of component a, b, and d or all of components a, b, and d; comprising in order, (i), (ii), or (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical comprising setomeranotide, component a, component b, component d, and a predetermined amount of alcohol, for example 10 wt% alcohol, for example, ethanol.

[0072] In another aspect, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), a method for producing a pharmaceutical comprising component (e), component a (e.g., GDO), component b (e.g., soy PC), component d (e.g., a polar solvent such as a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol is Setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) containing component (e); combining component a (e.g., GDO), component b (e.g., soy PC), component d (e.g., a polar solvent, e.g., a buffer, e.g., citrate buffer at pH 6.4), and an amount of alcohol added, where the amount of alcohol added provides a predetermined amount of alcohol in the pharmaceutical, and the order specified is the following steps: (i) Setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection PComponent (e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) and a mixture (component (e)-alcohol mixture) containing an added amount of alcohol, for example, alcohol such as ethanol, in contact with, for example, dissolved or dispersed therein, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P Providing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); and (ii) Combining the component (e)-alcohol mixture with an amount of component a (for example, GDO), component b (for example, soy PC), and component d (for example, citrate buffer at pH 6.4), or all of components a, b, and d; Including in sequence, (i), (ii) or (i) and (ii) are carried out in a sealed container, whereby setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection PManufacturing a pharmaceutical product comprising a component (e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); component a (for example, GDO), component b (for example, soy PC), component d (for example, a polar solvent, for example, a buffer, for example, a citrate buffer at pH 6.4), and a predetermined amount of alcohol, for example, 10% by weight of alcohol, for example, ethanol.

[0073] In one embodiment, the pharmaceutical product comprises setomelotide.

[0074] In another aspect, a method for manufacturing a pharmaceutical product comprising setomelotide, component a (for example, GDO), component b (for example, soy PC), component d (for example, a polar solvent, for example, a buffer, for example, a citrate buffer at pH 6.4), and a predetermined amount of alcohol is In the order specified, combining setomelotide; component a (for example, GDO), component b (for example, soy PC), component d (for example, a polar solvent, for example, a buffer, for example, a citrate buffer at pH 6.4), and the added amount of alcohol, where the added amount of alcohol provides the predetermined amount of alcohol in the pharmaceutical product, and the order specified is the following steps: (i) Providing a mixture containing setomelotide and the added amount of alcohol (setomelotide partial-alcohol mixture), for example, alcohol, for example, ethanol, in contact with, for example, setomelotide dissolved or dispersed therein; and (ii) Combining the setomelotide-alcohol mixture with an amount of component a (for example, GDO), component b (for example, soy PC), and component d (for example, citrate buffer at pH 6.4), or all of components a, b, and d; Including in order, (i), (ii), or both (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical product comprising setomelanotide, component a (e.g., GDO), component b (e.g., soy PC), component d (e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol, e.g., 10% by weight of alcohol, e.g., ethanol.

[0075] In another aspect, setomelanotide; setomelanotide as the sole pharmaceutical active ingredient formulated for injection; setomelanotide as the sole active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A method for producing a pharmaceutical product comprising component (e) (e.g., BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11), component a, component b, component d, and a predetermined amount of alcohol is In the order specified, setomelanotide; setomelanotide as the sole pharmaceutical active ingredient formulated for injection; setomelanotide as the sole active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Comprising combining component (e) (e.g., BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11), component a, component b, component d, and the added amount of alcohol, where the added amount of alcohol results in the predetermined amount of alcohol in the pharmaceutical product, and the order specified is the following steps: (i) Setomeranotide; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as the only active ingredient; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Component (e) containing (for example, BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11); a mixture (component (e) - buffer mixture) containing an added amount of alcohol and component d, for example, a polar solvent, for example, a buffer solution, for example, a citrate buffer at pH 6.4, for example, Setomeranotide in contact with, for example, dissolved or dispersed therein, alcohol, for example, ethanol and a citrate buffer at pH 6.4; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as the only active ingredient; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Providing (for example, BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11); and (ii) Combining the component (e) - alcohol - buffer mixture with an amount of component a and b or all of component a and b; Including in sequence, (i), (ii), or both (i) and (ii) are carried out in a sealed container, whereby setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P Manufacturing a pharmaceutical comprising a component (e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); component a, component b, component d, and a predetermined amount of alcohol, for example 10% by weight of alcohol, for example ethanol.

[0076] In one embodiment, the pharmaceutical comprises setomeranotide.

[0077] In one embodiment, component (e) provides setomeranotide as the only active ingredient.

[0078] In one embodiment, component (e) provides setomeranotide as a pharmaceutical active ingredient.

[0079] In one embodiment, component (e) provides setomeranotide as a pharmaceutical active ingredient for injection.

[0080] In one embodiment, component (e) is MC4RA P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as the only active ingredient.

[0081] In one embodiment, component e) is MC4RA P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is provided as the sole active ingredient for injection.

[0082] In one embodiment, component e) is MC4RA P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is provided as a pharmaceutical active ingredient.

[0083] In one embodiment, component e) is MC4RA P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is provided as the pharmaceutical active ingredient for injection.

[0084] In one aspect, a method for manufacturing a pharmaceutical product comprising setmelanotide, component a, such as GDO, component b, such as soy PC, component d, such as a citrate buffer at pH 6.4, and a predetermined amount of alcohol, comprises combining, in the order specified, setmelanotide, component a, component b, component d, and the added amount of alcohol, where the added amount of alcohol results in the predetermined amount of alcohol in the pharmaceutical product, and the order specified is the following steps: (i) Providing a mixture (setomelanotide-alcohol-buffer mixture) comprising setomelanotide, an added amount of alcohol, and component d, e.g., a polar solvent such as a buffer, e.g., a citrate buffer at pH 6.4, e.g., in contact with alcohol such as ethanol and a citrate buffer at pH 6.4, e.g., setomelanotide dissolved or dispersed therein; and (ii) Combining the setomelanotide-alcohol-buffer mixture with an amount of component a and b or all of component a and b; in sequence, (i), (ii) or (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical product comprising setomelanotide, component a, component b, component d, and a predetermined amount of alcohol, e.g., 10 wt% alcohol, e.g., ethanol.

[0085] In another aspect, setomelanotide; setomelanotide as the sole pharmaceutical active ingredient formulated for injection; setomelanotide as the sole active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); A method for producing a pharmaceutical product comprising component (e), component a (e.g., GDO), component b (e.g., soy PC), component d (e.g., a polar solvent such as a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol is Setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P Component (e) comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); combining component a, component b, component d, and an amount of alcohol added, where the amount of alcohol added results in a predetermined amount of alcohol in the pharmaceutical, and the order specified is the following steps: (i) Setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) component (e); alcohol in an added amount, and component d, e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4, a mixture (component (e)-alcohol-buffer mixture), e.g., in contact with alcohol, e.g., ethanol and a citrate buffer at pH 6.4, e.g., cetomelotide dissolved or dispersed therein; cetomelotide as the only pharmaceutical active ingredient formulated for injection; cetomelotide as the only active ingredient; cetomelotide as a pharmaceutical active ingredient; cetomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P Providing component (e) comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); and (ii) Combining the component (e)-alcohol-buffer mixture with an amount of component a (e.g., GDO) and component b (e.g., soy PC) or all of components a and b; Including in sequence, (i), (ii) or (i) and (ii) are carried out in a sealed container, whereby cetomelotide; cetomelotide as the only pharmaceutical active ingredient formulated for injection; cetomelotide as the only active ingredient; cetomelotide as a pharmaceutical active ingredient; cetomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection PManufacturing a pharmaceutical product comprising a component (e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); component a (for example, GDO), component b (for example, soy PC), component d (for example, a polar solvent, for example, a buffer solution, for example, a citrate buffer at pH 6.4), and a predetermined amount of alcohol, for example, 10 wt% alcohol, for example, ethanol.

[0086] In one embodiment, the pharmaceutical product contains setomeranotide.

[0087] In one aspect, a method for manufacturing a pharmaceutical product containing setomeranotide, component a (for example, GDO), component b (for example, soy PC), component d (for example, a polar solvent, for example, a buffer solution, for example, a citrate buffer at pH 6.4), and a predetermined amount of alcohol comprises combining setomeranotide, component a, component b, component d, and the added amount of alcohol in the order specified, where the added amount of alcohol results in the predetermined amount of alcohol in the pharmaceutical product, and the order specified is the following steps: (i) Providing a mixture (setomeranotide-alcohol-buffer mixture) containing setomeranotide, the added amount of alcohol, and component d, for example, a polar solvent, for example, a buffer solution, for example, a citrate buffer at pH 6.4, for example, in contact with alcohol, for example, ethanol and a citrate buffer at pH 6.4, for example, with setomeranotide dissolved or dispersed therein; and (ii) Combining the setomeranotide-alcohol-buffer mixture with an amount of component a (for example, GDO) and component b (for example, soy PC) or all of components a and b; in that order, (i), (ii) or both (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical product comprising setomeranotide, component a (e.g., GDO), component b (e.g., soy PC), component d (e.g., a polar solvent, e.g., a buffer, e.g., citrate buffer at pH 6.4), and a predetermined amount of alcohol, e.g., 10% by weight of alcohol, e.g., ethanol.

[0088] In another aspect, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A method for producing a pharmaceutical product comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) comprises the following steps: i) Combining an amount of one or more (e.g., all) of components a, b, c, and d; ii) Adding to this mixture setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); and iii) Mix the mixture of (i) and (ii) for the indicated time to obtain setmelanotide; setmelanotide as the sole pharmaceutical active ingredient formulated for injection; setmelanotide as the sole active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, the sole active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P dissolve or disperse (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) in that order, thereby obtaining a pharmaceutical product of setmelanotide; setmelanotide as the sole pharmaceutical active ingredient formulated for injection; setmelanotide as the sole active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA P containing, for example, a pharmaceutical product of (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), for example, a predetermined amount of alcohol, for example 10% by weight of alcohol, for example ethanol, and setmelanotide; setmelanotide as the sole pharmaceutical active ingredient formulated for injection; setmelanotide as the sole active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, the sole active ingredient for injection, for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection PManufacturing a pharmaceutical product comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0089] In one embodiment, the pharmaceutical product comprises setomeranotide. In one embodiment, the mixing is carried out for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 hours. In one embodiment, the mixing is carried out for 1 to 30 hours. In another embodiment, the mixing is carried out for 30, 40, or 50 hours or less.

[0090] In one aspect, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P A method for manufacturing a pharmaceutical product comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) comprises the following steps: i) One or more (for example, all) of a certain amount of components a, b, d and setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection Pcombining (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); ii) providing a predetermined amount of component c to this mixture; and iii) mixing the mixture of (i) and (ii) for the indicated time to obtain setomelotide; setomelotide as the sole pharmaceutical active ingredient formulated for injection; setomelotide as the sole active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, the sole active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P dissolving or dispersing (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) in that order, thereby obtaining setomelotide; setomelotide as the sole pharmaceutical active ingredient formulated for injection; setomelotide as the sole active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, the sole active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection PA pharmaceutical product (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), for example, containing a predetermined amount of alcohol, such as 10% by weight of alcohol, such as ethanol, and setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Manufacturing a pharmaceutical product comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0091] In one embodiment, the pharmaceutical product contains setomeranotide.

[0092] In one embodiment, the mixing is carried out for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 hours. In one embodiment, the mixing is carried out for 1 to 30 hours. In another embodiment, the mixing is carried out for 30, 40, or 50 hours or less.

[0093] In another aspect, setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injectionP A method of administering to a subject (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), the method comprising administering to the subject an effective amount of a pharmaceutical of the present specification or a pharmaceutical produced by one or more of the methods described in the present specification is disclosed herein.

[0094] In one embodiment, the subject has or is at risk of having a disease responsive to the regulation of melanocortin-4 receptor (MC4R). In one embodiment, the disease is selected from type 1 diabetes, type 2 diabetes, obesity, insulin resistance, metabolic syndrome, male erectile dysfunction, female sexual dysfunction, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, substance use disorders including alcohol dependence, eating disorders, cachexia, inflammation, or anxiety. In one embodiment, the disease is obesity. In one embodiment, the disease is type 1 diabetes. In one embodiment, the disease is type 2 diabetes. In one embodiment, the disease is Prader-Willi syndrome. In one embodiment, the disease is Bardet-Biedl syndrome. In one embodiment (embodimdnet), the disease is Alström syndrome.

[0095] In one embodiment, the subject is between 1 and 80 years old. In one embodiment, the subject is 1 - 10 years old, 10 - 20 years old, 20 - 30 years old, 30 - 40 years old, 40 - 50 years old, 50 - 60 years old, 60 - 70 years old, or 70 - 80 years old. In one embodiment, the subject is over 80 years old.

[0096] In related aspects, the present disclosure provides a method of treating a subject, the method comprising administering to a subject in need thereof an effective amount of a composition comprising setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0097] In one embodiment, the subject has or is at risk of having a disease responsive to modulation of the melanocortin-4 receptor (MC4R). In one embodiment, the disease is selected from type 1 diabetes, type 2 diabetes, obesity, insulin resistance, metabolic syndrome, male erectile dysfunction, female sexual dysfunction, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, substance use disorders including alcohol dependence, eating disorders, cachexia, inflammation, or anxiety. In one embodiment, the disease is obesity. In one embodiment, the disease is type 1 diabetes. In one embodiment, the disease is type 2 diabetes. In one embodiment, the disease is Prader-Willi syndrome. In one embodiment, the disease is Bardet-Biedl syndrome. In one embodiment, the disease is Alström syndrome.

[0098] In one embodiment, the subject is between 1 and 80 years of age. In one embodiment, the subject is 1 to 10 years old, 10 to 20 years old, 20 to 30 years old, 30 to 40 years old, 40 to 50 years old, 50 to 60 years old, 60 to 70 years old, or 70 to 80 years old. In one embodiment, the subject is over 80 years old.

[0099] In one aspect, setomeranotide for use in the treatment of a subject in need thereof, comprising administering to the subject an effective amount of the composition; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Compositions are provided herein that include (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0100] In one embodiment, the subject has or is at risk of having a disease that responds to modulation of the melanocortin-4 receptor (MC4R). In one embodiment, the disease is selected from type 1 diabetes, type 2 diabetes, obesity, insulin resistance, metabolic syndrome, male erectile dysfunction, female sexual dysfunction, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, substance use disorders including alcohol dependence, eating disorders, cachexia, inflammation, or anxiety. In one embodiment, the disease is obesity. In one embodiment, the disease is type 1 diabetes. In one embodiment, the disease is type 2 diabetes. In one embodiment, the disease is Prader-Willi syndrome. In one embodiment, the disease is Bardet-Biedl syndrome. In one embodiment, the disease is Alström syndrome.

[0101] In one embodiment, the subject is between 1 and 80 years of age. In one embodiment, the subject is 1 to 10 years old, 10 to 20 years old, 20 to 30 years old, 30 to 40 years old, 40 to 50 years old, 50 to 60 years old, 60 to 70 years old, or 70 to 80 years old. In one embodiment, the subject is over 80 years old.

[0102] Setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P , for example, optimized pharmaceuticals including BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11 and methods for manufacturing and using the same are provided herein. Typically, the pharmaceutical comprises neutral diacylglycerol and / or tocopherol, phosphatidylcholine, alcohol, a polar solvent (optionally containing an antioxidant), and setomeranotide (or MC4RA P ) disclosed herein. In one embodiment, the pharmaceutical has a low viscosity phase such as an L2 (reverse micelle) phase. The pharmaceuticals disclosed herein are setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) provides controlled release.

[0103] In one embodiment, the pharmaceutical provides an optimized release profile, is relatively easy to manufacture, can be sterile filtered, has a low viscosity upon delivery (e.g., enabling easy and less painful administration with a thin needle, e.g., a 27-gauge or smaller diameter needle), a high level of setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is enabled to be incorporated (such that in embodiments, a smaller amount of the composition and / or setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) to enable, enable shallow injection (e.g., injection into the subcutaneous tissue layer), and / or form a depot, e.g., a non-lamellar depot, composition in vivo to form a depot having, e.g., a "non-burst" release profile. In one embodiment, the pharmaceutical is formed from a non-toxic, biotolerable, biodegradable material, can be administered by intramuscular (i.m.) or subcutaneous (s.c.) administration, and is suitable for self-administration. In one embodiment, the pharmaceutical minimizes or eliminates irritation (including transient irritation) upon injection.

[0104] While not wishing to be bound by theory, in one embodiment, the pharmaceutical is thought to result in a crystalline phase, e.g., a non-lamellar liquid crystal phase, after administration.

[0105] In one embodiment, the pharmaceutical is setomelanotide; setomelanotide as the only pharmaceutical active ingredient formulated for injection; setomelanotide as the only active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA PProviding a low initial release (a "non-burst profile") of (for example, as the only active ingredient for injection, as the only active ingredient for pharmaceuticals, or as the pharmaceutical active ingredient for injection) BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11. This can be defined such that the area under the drug concentration curve during the first few hours (for example, the first 6, 9, 12, 15, 18, 21, or 24 hours) after administration is less than 40% (for example, less than 35, 30, 25, 20, 15, 10%, or less) of the area under the drug concentration-time curve for a 7-day (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, or 28 days) steady-state dosing interval. In one embodiment, the area under the drug concentration curve during the first 6 hours after administration is less than 10% of the area under the drug concentration-time curve for a 7-day (for example, 168 hours) steady-state dosing interval. In one embodiment, the area under the drug concentration curve during the first 12 hours after administration is 10 - 20% (for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20%) of the area under the drug concentration-time curve for a 7-day (for example, 168 hours) steady-state dosing interval. In one embodiment, the area under the drug concentration curve during the first 24 hours after administration is 20 - 30% (for example, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30%) of the area under the drug concentration-time curve for a 7-day (for example, 168 hours) steady-state dosing interval.

[0106] In one embodiment, the pharmaceutical provides an average maximum plasma drug concentration (C max ) in the range of 5 - 20 ng / mL (for example, 11 ng / mL) at steady state after an infusion volume in the range of 5 - 20 mg (for example, an infusion volume of 10 mg) once a week (for example, once every 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days), but it has an average drug concentration (C aveis three times or less (e.g., 1, 1.5, 2, or 2.5 times higher). In one embodiment, the pharmaceutical provides an average maximum plasma drug concentration (C max ) at a steady state of 11 ng / ml after a weekly injection dose of 10 mg, which is three times or less than the average drug concentration (C ave ) of 4 ng / mL.

[0107] In one embodiment, the minimum plasma drug concentration (C min ) at steady state ranges from 1 to 3 ng / mL (e.g., 1.88 ng / mL) at the time of administration. In one embodiment, the mean accumulation index ranges from 1 to 3 (e.g., 1.48), and the mean fluctuation factor ranges from 180 to 210% (e.g., 199%). In one embodiment, setmelanotide in plasma at steady state; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) profile provides drug coverage over an administration interval of one week (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days).

[0108] In one embodiment, setomeranotide as described herein; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is optimized so that it can be formulated in a wide range of ratios with neutral diacyl lipids and / or tocopherol, and a phospholipid component. In one embodiment, the pharmaceutical has a higher ratio of neutral diacyl lipids and / or tocopherol to phospholipid than was previously achievable without the risk of phase separation and / or unacceptable high viscosity in the formulation. In one embodiment, the ratio of neutral diacyl lipids and / or tocopherol to phospholipid is 1:1 or a ratio between 0.5 to 1.0, 0.7 to 1.0, or 1 to 0.5, or 1 to 0.7.

[0109] The methods described herein enable more precise and accurate levels of alcohol in the formulation. The level of alcohol can affect the release rate, e.g., the burst profile. Levels that are too high can affect the release rate, e.g., the burst profile, and can have an adverse effect, for example. Therefore, control of the level of alcohol can enable a more predictable and repeatable achievement of an optimized release profile. The level of alcohol can also affect the viscosity prior to injection, and higher levels of alcohol result in lower viscosities. Therefore, a defined and repeatable level of alcohol can enable optimized performance. Described herein are methods of combining the addition of a known amount of alcohol with a process to minimize or control the level of loss due to evaporation. In one embodiment, the method of manufacturing a pharmaceutical described herein includes manufacturing the pharmaceutical using a controlled amount of alcohol. In one embodiment, the pharmaceutical is prepared to reduce or control evaporation, e.g., by use of a sealed container (so as to reduce or control evaporation in that way). Use of a sealed container can tightly control the amount of alcohol used in the manufacture of the pharmaceutical and can improve the reproducibility of the pharmaceutical. Prevention of loss due to evaporation is an important feature in reducing variability between batches of the pharmaceutical and between individual dosage units within a batch. The formulation is setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; or MC4RA as the only active ingredient, as the only pharmaceutical active ingredient for injection, or as the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) can be used for in vivo delivery, so that each batch of the pharmaceutical contains a similar amount of setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; or MC4RA P at a similar concentration, which is important.

[0110] Disclosed herein is, among other things, the stated order in which ingredients are added to a formulation. The stated order is based on the solubility of the ingredients with respect to each other, e.g., setmelanotide in a formulation; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) can have a significant effect on the solubility. In one embodiment, the method of manufacturing a pharmaceutical described herein includes the stated order of addition of ingredients for manufacturing the pharmaceutical. In one embodiment, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is contacted with alcohol and then contacted with one or more of the other components. The method can further optimize the time required for the preparation of the formulation. Setomeranotide resulting from a specific order of addition of components; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as the only active ingredient; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P The pharmaceutical of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) has a low viscosity and an amount of alcohol compatible with in vivo use.

[0111] In embodiments, the control of the alcohol content and the order of addition can be combined.

[0112] The present disclosure contemplates any one or more of all combinations of any of the foregoing aspects and / or embodiments, as well as combinations with any one or more of the embodiments described in the detailed description and examples.

[0113] Methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present invention, but the preferred methods and materials are described below. All publications, patent applications, patents, and other references (e.g., sequence database reference numbers) mentioned herein are incorporated by reference in their entirety. In certain embodiments, for example, the following are provided: (Item 1) a) Neutral diacyl lipids and / or tocopherols; b) Phospholipids; c) Alcohol; d) Optionally, a polar solvent, such as a buffer optionally containing an antioxidant; and e) Setomeranotide as the only pharmaceutical active ingredient comprising an injectable composition or formulation, for example, an injectable composition of a pharmaceutical. (Item 2) The injectable composition according to Item 1, comprising a neutral diacyl lipid. (Item 3) The injectable composition according to Item 4, wherein the neutral diacyl lipid comprises diacylglycerol. (Item 4) The injectable composition according to Item 4, wherein the neutral diacyl lipid comprises glycerol dioleate (GDO). (Item 5) The injectable composition according to Item 1, wherein the phospholipid comprises phosphatidylcholine (e.g., soy phosphatidylcholine). (Item 6) The injectable composition according to Item 1, wherein the alcohol comprises ethanol. (Item 7) The injectable composition according to Item 6, wherein the ethanol is provided in an amount sufficient to provide a solubility of at least 10 mg / g, 20 mg / g, or 30 mg / g of setomeranotide. (Item 8) The injectable composition according to Item 6, wherein the amount of ethanol by weight is more than 1% by weight, for example, between 1% and 20% by weight. (Item 9) The injectable composition according to Item 6, wherein the amount of ethanol is sufficiently low such that the composition can be easily and comfortably injected by an apparatus, such as a syringe, by a subject, such as a subject described herein. (Item 10) The injectable composition according to Item 6, wherein the amount of ethanol by weight is less than 20%, 15%, or 10%. (Item 11) The injectable composition according to Item 6, wherein the amount of ethanol is sufficiently high such that the composition has a viscosity sufficiently low such that the composition can be comfortably delivered by an apparatus, such as a syringe having a thin needle, such as a 27-gauge needle. (Item 12) The injectable composition according to Item 6, wherein the amount of ethanol is sufficiently low such that upon injection, the initial burst, e.g., initial release, of the drug after subcutaneous injection is less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), the ratio of the lowest concentration (C max ) in plasma to the highest concentration (C min ) in plasma before the next dose is administered. (Item 13) The injectable composition according to Item 6, wherein the amount of ethanol is sufficiently low such that upon injection, the pharmaceutical provides a low initial release of setomeranotide. (Item 14) The injectable composition according to item 13, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 6 hours) after administration, which is less than 10% or less of the area under the drug concentration-time curve at a steady-state dosing interval of 7 days. (Item 15) The injectable composition according to item 13, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 12 hours) after administration, which is less than 10 - 20% or less of the area under the drug concentration-time curve at a steady-state dosing interval of 7 days. (Item 16) The injectable composition according to item 13, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 24 hours) after administration, which is less than 20 - 30% or less of the area under the drug concentration-time curve at a steady-state dosing interval of 7 days. (Item 17) The injectable composition according to item 9, wherein the device may be a single-use device or a multi-use device. (Item 18) The injectable composition according to item 9, wherein the device is selected from a manual syringe (e.g., a syringe containing a needle (e.g., a needle having a suitable diameter, e.g., a 27-gauge needle)), or an auto-injector (e.g., a spring-loaded syringe or a pen-type syringe). (Item 19) The injectable composition according to item 1, wherein the polar solvent, e.g., the buffer solution, contains a citrate buffer, and optionally the pH of the buffer solution is 6.4. (Item 20) The injectable composition according to item 1, wherein the polar solvent, e.g., the buffer solution, contains citric acid monohydrate. (Item 21) The injectable composition according to item 1, wherein the polar solvent, e.g., the buffer solution, contains additional components, e.g., an antioxidant or a chemical or physical stabilizer. (Item 22) The injectable composition according to item 21, wherein the antioxidant is EDTA. (Item 23) The injectable composition according to item 1, wherein the polar solvent, e.g., the buffer solution, contains citric acid monohydrate, disodium EDTA, and water. (Item 24) The injectable composition according to item 1, wherein cetomelatide is present as a chloride salt. (Item 25) The injectable composition according to item 1, wherein the pharmaceutical product optionally contains an antibacterial agent or a microbial growth inhibitor, e.g., a bacteriostatic agent or a preservative. (Item 26) The injectable composition according to item 1, wherein the weight ratio of a:b is 70:30 - 40:60. (Item 27) The injectable composition according to item 1, wherein the ratio of a:b by weight is 70:30, 65:45, 60:40, 55:45, 50:50, 45:55, or 40:60. (Item 28) The injectable composition according to item 1, wherein component a is 20 - 80%, 30 - 70%, 33 - 60%, or 38 - 43% by weight of the total weight of components a, b, and c solution. (Item 29) The injectable composition according to item 1, wherein component b is 20 - 80%, 30 - 70%, 33 - 60%, or 38 - 43% by weight of the total weight of components a, b, and c solution. (Item 30) The injectable composition according to item 1, wherein component c, such as ethanol, is 0.5 - 50%, 2 - 30%, or 5 - 20% by weight of the total weight of components a, b, and c solution. (Item 31) The neutral diacyl lipid contains glycerol dioleate; The phospholipid contains phosphatidylcholine; The alcohol contains ethanol; and The polar solvent, such as the buffer solution, contains citrate buffer solution. The injectable composition according to item 1. (Item 32) The neutral diacyl lipid contains glycerol dioleate; The phospholipid contains soybean phosphatidylcholine; The alcohol contains ethanol; and The polar solvent, such as the buffer solution, contains citrate buffer solution with pH 6.4 containing EDTA. The injectable composition according to item 1. (Item 33) Per milliliter of the composition: 420 ± 20% mg of glycerol dioleate (GDO); 420 ± 20% mg of soybean phosphatidylcholine; 105 ± 20% mg of ethanol; 20 ± 20% mg of citrate buffer solution; and 30 ± 20% mg of cetomelatide. The injectable composition according to item 1. (Item 34) Per milliliter of the composition: 420 ± 10% mg of glycerol dioleate (GDO); 420 ± 10% mg of soybean phosphatidylcholine; 105 ± 10% mg of ethanol; 20 ± 10% mg of citrate buffer solution; and 30 ± 10% mg of cetomelatide. The injectable composition according to item 1. (Item 35) Per milliliter of the composition: 420 ± 5% mg of glycerol dioleate (GDO); 420 ± 5% mg of soybean phosphatidylcholine; 105 ± 5% mg of ethanol; 20 ± 5% mg of citrate buffer solution; and 30 ± 5% mg of cetomelatide. The injectable composition according to item 1. (Item 36) Per milliliter of the composition: 420 ± 2% mg of glycerol dioleate (GDO); 420 ± 2% mg of soy phosphatidylcholine; 105 ± 2% mg of ethanol; 20 ± 2% mg of citrate buffer; and 30 ± 2% mg of setomelanotide, The injectable composition according to item 1. (Item 37) Per milliliter of the composition 419.8 mg of glycerol dioleate (GDO); 419.8 mg of soy phosphatidylcholine; 105 mg of ethanol; 20 mg of citrate buffer; and 30 mg of setomelanotide, The injectable composition according to item 1. (Item 38) 20 - 80%, 30 - 70%, 33 - 60%, or 38 - 43% by weight of neutral diacyl lipid of component a in the components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition; 20 - 80%, 30 - 70%, 33 - 60%, or 38 - 43% by weight of phospholipid of component b in the components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition; 0.1 - 35%, 5 - 20%, 8 - 15%, or 9 - 11% by weight of alcohol of component c in the components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition; 0.5 - 10%, 1 - 5%, or 1 - 3% by weight of a polar solvent, such as a buffer, of component d in the components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition; and 0.1 - 10%, 0.2 - 8%, 0.5 - 6%, 1 - 4% by weight of setomelanotide in the components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition The injectable composition according to item 1. (Item 39) 42% ± 10, 42% ± 5, 42% ± 2, or 42% ± 1 by weight of neutral diacyl lipid in the components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition; 42% ± 10, 42% ± 5, 42% ± 2, or 42% ± 1 by weight of phospholipid in the components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition; 10% ± 8, 10% ± 6, 10% ± 5, or 10% ± 1 by weight of alcohol in the components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition; Component a, b, and c of the composition; component a, b, c, and d; or 2% ± 1, 2% ± 0.5, 2% ± 0.25, or 2% ± 0.1 by weight of component a, b, c, d, and e of a polar solvent, such as a buffer; and 3% ± 1.5, 3% ± 1, or 3% ± 0.5 by weight of component a, b, and c of the composition; component a, b, c, and d; or component a, b, c, d, and e of cetomelatide The injectable composition according to item 1, comprising (Item 40) The injectable composition according to item 1, which forms or is capable of forming at least one liquid crystal structure upon contact with an aqueous environment, such as injection, for example, subcutaneous injection into a subject. (Item 41) The viscosity is (i) low enough to be comfortably delivered by a device, such as a syringe with a thin needle, such as a 27-gauge needle; (ii) upon injection, the initial burst, such as the initial release, of cetomelatide from the pharmaceutical is less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), the ratio of the lowest concentration (C max ) in plasma to the highest concentration (C min ) in plasma before the next dose is administered; or (iii) upon injection, the pharmaceutical provides a low initial release of cetomelatide, the injectable composition according to item 1. (Item 42) When injected into a subject: (i) the initial burst, such as the initial release, of cetomelatide from the pharmaceutical is less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), the ratio of the lowest concentration (C max ) in plasma to the highest concentration (C min ) in plasma before the next dose is administered; or (ii) the pharmaceutical provides a low initial release of cetomelatide, the injectable composition according to item 1. (Item 43) The injectable composition according to item 41, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 6 hours) after administration and is less than 10% or less of the area under the drug concentration-time curve for a 7-day steady-state dosing interval. (Item 44) The injectable composition according to item 41, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 12 hours) after administration and is less than 10 - 20% or less of the area under the drug concentration-time curve for a 7-day steady-state dosing interval. (Item 45) The injectable composition according to item 41, wherein the low initial release is less than 20 to 30% or less thereof with respect to the area under the drug concentration-time curve at a steady-state dosing interval of 7 days, and is measured by the partial area under the drug concentration curve during the first few hours (e.g., the first 24 hours) after administration. (Item 46) A unit dosage form comprising the composition according to item 1. (Item 47) The unit dosage form according to item 46, comprising at least 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, or 0.2 mL of said composition. (Item 48) The unit dosage form according to item 46, disposed in a hermetic housing, such as a vial or a cartridge. (Item 49) The injectable unit dosage form according to item 46, disposed in an injection device, such as a single-use device or a multi-use device. (Item 50) The unit dosage form according to item 49, wherein said device is selected from a manual syringe (e.g., a syringe comprising a needle (e.g., a needle having a suitable diameter, e.g., a 27-gauge needle)), or an auto-injector (e.g., a spring-loaded syringe, or a pen-type syringe). (Item 51) The unit dosage form according to item 46, comprising 10 to 70; 20 to 60, 25 to 50; 25 to 40; 25 to 35 mg of cetomelatide. (Item 52) The unit dosage form according to item 46, comprising 50 ± 20%; 40 ± 20%; or 30 ± 20% mg of cetomelatide. (Item 53) The unit dosage form according to item 46, comprising 50 ± 10%; 40 ± 10%; or 30 ± 10% mg of cetomelatide. (Item 54) The unit dosage form according to item 46, comprising 50 ± 5%; 40 ± 5%; or 30 ± 5% mg of cetomelatide. (Item 55) The unit dosage form according to item 46, comprising 40, 35, or 30 mg of cetomelatide. (Item 56) The unit dosage form according to item 46, wherein said composition is suitable for injection, such as subcutaneous injection or intramuscular injection. (Item 57) Said viscosity is (i) low enough to be comfortably delivered by a device, such as a syringe having a thin needle, such as a 27-gauge needle; (ii) at the time of injection, is the initial burst of cetomelatide from said pharmaceutical after subcutaneous injection, e.g., the initial release, less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), the ratio of the lowest concentration (C max ) in plasma to the highest concentration (C min ) in plasma before the next dose is administered? Or (iii) The unit dosage form according to item 46, wherein upon injection, the pharmaceutical gives a sufficiently low initial release of cetomelatide. (Item 58) When administered to a subject, (i) The initial burst of cetomelatide from the pharmaceutical after subcutaneous injection, e.g., the initial release, is less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), the ratio of the highest concentration (C max ) in plasma before the next dose is administered to the lowest concentration (C min ) in plasma; or (ii) The unit dosage form according to item 46, wherein the pharmaceutical gives a low initial release of cetomelatide. (Item 59) The unit dosage form according to item 46, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 6 hours) after administration, which is less than 10% or less of the area under the drug concentration-time curve at a 7-day steady-state dosing interval. (Item 60) The unit dosage form according to item 58, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 12 hours) after administration, which is less than 10 - 20% or less of the area under the drug concentration-time curve at a 7-day steady-state dosing interval. (Item 61) The unit dosage form according to item 58, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 24 hours) after administration, which is less than 20 - 30% or less of the area under the drug concentration-time curve at a 7-day steady-state dosing interval. (Item 62) A method for producing a formulation or composition formulated for injection, e.g., a pharmaceutical composition, e.g., a formulation or composition having a controlled level of EtOH, containing cetomelatide as the sole pharmaceutical active ingredient, comprising: i) providing a mixture of cetomelatide, a first amount of EtOH, and one or more of the following components: a) neutral diacyl lipid and / or tocopherol; b) phospholipid; c) alcohol; and d) a polar solvent, e.g., a buffer ; and ii) adding a second amount of EtOH thereby producing a formulation or composition formulated for injection, e.g., a pharmaceutical composition, containing cetomelatide as the sole pharmaceutical active ingredient. (Item 63) The method according to item 62, wherein providing comprises forming the mixture. (Item 64) The method according to item 62, wherein the addition of the second amount of EtOH meets a reference value, for example, falls within a certain range of values, for example, a lower limit value and an upper limit value, for example, an upper limit value and a lower limit value of weight% EtOH, for example, an amount of EtOH that falls within a range defined by 10 to 0.5 weight%. (Item 65) The method according to item 64, wherein the reference value is a value within the range of 5 to 20; 8.5 to 12.5; and 9 to 11 weight% EtOH, for example, 10 weight%. (Item 66) The method according to item 64, wherein the reference value is a value within the range of 9 to 11 weight% EtOH, for example, 10 weight%. (Item 67) The method according to item 62, comprising measuring the amount of EtOH in the mixture by suitable analytical measurements. (Item 68) The method according to item 67, comprising selecting, according to the measurement, the amount of EtOH to be added to the mixture, for example, the amount that achieves the reference value. (Item 69) The method according to item 68, comprising adding the selected amount of EtOH to the mixture to form a mixture supplemented with EtOH. (Item 70) The method according to item 69, wherein the selected amount is added to the mixture as a single portion or as a plurality of portions of the same or different amounts. (Item 71) The method according to item 62, wherein less than 48 hours, less than 24 hours, or less than 4 hours elapses between the formation of the mixture and the measurement of the amount of EtOH in the mixture, the selection of the amount of EtOH to be added, or the addition of the second amount. (Item 72) The method according to item 62, comprising providing the amount of the component added to the mixture. (Item 73) The method according to item 72, wherein providing comprises weighing the amount of the component added to the mixture. (Item 74) The method according to item 62, comprising providing a value of the amount of EtOH in the mixture and determining the amount of EtOH that needs to be added to meet the standard of the amount of EtOH. (Item 75) The method according to item 62, wherein after forming the mixture, EtOH is lost from the mixture, for example, by evaporation, for example, evaporation into the upper space of a container, for example, a mixing container. (Item 76) The method according to item 62, comprising measuring the amount of EtOH in the mixture supplemented with EtOH after the second amount is added to the mixture. (Item 77) The method according to item 76, comprising selecting the amount of EtOH to be added to the mixture supplemented with the EtOH according to the measurement. (Item 78) The method according to item 77, comprising adding the selected amount of EtOH to the mixture supplemented with the EtOH to form a twice-supplemented mixture. (Item 79) The method according to item 62, further comprising providing a second formulation or composition, e.g., a pharmaceutical, formulated for injection and containing setomelanotide as the sole pharmaceutical active ingredient. (Item 80) Comprising manufacturing a mixture comprising setomelanotide, EtOH, neutral diacyl lipid and / or tocopherol, and phospholipid, wherein one or both of the neutral diacyl lipid and / or tocopherol and the phospholipid are added after setomelanotide and EtOH are combined, thereby manufacturing a setomelanotide composition or formulation, e.g., a pharmaceutical, formulated for injection, according to the method of item 62. (Item 81) Comprising manufacturing a mixture comprising setomelanotide, water or a polar solvent, e.g., a buffer, neutral diacyl lipid and / or tocopherol, and phospholipid, wherein one or both of the neutral diacyl lipid and / or tocopherol and the phospholipid are added after setomelanotide and water or the polar solvent, e.g., the buffer, are combined, thereby manufacturing a setomelanotide composition or formulation, e.g., a pharmaceutical, formulated for injection, according to the method of item 62. (Item 82) The order of formation of the mixture is i) contacting setomelanotide with EtOH (and optionally water or a polar solvent, e.g., a buffer); ii) adding the phospholipid to the mixture resulting from i); and iii) adding the neutral diacyl lipid and / or tocopherol to the mixture resulting from ii), which is the method according to item 62. (Item 83) A method for manufacturing a pharmaceutical formulated for injection and containing setomelanotide as the sole pharmaceutical active ingredient, component a, component b, component d, and a predetermined amount of alcohol, comprising (in any order) combining setomelanotide, component a, component b, component d, and alcohol to form a mixture, and comparing the value of the alcohol content in the mixture with a reference value of the alcohol content, thereby manufacturing a pharmaceutical formulated for injection and containing setomelanotide as the sole pharmaceutical active ingredient, component a, component b, component d, and a predetermined amount of alcohol. (Item 84) The method according to item 83, comprising increasing or decreasing the amount of alcohol in the mixture in response to said value or comparison to provide a formulation having a predetermined amount of alcohol. (Item 85) The method according to item 83, comprising adding an amount of alcohol to the mixture. (Item 86) The method according to item 85, wherein the amount of alcohol added is more than the predetermined amount of alcohol. (Item 87) A method for manufacturing a pharmaceutical formulation for injection, comprising cetomelatonin as the only pharmaceutical active ingredient, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol, combining (in any order) cetomelatonin, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4), and alcohol to form a mixture, and comparing the value of the alcohol content in the mixture with a reference value of the alcohol content, thereby, a method for manufacturing a pharmaceutical formulation for injection, comprising cetomelatonin as the only pharmaceutical active ingredient, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol. (Item 88) The method according to item 87, comprising adding an amount of alcohol to the mixture. (Item 89) The method according to item 88, wherein the amount of alcohol added is more than the predetermined amount of alcohol. (Item 90) The method according to item 87, wherein the predetermined amount is 5 - 20, 10 - 20, 15 - 20, 5 - 15, 5 - 10, 5 - 15, or 10 - 15% by weight. (Item 91) The method according to item 87, wherein the predetermined amount is 10 ± 5% by weight. (Item 92) The method according to item 87, wherein the predetermined amount is 10 ± 4% by weight. (Item 93) The method according to item 87, wherein the predetermined amount is 10 ± 3% by weight. (Item 94) The method according to item 87, wherein the predetermined amount is 10 ± 2% by weight. (Item 95) The method according to item 87, wherein the predetermined amount is 10 ± 1% by weight. (Item 96) The method according to item 87, wherein the predetermined amount is 10 ± 0.5% by weight. (Item 97) The method according to item 87, comprising manufacturing a plurality of batches of the formulation. (Item 98) The method according to item 97, wherein each batch of the plurality of batches has an alcohol content within 2, 1, or 0.5% by weight of the alcohol content of a plurality of other batches. (Item 99) The method according to item 97, wherein each batch of the plurality of batches has an alcohol content within 2, 1, or 0.5% by weight of a reference value. (Item 100) The reference value is 5 to 20, 10 to 20, 15 to 20, 5 to 15, 5 to 10, 5 to 15, or 10 to 15% by weight; 10 ± 5% by weight; 10 ± 4% by weight; 10 ± 3% by weight; 10 ± 2% by weight; 10 ± 1% by weight; or 10 ± 0.5% by weight and is a value within the range of the method according to item 99. (Item 101) The reference value is a value within the range of 10 ± 2% by weight, and each batch of the plurality of batches has an alcohol content within 1 or 0.5% by weight of the reference value. The method according to item 99. (Item 102) The reference value is 10% by weight, and each batch of the plurality of batches has an alcohol content within 0.5% by weight of the reference value. The method according to item 99. (Item 103) The method according to item 99, wherein each batch of the plurality of batches has a sufficiently high alcohol content such that the composition has a sufficiently low viscosity to be comfortably delivered by an apparatus, such as a syringe having a thin needle, such as a 27-gauge needle. (Item 104) Each batch of the plurality of batches has, at the time of injection, an alcohol content sufficiently low to give a ratio of the minimum plasma concentration (C max ) to the maximum plasma concentration (C min ) of the initial burst of cetomelatide after subcutaneous injection, for example, an initial release of less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), before the next dose is administered. The method according to item 99. (Item 105) The method according to item 99, wherein each batch of the plurality of batches has an alcohol content sufficiently low such that the pharmaceutical gives a low initial release of cetomelatide at the time of injection. (Item 106) The low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 6 hours) after administration, which is less than 10% or less with respect to the area under the drug concentration-time curve for a 7-day steady-state dosing interval. The method according to item 105. (Item 107) The method according to item 105, wherein the low initial release is less than 10 to 20% or less thereof with respect to the area under the drug concentration-time curve at a steady-state dosing interval of 7 days, and is measured by the partial area under the setomelanotide concentration curve during the first few hours (e.g., the first 12 hours) after administration. (Item 108) The method according to item 105, wherein the low initial release is less than 20 to 30% or less thereof with respect to the area under the drug concentration-time curve at a steady-state dosing interval of 7 days, and is measured by the partial area under the setomelanotide concentration curve during the first few hours (e.g., the first 24 hours) after administration. (Item 109) The method according to item 103, wherein the device may be a single-use device or a multi-use device. (Item 110) The method according to item 103, wherein the device is selected from a manual syringe (e.g., a syringe including a needle (e.g., a needle having a suitable diameter, e.g., a 27-gauge needle)), or an auto-injector (e.g., a spring-loaded syringe, or a pen-type syringe). (Item 111) The method according to item 87, wherein the predetermined amount of alcohol is added as a single portion. (Item 112) The method according to item 87, wherein the predetermined amount of alcohol is added as a plurality of portions. (Item 113) The method according to item 87, wherein at least a part of the process after the addition of alcohol is carried out in a sealed container. (Item 114) The method according to item 87, wherein the process after the addition of alcohol is carried out in a sealed container. (Item 115) The method according to item 87, wherein at least a part of the process before the addition of alcohol is carried out in a sealed container. (Item 116) The method according to item 87, wherein the process before the addition of alcohol is carried out in a sealed container. (Item 117) A method for manufacturing a pharmaceutical formulated for injection containing setomelanotide as the only pharmaceutical active ingredient, comprising: (i) providing a mixture (setomelanotide-alcohol mixture) containing setomelanotide and alcohol, for example, in contact with alcohol, for example, ethanol, and for example, dissolved or dispersed therein; and (ii) combining the setomelanotide-alcohol mixture with an amount of components a, b, and d, or all of components a, b, and d The method comprising. (Item 118) The method according to item 117, wherein step (i), (ii), or (i) and (ii) are carried out in a sealed container. (Item 119) A method for manufacturing a pharmaceutical formulated for injection containing setomelatonin as the sole pharmaceutical active ingredient, comprising: (i) providing a mixture containing setomelatonin and alcohol (setomelatonin-alcohol mixture), for example, alcohol such as ethanol, in which setomelatonin is in contact with, for example, dissolved or dispersed therein; and (ii) combining said setomelatonin-alcohol mixture with an amount of component a (e.g., GDO), component b (e.g., soy PC), and component d (e.g., citrate buffer at pH 6.4), or all of components a, b, and d A method comprising. (Item 120) The method according to item 119, wherein step (i), (ii), or (i) and (ii) are carried out in a sealed container. (Item 121) A method for manufacturing a formulation of setomelatonin as the sole pharmaceutical active ingredient formulated for injection or evaluating a candidate formulation for, for example, quality control or shipping specifications, comprising: providing a value of the amount of EtOH in a candidate formulation of setomelatonin; and comparing said value with a reference value of the amount of EtOH Thereby, a method for manufacturing a formulation of setomelatonin as the sole pharmaceutical active ingredient formulated for injection. (Item 122) The method according to item 121, further comprising selecting said candidate formulation of setomelatonin according to said comparison. (Item 123) The method according to item 121, wherein said reference value includes a range defined by a lower limit value and an upper limit value, for example, an upper limit value and a lower limit value of wt% EtOH, for example, 10 wt%. (Item 124) The method according to item 123, wherein satisfying said reference value includes falling within said range. (Item 125) The method according to item 121, wherein said reference value is a value within the range of 5-20; 8.5-12.5; and 9-11 wt% EtOH, for example, 10 wt%. (Item 126) The method according to item 125, wherein said reference value is a value within the range of 9-11 wt% EtOH, for example, 10 wt%. (Item 127) providing a value of the amount of EtOH in a second candidate formulation of setomelatonin formulated for injection; and comparing said value with a reference value of the amount of EtOH The method according to item 121, comprising. (Item 128) Providing values of the amount of EtOH in N candidate formulations of setmelanotide as the only pharmaceutical active ingredient formulated for injection, where N is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 50, 100, or 1,000 or more; and comparing said values to a reference value of the amount of EtOH The method according to item 121, comprising. (Item 129) The method according to item 128, wherein the amount of EtOH in each of said plurality of formulations is within 5, 2, 1, or 0.5% of each other. (Item 130) The method according to item 128, wherein the amount of EtOH in each of said plurality of formulations is within 2% of each other. (Item 131) The method according to item 128, wherein the amount of EtOH in each of said plurality of formulations is within 0.5% of each other. (Item 132) The method according to item 128, wherein a plurality of first formulations and second formulations are manufactured within 10, 20, 30, 60, 180, or 365 days of each other. (Item 133) The method according to item 128, wherein the second formulation is manufactured less than 10, 20, 30, 60, 180, or 365 days after said first formulation. (Item 134) A method of manufacturing a composition or formulation, such as a pharmaceutical, formulated for injection and containing setmelanotide as the only pharmaceutical active ingredient, comprising manufacturing a mixture comprising setmelanotide, EtOH, neutral diacyl lipid and / or tocopherol, and phospholipid, wherein one or both of the neutral diacyl lipid and / or tocopherol and the phospholipid are added after the component (e) containing setmelanotide is combined with EtOH, thereby producing a composition or formulation, such as a pharmaceutical, formulated for injection and containing setmelanotide as the only pharmaceutical active ingredient. (Item 135) The method according to item 134, wherein one or both of the neutral diacyl lipid and / or tocopherol and the phospholipid are added after at least 10, 25, 50, 75, or all of setmelanotide has been solubilized. (Item 136) The order of formation of said mixture is i) contacting setmelanotide with EtOH (and optionally water or buffer); ii) adding phospholipid to the mixture resulting from i); and iii) adding neutral diacyl lipid and / or tocopherol to the mixture resulting from ii) The method according to item 134, which is. (Item 137) A method for manufacturing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, comprising the following steps: (i) Providing a mixture containing setmelanotide and alcohol (setmelanotide-alcohol mixture), for example, alcohol such as ethanol, in contact with, for example, setmelanotide dissolved or dispersed therein; and (ii) Combining said setmelanotide-alcohol mixture with one or more of a certain amount of components a, b, and d in sequence, thereby producing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, for example, containing a predetermined amount of alcohol, such as 10% by weight of alcohol, such as ethanol, and containing setmelanotide as the only pharmaceutical active ingredient. (Item 138) A method for manufacturing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, comprising the following steps: (i) Providing a mixture containing setmelanotide and alcohol, for example, alcohol such as ethanol, in contact with, for example, setmelanotide dissolved or dispersed therein; and (ii) Combining said mixture with a certain amount of component a (e.g., GDO), component b (e.g., soy PC), and component d (e.g., citrate buffer at pH 6.4), or with all of a certain amount of components a, b, and d; in sequence, thereby producing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, for example, containing a predetermined amount of alcohol, such as 10% by weight of alcohol, such as ethanol, and containing setmelanotide as the only pharmaceutical active ingredient formulated for injection. (Item 139) A method for manufacturing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, comprising the following steps: (i) Providing a mixture containing setmelanotide, alcohol, and component d, for example, a polar solvent such as a buffer, for example, alcohol such as ethanol and a buffer, in contact with, for example, setmelanotide dissolved or dispersed therein; and (ii) Combining said mixture with one or more of a certain amount of components a and b; in sequence, A method for producing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, for example, containing a predetermined amount of alcohol, for example 10% by weight of alcohol, for example ethanol, and containing setmelanotide as the only pharmaceutical active ingredient formulated for injection. (Item 140) A method for producing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, comprising the following steps: (i) Providing a mixture containing setmelanotide, alcohol, and component d, for example a polar solvent, for example a buffer, for example a citrate buffer at pH 6.4, for example, in contact with alcohol, for example ethanol and a citrate buffer at pH 6.4, for example, containing setmelanotide dissolved or dispersed therein; and (ii) Combining the mixture with an amount of component a (for example GDO) and component b (for example soy PC), or all of an amount of components a and b; Including in order, Thereby, a method for producing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, for example, containing a predetermined amount of alcohol, for example 10% by weight of alcohol, for example ethanol, and containing setmelanotide as the only pharmaceutical active ingredient formulated for injection. (Item 141) A method for producing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, component a, component b, component d, and a predetermined amount of alcohol, comprising In the specified order, combining setmelanotide, component a, component b, component d, and an added amount of alcohol, wherein the added amount of alcohol provides the predetermined amount of alcohol in the pharmaceutical product, and the specified order is the following steps: (i) Providing a mixture containing setmelanotide and an added amount of alcohol, for example, in contact with alcohol, for example ethanol, for example, containing setmelanotide dissolved or dispersed therein; and (ii) Combining the mixture with an amount of components a, b, and d or all of components a, b, and d Including in order; (i), (ii) or (i) and (ii) are carried out in a sealed container, thereby, a method for producing a pharmaceutical product containing setmelanotide as the only pharmaceutical active ingredient formulated for injection, component a, component b, component d, and a predetermined amount of alcohol, for example 10% by weight of alcohol, for example ethanol. (Item 142) Setomelotide as the only pharmaceutical active ingredient formulated for injection; A method for manufacturing a pharmaceutical product comprising component a, component b, component d, and a predetermined amount of alcohol, comprising: Combining setomelotide, component a, component b, component d, and the added amount of alcohol in the order specified, wherein the added amount of alcohol results in the predetermined amount of alcohol in the pharmaceutical product, and the specified order is the following steps: (i) Providing a mixture comprising setomelotide and the added amount of alcohol (setomelotide-alcohol mixture), for example, alcohol such as ethanol, in contact with, for example, setomelotide dissolved or dispersed therein; and (ii) Combining the setomelotide-alcohol mixture with an amount of component a, b, and d or all of components a, b, and d in sequence; (i), (ii) or (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical product comprising setomelotide, component a, component b, component d, and a predetermined amount of alcohol, for example 10% by weight of alcohol, for example ethanol. (Item 143) A method for manufacturing a pharmaceutical product comprising setomelotide as the only pharmaceutical active ingredient formulated for injection, component a (e.g., GDO), component b (e.g., soy PC), component d (e.g., a polar solvent such as a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol, comprising: Combining setomelotide, component a (e.g., GDO), component b (e.g., soy PC), component d (e.g., a polar solvent such as a buffer, e.g., a citrate buffer at pH 6.4), and the added amount of alcohol in the order specified, wherein the added amount of alcohol results in the predetermined amount of alcohol in the pharmaceutical product, and the specified order is the following steps: (i) Providing a mixture comprising setomelotide and the added amount of alcohol, for example, alcohol such as ethanol, in contact with, for example, setomelotide dissolved or dispersed therein; and (ii) Combining the mixture with an amount of component a (e.g., GDO), component b (e.g., soy PC), and component d (e.g., a citrate buffer at pH 6.4), or all of components a, b, and d in sequence; (i), (ii) or (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical product containing setomelanotide as the only pharmaceutical active ingredient formulated for injection, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., citrate buffer at pH 6.4), and a predetermined amount of alcohol, e.g., 10% by weight of alcohol, e.g., ethanol. (Item 144) A method for producing a pharmaceutical product containing setomelanotide as the only pharmaceutical active ingredient formulated for injection, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., citrate buffer at pH 6.4), and a predetermined amount of alcohol, comprising: combining, in the order specified, setomelanotide; ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., citrate buffer at pH 6.4), and the added amount of alcohol, the added amount of alcohol resulting in the predetermined amount of alcohol in the pharmaceutical product, and the specified order being the following steps: (i) providing a mixture containing setomelanotide and the added amount of alcohol (setomelanotide partial-alcohol mixture), e.g., alcohol, e.g., ethanol, in contact with, e.g., dissolved or dispersed therein, setomelanotide; and (ii) combining the setomelanotide-alcohol mixture with an amount of ingredient a (e.g., GDO), ingredient b (e.g., soy PC), and ingredient d (e.g., citrate buffer at pH 6.4), or all of ingredients a, b, and d in that order, (i), (ii) or (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical product containing setomelanotide, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., citrate buffer at pH 6.4), and a predetermined amount of alcohol, e.g., 10% by weight of alcohol, e.g., ethanol. (Item 145) A method for producing a pharmaceutical product containing setomelanotide as the only pharmaceutical active ingredient formulated for injection, ingredient a, ingredient b, ingredient d, and a predetermined amount of alcohol, comprising: comprising combining, in the order indicated, cetomelatide, ingredient a, ingredient b, ingredient d, and an amount of alcohol that provides a predetermined amount of alcohol in the pharmaceutical, and the order indicated comprises the following steps: (i) providing a mixture comprising cetomelatide, an amount of alcohol, and ingredient d, such as a polar solvent, such as a buffer, such as a citrate buffer at pH 6.4, e.g., a mixture of alcohol, such as ethanol, and a citrate buffer at pH 6.4, in contact with, e.g., dissolved or dispersed therein, cetomelatide; and (ii) combining the ingredient (e)-alcohol-buffer mixture with an amount or all of ingredients a and b in that order; (i), (ii), or (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical comprising cetomelatide, ingredient a, ingredient b, ingredient d, and a predetermined amount of alcohol, such as 10 wt% alcohol, such as ethanol, as the only pharmaceutical active ingredient formulated for injection. (Item 146) A method of producing a pharmaceutical comprising cetomelatide, ingredient a, ingredient b, ingredient d, and a predetermined amount of alcohol as the only pharmaceutical active ingredient formulated for injection, comprising combining, in the order indicated, cetomelatide, ingredient a, ingredient b, ingredient d, and an amount of alcohol that provides a predetermined amount of alcohol in the pharmaceutical, and the order indicated comprises the following steps: (i) providing a mixture (cetomelatide-alcohol-buffer mixture) comprising cetomelatide, an amount of alcohol, and ingredient d, such as a polar solvent, such as a buffer, such as a citrate buffer at pH 6.4, e.g., a mixture of alcohol, such as ethanol, and a citrate buffer at pH 6.4, in contact with, e.g., dissolved or dispersed therein, cetomelatide; and (ii) combining the cetomelatide-alcohol-buffer mixture with an amount or all of ingredients a and b in that order; (i), (ii), or (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical comprising cetomelatide, ingredient a, ingredient b, ingredient d, and a predetermined amount of alcohol, such as 10 wt% alcohol, such as ethanol, as the only pharmaceutical active ingredient formulated for injection. (Item 147) A method for manufacturing a pharmaceutical product containing setomelotide as the only pharmaceutical active ingredient formulated for injection, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol, comprising: combining setomelotide, ingredient a, ingredient b, ingredient d, and the added amount of alcohol in the order specified, wherein the added amount of alcohol provides the predetermined amount of alcohol in the pharmaceutical product, and the specified order is the following steps: (i) providing a mixture comprising setomelotide, the added amount of alcohol, and ingredient d, e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4, e.g., a mixture in contact with alcohol, e.g., ethanol and a citrate buffer at pH 6.4, and containing setomelotide dissolved or dispersed therein; and (ii) combining the mixture with an amount of ingredient a (e.g., GDO) and all of ingredient b (e.g., soy PC) or ingredients a and b in that order; (i), (ii), or (i) and (ii) are carried out in a sealed container, thereby producing a pharmaceutical product containing setomelotide as the only pharmaceutical active ingredient formulated for injection, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol, e.g., 10 wt% alcohol, e.g., ethanol. (Item 148) A method for manufacturing a pharmaceutical product containing setomelotide as the only pharmaceutical active ingredient formulated for injection, ingredient a (e.g., GDO), ingredient b (e.g., soy PC), ingredient d (e.g., a polar solvent, e.g., a buffer, e.g., a citrate buffer at pH 6.4), and a predetermined amount of alcohol, comprising: combining setomelotide, ingredient a, ingredient b, ingredient d, and the added amount of alcohol in the order specified, wherein the added amount of alcohol provides the predetermined amount of alcohol in the pharmaceutical product, and the specified order is the following steps: (i) A mixture (setomelatonin-alcohol-buffer mixture) containing setomelatonin, an added amount of alcohol, and component d, such as a polar solvent, such as a buffer, such as a citrate buffer at pH 6.4, for example, contacting with alcohol, such as ethanol, and a citrate buffer at pH 6.4, for example, providing setomelatonin dissolved or dispersed therein; and (ii) Combining the setomelatonin-alcohol-buffer mixture with an amount of component a (such as GDO) and all of component b (such as soy PC) or components a and b in sequence; A method for producing a pharmaceutical product containing, as the only pharmaceutical active ingredient formulated for injection, setomelatonin, component a (such as GDO), component b (such as soy PC), component d (such as a polar solvent, such as a buffer, such as a citrate buffer at pH 6.4), and a predetermined amount of alcohol, such as 10% by weight of alcohol, such as ethanol, wherein (i), (ii) or (i) and (ii) are carried out in a sealed container. (Item 149) A method for producing a pharmaceutical product containing setomelatonin as the only pharmaceutical active ingredient formulated for injection, comprising the following steps: i) Combining one or more (such as all) of an amount of components a, b, c, and d; ii) Providing a component (e) containing setomelatonin to this mixture; and iii) Mixing the mixture of (i) and (ii) for a specified time to dissolve or disperse setomelatonin in sequence, thereby producing a pharmaceutical product containing setomelatonin as the only pharmaceutical active ingredient formulated for injection, for example, containing a predetermined amount of alcohol, such as 10% by weight of alcohol, such as ethanol, and containing setomelatonin as the only pharmaceutical active ingredient formulated for injection. (Item 150) The method according to item 149, wherein the mixing is carried out for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 hours. (Item 151) The method according to item 149, wherein the mixing is carried out for 1 to 30 hours. (Item 152) The method according to item 149, wherein the mixing is carried out for 30, 40, or 50 hours or less. (Item 153) A method for manufacturing a pharmaceutical product containing setomelanotide as the only pharmaceutical active ingredient formulated for injection, comprising the following steps: i) Combining an amount of one or more (e.g., all) of components a, b, d with setomelanotide; ii) Providing a predetermined amount of component c to this mixture; and iii) Mixing the mixture of (i) and (ii) for the specified time to dissolve or disperse setomelanotide in sequence; Thereby, a pharmaceutical product containing setomelanotide as the only pharmaceutical active ingredient formulated for injection, for example, containing a predetermined amount of alcohol, such as 10% by weight of alcohol, such as ethanol, and a method for manufacturing a pharmaceutical product containing setomelanotide as the only pharmaceutical active ingredient formulated for injection. (Item 154) The method according to item 153, wherein the mixing is carried out for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 hours. (Item 155) The method according to item 153, wherein the mixing is carried out for 1 to 30 hours. (Item 156) The method according to item 153, wherein the mixing is carried out for 30, 40, or 50 hours or less. (Item 157) A plurality of formulations of a pharmaceutical product containing setomelanotide as the only pharmaceutical active ingredient formulated for injection, for example, a first formulation, a second formulation, a third formulation, or more formulations, wherein each of the plurality of formulations has an amount of EtOH within a predetermined range, for example, a plurality of formulations manufactured by the method described in item 62. (Item 158) The plurality of formulations according to item 157, wherein the amount of EtOH in each of the plurality of formulations is within 2, 1, or 0.5% by weight of each other. (Item 159) The plurality of formulations according to item 157, wherein the amount of EtOH in each of the plurality of formulations is within the range of 10% ± 5, 10% ± 4, 10% ± 3, 10% ± 2, or 10% ± 1 of each other's weight. (Item 160) The plurality of formulations according to item 157, wherein the plurality of first formulations and second formulations are manufactured within 10, 20, 30, 60, 180, or 365 days of each other. (Item 161) The plurality of formulations according to item 157, wherein the second formulation is manufactured less than 10, 20, 30, 60, 180, or 365 days after the first formulation. (Item 162) A method of administering setmelanotide as the sole pharmaceutical active ingredient formulated for injection to a subject, the method comprising administering to the subject an effective amount of the injectable composition according to item 1. (Item 163) The method according to item 162, wherein the subject has or is at risk of having a disease responsive to the modulation of melanocortin-4 receptor (MC4R). (Item 164) The method according to item 163, wherein the disease is selected from type 1 diabetes, type 2 diabetes, obesity, insulin resistance, metabolic syndrome, male erectile dysfunction, female sexual dysfunction, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, substance use disorders including alcohol dependence, eating disorders, cachexia, inflammation, or anxiety, Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome. (Item 165) The method according to item 164, wherein the disease is obesity. (Item 166) The method according to item 164, wherein the disease is type 1 diabetes. (Item 167) The method according to item 164, wherein the disease is type 2 diabetes. (Item 168) The method according to item 164, wherein the disease is Prader-Willi syndrome. (Item 169) The method according to item 164, wherein the disease is Bardet-Biedl syndrome. (Item 170) The method according to item 164, wherein the disease is Alström syndrome.

Brief Description of the Drawings

[0114]

Figure 1A

Figure 1B

Figure 2A

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Figure 7

[0115] The present disclosure relates, at least in part, to setmelanotide (also known as RM493); setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or another pharmaceutical composition having as its main mechanism of action an agonist at the MC4 receptor as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection (referred to as MC4RA P ), e.g., BIM-22511 (also known as RM511), BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or the MC4 receptor agonist disclosed as SEQ ID NO: 11 in WO 2008 / 147556 (referred to as MC4R-11).

[0116] The pharmaceutical of the present disclosure forms a non-lamellar liquid crystalline phase upon administration. The use of non-lamellar phase structures (such as liquid crystalline phases) in the delivery of bioactive agents is known in the art. Exemplary lipid depot systems are described, for example, in WO 2005 / 117830, which is incorporated herein by reference in its entirety.

[0117] All percentages are by weight throughout this specification unless otherwise specified. Further, the weight percentages shown are percentages relative to the entire pharmaceutical composition including all of the components shown herein. The pharmaceutical composition may optionally consist essentially of only the components shown herein (including, in the case of appropriate additional optional components, as shown hereinafter and in the appended claims), and in one embodiment, consists entirely of such components.

[0118] In one embodiment, the pharmaceutical composition has an L2 phase structure. In one embodiment, the pharmaceutical composition forms a non-lamellar, e.g., liquid crystalline, phase upon administration.

[0119] In one embodiment, the pharmaceutical composition is capable of controlling the peak concentration (C max ) of the drug in the plasma below a level that is tolerable to the subject in order to avoid side effects such as, for example, headache, changes in blood pressure, heart rate, respiratory rate, excessive sweating, or other undesirable or unwanted effects, while providing or achieving an effective, e.g., therapeutically effective, level over the period of release. Generally, the average concentration, C ave , during the release period before the next dose is administered, falls within the therapeutic range. Control of the maximum concentration (C max ) and minimum concentration (C min ) over a defined dosing period, e.g., once weekly or once monthly, is also important to achieve an effective and safe treatment over time. In one embodiment, the initial burst is not the C max of the release profile.

[0120] Regardless of whether the initial burst is also the C max , the C max / C ave ratio is 10 or less. In one embodiment, the C ave / C min ratio is 10 or less, e.g., 9, 8, 7, 6, 5, 4, 3, 2, or 1 or less. In one embodiment, the C ave / C min ratio is less than 3. The C maxis defined as the peak or maximum plasma concentration observed during the release period before the next dose is administered, C ave is defined as the average plasma concentration during that release period. C min correspondingly, is the lowest concentration during that period. C ave can be calculated as the area under the curve (AUC) above the selected period, generally the entire release period before the administration of the next dose, by calculating the drug present in the plasma and dividing by that period.

[0121] Component (a) - neutral diacyl lipid and / or tocopherol Component "a" described herein is a neutral lipid containing a polar "head" group and a nonpolar "tail" group. Generally, the head and tail portions of the lipid are linked by an ester moiety, although this linkage may be by an ether, amide, carbon-carbon bond, or other bond. In one embodiment, the polar head group includes a nonionic head group containing a polyol, such as glycerol, diglycerol, or a sugar moiety (e.g., inositol or glucosyl moiety), and an ester of the polyol, such as an acetate ester or a succinate ester. In one embodiment, the polar "head" group includes glycerol or diglycerol.

[0122] In one embodiment, component (a) includes a diacyl lipid having two nonpolar "tail" groups. The two nonpolar groups can have the same or different numbers of carbon atoms and can each independently be saturated or unsaturated. In embodiments, the two nonpolar "tail" groups can have the same or different numbers of carbon atoms and can each independently be saturated or unsaturated. In one embodiment, the nonpolar groups include C6-C32 alkyl and alkenyl groups, which typically exist as esters of long-chain carboxylic acids. These are often described with reference to the number of carbon atoms and the number of unsaturations in the carbon chain. Thus, CX:Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations.

[0123] In one embodiment, the nonpolar "tail" group of component (a) is selected from lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoyl (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3), arachidonoyl (C20:4), behenoyl (C22:0), or lignoceroyl (C24:9). Typically, the nonpolar chain is based on the fatty acids of natural ester lipids, including caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, phytic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, arachidonic acid, behenic acid, or lignoceric acid, or the corresponding alcohols. In one embodiment, the nonpolar "tail" group of component (a) is selected from palmitic acid, stearic acid, oleic acid, or linoleic acid. In one embodiment, the nonpolar "tail" group of component (a) is oleic acid.

[0124] In one embodiment, the diacyl lipid of component (a) is selected from butyric acid (C4), valeric acid (C5), caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), myristic acid (C14), pentadecanoic acid (C15), palmitic acid (C16), margaric acid (C17), stearic acid (C18), nonadecylic acid (C19), arachidic acid (C20), henicosylic acid (C21), behenic acid (C22), tricosylic acid (C23), lignoceric acid (C24), pentacosylic acid (C25), cerotic acid (C26), heptacosylic acid (C27), montanic acid (C28), nonacosylic acid (C29), melissic acid (C30), hentriacontylic acid (C31), lacceroic acid (C32), psyllic acid (C33), gedanic acid (C34), ceroplastic acid (C35), hexatriacontylic acid (C36), heptatriacontanoic acid (C37), octatriacontanoic acid (C38), α-linolenic acid (18:3), stearidonic acid (18:4), eicosapentaenoic acid (20:5), docosahexaenoic acid (22:6), linoleic acid (18:2), γ-linolenic acid (18:3), dihomo-γ-linolenic acid (20:3), arachidonic acid (20:4), adrenic acid (22:4), palmitoleic acid (16:1), vaccenic acid (18:1), paullinic acid (20:1), oleic acid (18:1), elaidic acid (trans-18:1), gondoic acid (20:1), erucic acid (22:1), nervonic acid (24:1), and mead acid (20:3), or a pharmaceutically acceptable ester formed by the acid.

[0125] In one embodiment, a mixture of any number of diacyl lipids can be used as component (a). In one embodiment, component (a) includes a portion of C18 lipids (e.g., a diacylglycerol having one or more C18:0, C18:1, C18:2, or C18:3 nonpolar "tail" groups), for example, glycerol dioleate (GDO) or glycerol dilinoleate (GDL).

[0126] In one embodiment, the diacyl lipid of component (a) includes diacylglycerol (DAG), for example, glycerol dioleate (GDO). In one embodiment, the DAG of component (a) is GDO.

[0127] In one embodiment, component (a) is a DAG containing at least 50 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, or 100 wt% of GDO. In one embodiment, component (a) contains 100 wt% of GDO.

[0128] In one embodiment, when the diacyl lipid is used as all or part of component (a), it may be synthetic or derived from a purified and / or chemically modified natural source, for example, vegetable oil. In one embodiment, the diacyl lipid (e.g., DAG, e.g., GDO) is synthetic. In one embodiment, the diacyl lipid (e.g., DAG, e.g., GDO) is derived from a natural source, for example, a plant source or a bacterial source.

[0129] In one embodiment, the diacyl lipid has a purity of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, or more. In some embodiments, the diacyl lipid is GDO. In one embodiment, GDO has a purity of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, or more. In one embodiment, GDO has a purity of at least 50%. In one embodiment, GDO has a purity of at least 75%. In one embodiment, GDO has a purity of at least 85%. In one embodiment, GDO has a purity of at least 90%. In one embodiment, GDO has a purity of at least 95%. In one embodiment, GDO has a purity of at least 98%. In one embodiment, GDO has a purity of at least 99%. In one embodiment, GDO has a purity between about 50% - 100%, about 75% - about 100%, or about 90% - 100%. In one embodiment, GDO has a purity between about 85% - 99%, about 88% - 96%, about 90% - 98%, about 90% - 96%, about 90% - 94%, about 90% - 92%, about 92% - 98%, about 92% - 96%, about 92% - 94%, about 94% - 98%, about 94% - 96%, about 96% - 98%, or 98% - 100%.

[0130] In one embodiment, the GDO described herein refers to any commercial grade GDO having accompanying impurities (i.e., GDO of commercial purity). Exemplary impurities include undesirable lipids and fatty acid compounds. These impurities can be separated and removed by purification. In one embodiment, the GDO includes chemically pure GDO, for example, GDO having a purity of at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%. In one embodiment, the GDO includes less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 2.5%, 1%, or 0.5% impurities, such as undesirable lipids or fatty acid compounds. In one embodiment, the GDO includes less than about 20% impurities, such as undesirable lipids or fatty acid compounds. In one embodiment, the GDO includes less than about 10% impurities, such as undesirable lipids or fatty acid compounds. In one embodiment, the GDO includes less than about 5% impurities, such as undesirable lipids or fatty acid compounds. In one embodiment, the GDO includes less than about 2% impurities, such as undesirable lipids or fatty acid compounds. In one embodiment, the GDO includes less than about 1% impurities, such as undesirable lipids or fatty acid compounds.

[0131] In one embodiment, the undesirable lipid or fatty acid compound is a saturated lipid or an unsaturated lipid. Exemplary undesirable lipid or fatty acid compounds include propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, tridecylic acid, myristic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosylic acid, montanic acid, nonacosylic acid, melissic acid, henatriacontylic acid, laceroleic acid, psyllic acid, gedanic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanic acid, octatriacontanic acid, myristoleic acid, palmitoleic acid, vaccenic acid, cis-vaccenic acid, paullinic acid, oleic acid, elaidic acid, 11-eicosenoic acid (i.e., gondoic acid), erucic acid, brassidic acid, nervonic acid, sapienic acid, gadoleic acid, petroselinic acid, and linoleic acid (e.g., α-linolenic acid), or an isomer or variant thereof.

[0132] In one embodiment, component (a) comprises tocopherol. In one embodiment, the tocopherol of component (a) comprises a nonionic lipid tocopherol, such as vitamin E, or any suitable salt or analog thereof. In one embodiment, suitable analogs of tocopherol include those that impart the following properties: phase behavior, lack of toxicity, and phase change upon exposure to an aqueous fluid.

[0133] In one embodiment, the tocopherol is purified from a natural source and contains less than 10 wt% of a non-tocopherol "admixture", e.g., less than 10, 5, 4, 3, 2, 1 wt% or less of the admixture. In one embodiment, component (a) comprises at least 50, 80, 85, 90, 95, 99 wt% or more of tocopherol, such as vitamin E, or any suitable salt or analog thereof. In one embodiment, component (a) comprises 100 wt% tocopherol, such as vitamin E, or any suitable salt or analog thereof.

[0134] Component (b) - Phosphatidylcholine Component "b" described herein includes phospholipids containing a polar head group and at least one non-polar tail group. The non-polar tail group can be derived from the fatty acids or corresponding alcohols described above with respect to component a. In one embodiment, the phospholipid of component (b) contains two non-polar tail groups. In one embodiment, the phospholipid of component (b) contains a C18 group and can be combined with other suitable non-polar tail groups, particularly a C16 group. In one embodiment, the phospholipid of component (b) contains two identical non-polar tail groups.

[0135] In one embodiment, the phospholipid of component (b) contains a polar head group selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol. In one embodiment, the polar head group of the phospholipid of component (b) is phosphatidylcholine (PC). In one embodiment, component (b) contains at least 50 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, at least 99 wt%, or 100 wt% of PC. In one embodiment, component (b) contains PC.

[0136] In one embodiment, the PC of component (b) can be of natural origin, such as egg PC, heart PC (e.g., bovine heart PC), brain PC, liver PC (e.g., bovine brain PC, or bovine liver PC), and plants (e.g., soy PC). In one embodiment, the PC of natural origin can include any mixture of phospholipids. In one embodiment, the PC of natural origin includes soy PC or egg PC. In one embodiment, the PC of natural origin includes soy PC. In one embodiment, the PC contains at least 50 wt% of soy PC or egg PC, at least 75 wt% of soy PC or egg PC, at least 80 wt% of soy PC or egg PC, at least 90 wt% of soy PC or egg PC, at least 95 wt% of soy PC or egg PC, at least 99 wt% of soy PC or egg PC, or 100 wt% of soy PC or egg PC.

[0137] In one embodiment, the PC of component (b) is soy PC. In one embodiment, the PC contains 18:2 fatty acid as the primary fatty acid component and contains 16:0 and / or 18:1 as the secondary fatty acid component, but the ratio of the primary acid component to the secondary acid component is between 1.5:1 and 6:1. In one embodiment, the PC of component (b) contains 60 - 65% of 18:2, 10 - 20% of 16:0, 5 - 15% of 18:1, and the balance is mainly other 16 - and 18 - carbon fatty acids. In one embodiment, the PC comprising of soy PC has the above - described composition.

[0138] In one embodiment, the PC of component (b) contains synthetic dioleoyl PC. Synthetic dioleoyl PC is considered to provide increased stability, and thus, it is necessary to be stable during long - term storage and / or is suitable for compositions having a long release period in vivo. In one embodiment, the PC of component (b) contains at least 50 wt%, at least 75 wt%, at least 80 wt%, at least 90 wt%, at least 95 wt%, at least 99 wt%, or 100 wt% of synthetic dioleoyl PC.

[0139] In one embodiment, the phospholipid of component (b) has a purity of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, or more. In some embodiments, the phospholipid of component (b) is phosphatidylcholine (PC). In one embodiment, the PC has a purity of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, or more.

[0140] In one embodiment, component (b) includes synthetic or highly purified PCs, such as dioleoylphosphatidylcholine (DOPC). In one embodiment, the synthetic dioleoyl PC is 1,2-dioleoyl-sn-glycero-3-phosphocholine, as well as other synthetic PC components, such as DDPC (1,2-didecanoyl-sn-glycero-3-phosphocholine); DEPC (1,2-diervanoyl-sn-glycero-3-phosphocholine); DLOPC (1,2-dilinoleoyl-sn-glycero-3-phosphocholine); DLPC (1,2-dilauroyl-sn-glycero-3-phosphocholine); DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine); DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine); DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine); DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine); MPPC (1-myristoyl-2-palmitoyl-sn-glycero 3-phosphocholine); MSPC (1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine); PMPC (1-palmitoyl-2-myristoyl-sn-glycero-3-phosphocholine); POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine); PSPC (1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine); SMPC (1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine); SOPC (1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine); and SPPC (1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine), or any combination thereof.

[0141] In an embodiment, component (b) containing synthetic or highly purified PC (e.g., DOPC) can impart higher stability to the active pharmaceutical agent in the formulation. In one embodiment where the formulation does not contain an antioxidant, component (b) contains synthetic or highly purified (e.g., with a purity exceeding 90%) PC (e.g., DOPC) (e.g., containing at least 75% by weight). In one embodiment where the formulation contains an antioxidant, component (b) contains naturally derived PC, such as soy PC or egg PC (e.g., at least 75% by weight).

[0142] In one embodiment, the pharmaceutical product contains component (a) in the range of 20 - 80% by weight, 30 - 70% by weight, 33 - 60% by weight, or 38 - 43% by weight. In one embodiment, the pharmaceutical product contains component (b) in the range of 20 - 80% by weight, 30 - 70% by weight, 33 - 55% by weight, or 38 - 43% by weight.

[0143] In one embodiment, the pharmaceutical product contains 42% by weight of component (a). In one embodiment, the pharmaceutical product contains 42% by weight of component (a), and the neutral diacyl lipid is glycerol dioleate (GDO).

[0144] In one embodiment, the pharmaceutical product contains 42% by weight of component (b). In one embodiment, the pharmaceutical product contains 42% by weight of component (b), and the phospholipid is phosphatidylcholine (PC). In one embodiment, the PC is soy PC.

[0145] In one embodiment, the pharmaceutical product contains at least 80, 70, 60, 50, 40, 30, or 20% by weight of component (a). In one embodiment, the pharmaceutical product contains at least 80, 70, 60, 50, 40, 30, or 20% by weight of component (b). In one embodiment, the pharmaceutical product contains at least 42% of component (a), such as GDO, and at least 42% of component (b), such as soy PC.

[0146] In one embodiment, the pharmaceutical product contains components (a) and (b), and component (a), such as GDO, is present at 42% by weight ±10, 42% by weight ±5, 42% by weight ±2, or 42% by weight ±1.

[0147] In one embodiment, the pharmaceutical product comprises components (a) and (b), and component (b), such as soy PC, is present at 42% by weight ±10, 42% by weight ±5, 42% by weight ±2, or 42% by weight ±1.

[0148] In one embodiment, the pharmaceutical product comprises components (a) and (b), and component (a), such as GDO, and component (b), such as soy PC, are each present at 42% by weight ±10, 42% by weight ±5, 42% by weight ±2, or 42% by weight ±1.

[0149] In one embodiment, the ratio of component (a):(b) is 40:60 to 70:30, 45:55 to 55:45, or 40:60 to 54:46. In one embodiment, the ratio of (a):(b) is 50:50.

[0150] In one embodiment, components (a) and (b) constitute 95% by weight of the lipid component of the pharmaceutical product, for example, at least 95, 96, 97, 98, 99% by weight or more. In one embodiment, components (a) and (b) constitute 99% by weight of the total lipid content of the formulation. In one embodiment, the lipid component of the pharmaceutical product contains substantially all, for example, 100% by weight of components (a) and (b).

[0151] Component (c) - alcohol Component (c) described herein contains alcohol. Since the pharmaceutical product is useful for generating a depot composition typically upon contact with an excess of aqueous fluid after administration (e.g., in vivo), it is desirable that the alcohol is tolerable to the subject, mixable with the aqueous fluid, and / or diffusible or soluble from the formulation into the aqueous fluid. In one embodiment, component (c) contains an alcohol having at least moderate water solubility.

[0152] In one embodiment, the alcohol of component (c) includes ethanol, propanol, isopropanol, or a mixture thereof. In one embodiment, component (c) contains ethanol.

[0153] In one embodiment, the addition or presence of less than 20% by weight of alcohol (e.g., less than 20, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3.5, 3, 2.5, 2, 1% by weight or less) to the mixture containing (a) and (b) results in a significant decrease in viscosity, e.g., a decrease in viscosity of 30 - 70%, e.g., a decrease of 30, 40, 50, 60 or 70%, or a viscosity decrease exceeding that. In one embodiment, the addition or presence of 10% by weight of alcohol to the mixture containing (a) and (b) results in a 50% decrease in viscosity.

[0154] In one embodiment, the addition or presence of at least 10% by weight of alcohol to the mixture containing (a) and (b) results in a decrease in viscosity of at least 50% (e.g., a decrease in viscosity of at least 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60%). In one embodiment, the addition or presence of at least 2.5% by weight of alcohol to the mixture containing (a), (b), and at least 10% by weight of alcohol results in a further decrease in viscosity of at least 50% (e.g., a decrease in viscosity of at least 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60%). In one embodiment, the addition or presence of at least 3.5% by weight of alcohol to the mixture containing (a), (b) and at least 12.5% by weight of alcohol results in a further decrease in viscosity of at least 50% (e.g., a decrease in viscosity of at least 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60%).

[0155] The amount of component (c) in the pharmaceutical can have a significant impact on several characteristics. In particular, the viscosity and the rate (and duration) of release vary with the alcohol level. Therefore, the amount of alcohol is at least sufficient to provide a low-viscosity mixture that can be easily and comfortably injected by the patient applying hand pressure to the injection device, but is further determined to provide a release rate.

[0156] Physical attributes such as viscosity and reproducibility, such as reproducibility between batches or injections, are important when the pharmaceutical is administered using a device that assists injection by applying a force greater than the force applied by mechanical or other driving means, such as by hand, for example an autoinjector. The consistency of alcohol content, such as ethanol, within and between lots is important for reproducible performance, such as optimized pharmacokinetics, when the pharmaceutical is administered using such a device, for example an autoinjector.

[0157] Typically, an alcohol level of 0.1 to 35% by weight, or 5 to 20% by weight, will provide suitable release and viscosity properties. The amount of alcohol is cetomelanotide; cetomelanotide as the only pharmaceutical active ingredient formulated for injection; cetomelanotide as the only active ingredient; cetomelanotide as a pharmaceutical active ingredient; cetomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) will also be at least sufficient to ensure solubility. In one embodiment, the pharmaceutical is cetomelanotide; cetomelanotide as the only pharmaceutical active ingredient formulated for injection; cetomelanotide as the only active ingredient; cetomelanotide as a pharmaceutical active ingredient; cetomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PComponent (c), such as ethanol, in an amount sufficient to provide a solubility of at least 10 mg / g, 20 mg / g, 30 mg / g, 40 mg / g, 50 mg / g or more of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is included. In one embodiment, the pharmaceutical is setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Component (c), such as ethanol, in an amount sufficient to provide a solubility of at least 30 mg / g of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is included.

[0158] In one embodiment, the amount of component (c) in the pharmaceutical is such that, upon injection, the initial burst of the drug after subcutaneous injection is less than 8 (for example, less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), the ratio of the highest concentration (C max ) to the lowest concentration (C min ) in the plasma before the next dose is administered.

[0159] In one embodiment, the pharmaceutical product contains 0.1 to 35% by weight, 5 to 20% by weight, 8 to 15% by weight, or 9 to 11% by weight of component (c). In one embodiment, the pharmaceutical product contains 20, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5% by weight or less of component (c), and the alcohol of component (c) is ethanol. In one embodiment, the pharmaceutical product contains 10% by weight of component (c), and the alcohol of component (c) is ethanol.

[0160] The amount of component (c) in the pharmaceutical product described herein is sufficient to provide a low-viscosity mixture (e.g., a molecular solution) of components (a), (b), (c), and (d), and can be determined by standard methods for a particular combination of components.

[0161] In one embodiment, component (c) contains less than 5% by weight (e.g., less than 5, 4, 3, 2, 1% by weight, or less) of a halogen-substituted hydrocarbon with low biocompatibility.

[0162] Phase behavior can be analyzed by techniques such as polarized light microscopy, X-ray scattering and diffraction techniques, nuclear magnetic resonance, and visual observation combined with cryo-transmission electron microscopy (cryo-TEM) to search for molecular solutions, L2 or L3 phases, or liquid crystal phases, or dispersed fragments of such phases as in the case of cryo-TEM. Viscosity can be measured directly by standard means. In one embodiment, a suitable practical viscosity is one that can apply an effective pressure to a device containing the pharmaceutical product, such as a syringe, such as a manual syringe (e.g., by hand pressure), or a spring-loaded syringe (e.g., an autoinjector). In one embodiment, a pharmaceutical product having a suitable practical viscosity can apply pressure to a syringe with a needle, such as a needle with a small diameter suitable for injection (e.g., a 27-gauge needle), to administer, e.g., release, the pharmaceutical product. In one embodiment, a pharmaceutical product having a suitable practical viscosity can be sterilization-filtered through a filter with a pore size of 0.2 microns or less.

[0163] In one embodiment, component (c) comprises a single alcohol or a mixture of alcohols, such as an alcohol having a low viscosity. In one embodiment, the formulations provided herein are of low viscosity, and the first role of a suitable solvent is to reduce this viscosity. This reduction will be a combination of the effect of the lower viscosity of the solvent and the effect of the molecular interactions between the solvent and the lipid composition. Disclosed herein is the observation that the low viscosity oxygen-containing solvents described herein are advantageous and have molecular interactions with the lipid moiety of the composition, and for this reason, the addition of a small amount of solvent results in a non-linear decrease in viscosity.

[0164] In one embodiment, the viscosity of the low viscosity alcohol (single solvent or mixture) of component (c) is 18 mPas or less at 20 °C, such as 15 mPas or less, 10 mPas, or 7 mPas.

[0165] In one embodiment, the pharmaceutical comprises components (a), (b), and (c), component (a) is GDO, component (b) is soy PC, and component (c) is ethanol. In one embodiment, the pharmaceutical comprises 42 wt% of component (a), 42 wt% of component (b), and 10 wt% of component (c), component (a) is GDO, component (b) is soy PC, and component (c) is ethanol.

[0166] Component (d) - polar solvent or buffer In one embodiment, the use of an alcohol in combination with a polar solvent such as a diol or water or an aqueous solution, such as an aqueous buffer, such as a citrate buffer, enables improvement in the performance of the lipid-based controlled release composition. The addition of a diol such as propylene glycol or water is cetomelatide; cetomelatide as the only pharmaceutical active ingredient formulated for injection; cetomelatide as the only active ingredient; cetomelatide as a pharmaceutical active ingredient; cetomelatide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) without adversely affecting the release profile; cetomelatonin as the only pharmaceutical active ingredient formulated for injection; cetomelatonin as the only active ingredient; cetomelatonin as a pharmaceutical active ingredient; cetomelatonin as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); it has been observed that the viscosity of the pharmaceutical is reduced and / or it is possible to increase the ratio of alcohol without adversely affecting the release profile and / or it is possible to improve the release profile. As used herein, "adversely affecting the release profile" means that the ratio of C max / C ave increases and / or the ratio of C max / C min increases, for example, by at least 1.2-fold. Similarly, as used herein, "improving the release profile" means that the ratio of C max / C ave and / or the ratio of C max / C min decreases, for example, to at least one-twelfth.

[0167] In one embodiment, when a polar solvent, such as a polar solvent containing water, is included, improvement in the control of initial release becomes possible, and setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) allows for a higher stable loading. In one embodiment, when a polar solvent, such as a polar solvent containing water, is included, the depot is formed faster and / or the discomfort during injection is further reduced. Any one of these factors provides a significant improvement in the situation of therapeutic drug delivery, patient health, and / or patient compliance.

[0168] Component (d) described herein includes a polar solvent that stabilizes the pH of the pharmaceutical, such as water and a solvent optionally containing a pH adjusting or buffering compound. In one embodiment, the polar solvent of component (d) is selected from a histidine buffer, a citrate buffer, a succinate buffer, an acetate buffer, or a phosphate buffer, or a mixture thereof. In one embodiment, component (d) includes a citrate buffer, an L-histidine buffer, or a mixture of an L-histidine buffer and an L-histidine hydrochloride buffer. In one embodiment, component (d) is a citrate buffer.

[0169] In one embodiment, the citrate buffer of component (d) includes a pH in the range of 5.8 to 7, such as a pH of 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. In one embodiment, the citrate buffer of component (d) includes a pH of 6.4.

[0170] In one embodiment, the pharmaceutical product contains at least 10% by weight (e.g., at least 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5% by weight or less) of component (d), and component (d) is a buffer solution, such as a citrate buffer solution with a pH of 6.4. In one embodiment, the pharmaceutical product contains component (d) in the range of 0.5 - 10% by weight, 1 - 5% by weight, or 1 - 3% by weight, and component (d) is a buffer solution, such as a citrate buffer solution with a pH of 6.4. In one embodiment, the pharmaceutical product contains 2% by weight of component (d), and component (d) is a buffer solution, such as a citrate buffer solution with a pH of 6.4.

[0171] In one embodiment, the citrate buffer solution of component (d) contains citric acid monohydrate and optionally an antioxidant, such as disodium edetate (EDTA disodium salt). In one embodiment, component (d) contains a solution of 30 mM citric acid monohydrate, such as a solution of 30 mM, 25 mM, 24 mM, 23 mM, 22 mM, 21 mM, 20 mM, 15 mM, 10 mM, or 5 mM citric acid monohydrate. In one embodiment, component (d) contains a solution of 23 mM citric acid monohydrate.

[0172] In one embodiment, the citrate buffer solution of component (d) contains citric acid monohydrate and an antioxidant. For example, the antioxidant is disodium edetate (EDTA). In one embodiment, component (d) contains a solution of 30 mM citric acid monohydrate (e.g., 30, 25, 24, 23, 22, 21, 20, 15, 10, or 5 mM citric acid monohydrate) and a solution of 350 μM disodium edetate (e.g., 350, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 200, 100, or 50 μM disodium edetate). In one embodiment, component (d) contains a solution of 23 mM citric acid monohydrate and a solution of 300 μM disodium edetate.

[0173] In one embodiment, component (d) comprises an antioxidant or a chemical or physical stabilizer selected from optional components such as EDTA (including pharmaceutically acceptable salts such as edetate, sodium, calcium, magnesium, etc., but not limited thereto), BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), ascorbic acid, alpha-tocopherol (vitamin-E), or thiosulfate (including pharmaceutically acceptable salts such as sodium or calcium, but not limited thereto).

[0174] In one embodiment, the optional component of component (d), such as an antioxidant or a chemical or physical stabilizer, is setomeranotide as described herein; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) can be stabilized and oxidative degradation can be suppressed. In one embodiment, the optional component of component (d), such as an antioxidant or a chemical or physical stabilizer, is setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection PDo not reduce the solubility of (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11); or do not reduce the transparency of the pharmaceutical, e.g., the transparency of the solution. In one embodiment, the optional component of component (d), such as an antioxidant or a chemical or physical stabilizer, does not reduce the ability of the pharmaceutical to form an organized gel-like structure upon injection or upon contact with simulated physiological fluids.

[0175] In one embodiment, the antioxidant of component (d) is cetomelatonin in dissolved or dispersed form; cetomelatonin as the only pharmaceutical active ingredient formulated for injection; cetomelatonin as the only active ingredient; cetomelatonin as a pharmaceutical active ingredient; cetomelatonin as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection. P Increase the physical and chemical stability of (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) to give cetomelatonin in the presence of an antioxidant; cetomelatonin as the only pharmaceutical active ingredient formulated for injection; cetomelatonin as the only active ingredient; cetomelatonin as a pharmaceutical active ingredient; cetomelatonin as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection. P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) in a greater amount. In one embodiment, the antioxidant of component (d) is, for example, setomelotide in a lipid formulation under typical storage conditions of 0 to 5 °C or 20 to 25 °C; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection. P Increase the chemical and / or physical stability of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0176] Including any polar solvent (especially water) miscible with the alcohol component can substantially eliminate the slight sensation that may occur at the injection site by including alcohol. In one embodiment, the pharmaceutical product contains a ratio of component (c):(d) between 10:90 to 90:10, 20:80 to 80:20, 30:70 to 70:30, or 40:60 to 60:40.

[0177] In one embodiment, the pharmaceutical product contains components (c) and (d), component (c) contains ethanol (for example, ethanol of at least 20, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5% by weight or less), and component (d) contains a citrate buffer optionally containing an antioxidant (for example, a citrate buffer of at least 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5% by weight or less, optionally containing an antioxidant). In one embodiment, the formulation contains 10% ethanol and 2% citrate buffer, and the buffer optionally contains an antioxidant.

[0178] In one embodiment, the pharmaceutical product described herein contains GDO (for example, 40 - 70% by weight of GDO), soy PC (for example, 40 - 70% by weight of GDO), ethanol (for example, 5 - 20% by weight of ethanol), and a citrate buffer containing disodium edetate (for example, a 0.5 - 10% by weight 23 mM citrate buffer containing 300 mM disodium edetate), or a mixture thereof. In one embodiment, the pharmaceutical product contains 42% by weight of GDO, 42% by weight of soy PC, 10% by weight of ethanol, a 2% by weight 23 mM citrate buffer containing 300 mM disodium edetate, or a mixture thereof.

[0179] Component (e) Component (e) described herein is setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P (for example, BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11). In one embodiment, component (e) contains setmelanotide.

[0180] In any of the embodiments described herein, component (e) is setomeranotide in a suitable salt or gel form; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). In one embodiment, the salt form is a pharmaceutically acceptable salt. Exemplary salts (e.g., pharmaceutically acceptable salts) include acetate, benzenesulfonate, benzoate, bicarbonate, bicarbonate tartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylic acid salt, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theocurate, tosylate, triethiodide, and trifluoroacetate. In one embodiment, component (e) comprises a suitable salt, such as cetomelatonin chloride salt. In one embodiment, component (e) is cetomelatonin; cetomelatonin as the sole pharmaceutical active ingredient formulated for injection; cetomelatonin as the sole active ingredient; cetomelatonin as a pharmaceutical active ingredient; cetomelatonin as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PIt contains a chloride salt of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). In one embodiment, component (e) contains a chloride salt of setomeranotide.

[0181] In one embodiment, component (e) is MC4RA P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). Exemplary MC4RA P The structure of the compound is described in Table 1.

[0182]

Table 1

[0183] In one embodiment, component (e) is MC4RA P and includes, for example, a compound containing SEQ ID NO: 11 described in the pamphlet of International Patent Application Publication No. WO 2008 / 147556, which is incorporated herein by reference in its entirety. In one embodiment, the compound containing SEQ ID NO: 11 is referred to herein as MC4R-11.

[0184] In one embodiment, examples of the compound containing SEQ ID NO: 11, such as MC4R-11, include cyclo[hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; cyclo[hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2; or Cyclo[hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2; Or a pharmaceutically acceptable salt thereof, particularly Cyclo[hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2.

[0185] In one embodiment, the compound comprising SEQ ID NO:11, also known as MC4R-11, comprises the following amino acid sequence: HXRWX (SEQ ID NO:11), where X can be selected from ornithine (Orn); 2,4-diaminobutyric acid (Dab); or 2,3-diaminopropionic acid (Dap).

[0186] In one embodiment, the pharmaceutical is 0.02 to 12% by weight of setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). In one embodiment, the pharmaceutical comprises 0.02 to 12% by weight of setmelanotide.

[0187] In one embodiment, the pharmaceutical product is 0.1-10% by weight, 0.2-8% by weight, 0.5-6% by weight, 1-4% by weight of setmelanotide; setmelanotide as the only active pharmaceutical ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as an active pharmaceutical ingredient; setmelanotide as an active pharmaceutical ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the active pharmaceutical ingredient, or the active pharmaceutical ingredient for injection P (such as BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). In one embodiment, the pharmaceutical product contains 0.1-10% by weight, 0.2-8% by weight, 0.5-6% by weight, 1-4% by weight of setmelanotide.

[0188] In one embodiment, the pharmaceutical product is about 1 mg / mL, 2 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL or more of setmelanotide; setmelanotide as the only active pharmaceutical ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as an active pharmaceutical ingredient; setmelanotide as an active pharmaceutical ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the active pharmaceutical ingredient, or the active pharmaceutical ingredient for injection P (such as BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0189] In one embodiment, the pharmaceutical product contains about 5 mg / mL of setmelanotide. In one embodiment, the pharmaceutical product contains about 10 mg / mL of setmelanotide. In one embodiment, the pharmaceutical product contains about 20 mg / mL of setmelanotide. In one embodiment, the pharmaceutical product contains about 25 mg / mL of setmelanotide. In one embodiment, the pharmaceutical product contains about 30 mg / mL of setmelanotide. In one embodiment, the pharmaceutical product contains about 35 mg / mL of setmelanotide. In one embodiment, the pharmaceutical product contains about 40 mg / mL of setmelanotide.

[0190] In one embodiment, the pharmaceutical product is setmelanotide at greater than about 1 mg / mL, 2 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL or more; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0191] In one embodiment, the pharmaceutical product is setmelanotide at less than about 50 mg / mL, 40 mg / mL, 35 mg / mL, 30 mg / mL, 25 mg / mL, 20 mg / mL, 15 mg / mL, 10 mg / mL, 5 mg / mL, 2 mg / mL, or 1 mg / mL; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (such as BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0192] In one embodiment, the pharmaceutical product is setmelanotide at 3% by weight; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (such as BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). In one embodiment, the pharmaceutical product contains 3% by weight of setmelanotide.

[0193] In one embodiment, the pharmaceutical product is 3% by weight of setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) and contains; at 25°C for at least 1 to 6 months, e.g., at least 1, 2, 3, 4, 5, 6 months, or longer, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is stable against storage without loss or decomposition. In one embodiment, the pharmaceutical product contains 3% by weight setmelanotide.

[0194] In one embodiment, the pharmaceutical product, e.g., 3% by weight of setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PFormulations containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) are stable for storage for at least 1 to 6 months at 5°C, for example, at least 1, 2, 3, 4, 5, 6 months, or longer; setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P Loss or degradation of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is absent and it is stable for storage. In one embodiment, the pharmaceutical contains 3% by weight of setmelanotide.

[0195] In one embodiment, setmelanotide at about 1 mg / mL, 2 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL or more; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PA pharmaceutical containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is cetomelatide at 25°C for at least 1 to 6 months, for example at least 1, 2, 3, 4, 5, 6 months, or longer; cetomelatide as the only pharmaceutical active ingredient formulated for injection; cetomelatide as the only active ingredient; cetomelatide as a pharmaceutical active ingredient; cetomelatide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P It is stable for storage without loss or decomposition of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0196] In one embodiment, cetomelatide at about 1 mg / mL, 2 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL or more; cetomelatide as the only pharmaceutical active ingredient formulated for injection; cetomelatide as the only active ingredient; cetomelatide as a pharmaceutical active ingredient; cetomelatide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PA pharmaceutical product containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection, for at least 1 to 6 months, for example at least 1, 2, 3, 4, 5, 6 months, or longer at 5°C. P It is stable for storage without loss or decomposition of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0197] Setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection. P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is highly soluble in the alcohol of component (c). In one embodiment, setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, the sole active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P The solubility of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) in alcohol is controlled.

[0198] While not wishing to be bound by theory, in one embodiment, setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, the sole active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), due to the excessive solubility of component (c) in alcohol, alcohol is a significant amount of setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is considered to be transported out of the depot composition when the depot composition is formed in vivo. In one embodiment, the polar solvent of the pharmaceutical aids in controlling the release profile, the setomelotide in the pharmaceutical; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is used to control the solubility. In one embodiment, the pharmaceutical comprises setomelotide.

[0199] In one embodiment, the present disclosure provides cetomelatonin in a low-viscosity mixture comprising: (a) 40 to 70 wt% of diacylglycerol and / or tocopherol; (b) 40 to 70 wt% of phospholipid; (c) 5 to 20 wt% of alcohol; (e) 1 to 4 wt% of peptide; and (d) 0.5 to 10 wt% of a polar solvent optionally containing an antioxidant; cetomelatonin as the only pharmaceutical active ingredient formulated for injection; cetomelatonin as the only active ingredient; cetomelatonin as a pharmaceutical active ingredient; cetomelatonin as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P A method of controlling the solubility of (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) to form a depot pharmaceutical is provided. In one embodiment, the pharmaceutical comprises cetomelatonin

[0200] In one embodiment, the present disclosure provides cetomelatonin from a depot composition formed by injection of a low-viscosity mixture comprising: (a) 40 to 70 wt% of diacylglycerol and / or tocopherol; (b) 40 to 70 wt% of phospholipid; (c) 5 to 20 wt% of alcohol; (e) 1 to 4 wt% of cetomelatonin; and (d) 0.5 to 10 wt% of a polar solvent optionally containing an antioxidant; cetomelatonin as the only pharmaceutical active ingredient formulated for injection; cetomelatonin as the only active ingredient; cetomelatonin as a pharmaceutical active ingredient; cetomelatonin as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection PA method is provided for adjusting the release profile of (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) in the low-viscosity mixture to form a depot pharmaceutical. In one embodiment, the pharmaceutical comprises setomelotide.

[0201] In one embodiment, the present disclosure provides a method and use for reducing the discomfort at the injection site, reducing the viscosity of the pharmaceutical, and / or reducing the initial burst release in the low-viscosity mixture of a low-viscosity mixture comprising (a) 40 to 70 wt% of diacylglycerol and / or tocopherol; (b) 40 to 70 wt% of phospholipid; (c) 5 to 20 wt% of alcohol; (e) 1 to 4 wt% of setomelotide; and (d) optionally 0.5 to 10 wt% of a polar solvent containing an antioxidant for forming a depot of the pharmaceutical. In one embodiment, the pharmaceutical comprises setomelotide.

[0202] In one embodiment, the present disclosure provides setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A method and use are provided for improving the properties of a pharmaceutical and / or the resulting depot composition without adversely affecting the release profile of (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). In one embodiment, the pharmaceutical comprises setomelotide.

[0203] Optional additional components In one embodiment, the pharmaceutical disclosed herein does not contain (or contains less than 5, 2, 1, or 0.5 wt%) a fragmentation agent such as polyethylene oxide or poly(ethylene glycol) (PEG) fragmentation agent, e.g., PEG-grafted lipid and / or surfactant.

[0204] In one embodiment, the pharmaceutical disclosed herein does not contain (or contains less than 5, 2, 1, or 0.5 wt%) a fragmentation agent such as Polysorbate 80 (P80), or other Polysorbate (e.g., Polysorbate 20), pegylated lipids (PEG-lipids such as DSPE-PEG(2000), DSPE-PEG(5000), DOPE-PEG(2000), and DOPE-PEG(5000)), Solutol HS 15, pegylated fatty acids (e.g., PEG-oleate), block copolymers such as Pluronic.RTM.F127 and Pluronic.RTM.F68, ethoxylated castor oil derivatives (e.g., Chremophores), pegylated glyceryl fatty acid esters (such as TMGO-15 from Nikko Chemicals), and pegylated tocopherols (such as d-α tocopheryl poly(ethylene glycol) 1000 succinate known as Eastman's Vitamin E TPGS).

[0205] In one embodiment, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is, for example, a powder in the kit. In one embodiment, the kit contains setomelotide.

[0206] In one embodiment, setomelotide; setomelotide as the only pharmaceutical active ingredient formulated for injection; setomelotide as the only active ingredient; setomelotide as a pharmaceutical active ingredient; setomelotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is dissolved in a lipid pharmaceutical and stabilized, for example, by an additive containing a specific stabilizing additive, such as a sugar (e.g., sucrose, trehalose, or lactose), a polymer (e.g., a polyol such as carboxymethyl cellulose), an amino acid (e.g., methionine, glutamate, or lysine), a lipid-soluble acid component (e.g., HCl), an anionic lipid or surfactant (e.g., dioleoyl phosphatidylglycerol (DOPG), palmitoyl oleoyl phosphatidylglycerol (POPG), or oleic acid (OA)) to obtain stability, for example, storage and in vivo stability. In some embodiments, the lipid pharmaceutical contains setomelotide.

[0207] In one embodiment, the pharmaceutical compositions described herein include single-dose formats or multi-dose formats. In one embodiment, the single-dose or multi-dose formats of the pharmaceutical compositions can be stored in a pharmaceutically acceptable glass or plastic container. In one embodiment, the single-dose format of the pharmaceutical composition is stable, e.g., chemically and physically stable, and retains its potency during storage prior to use, but is disposable after single use. In one embodiment, the single-dose or multi-dose formats of the pharmaceutical compositions are stable at 4°C, e.g., 0, 1, 2, 3, or 4°C, for at least 36 months, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 25, 30, or 36 months. In one embodiment, the single-dose or multi-dose formats of the pharmaceutical compositions are stable at 30°C, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30°C, for at least 36 months, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 25, 30, or 36 months. In one embodiment, the multi-dose format of the pharmaceutical composition is stable, e.g., chemically and physically stable, and retains its potency during storage prior to use, and remains stable, e.g., chemically and physically stable, potent, and relatively bacteria-free, over the multiple-dose usage regimen administration period after the first use when the seal is breached. In one embodiment, the multi-dose format of the pharmaceutical composition includes an antibacterial or microbial-static agent, e.g., a bacteriostatic agent or preservative.

[0208] In one embodiment, the pharmaceutical described herein optionally contains an antimicrobial agent or a microbial growth inhibitor, such as a bacteriostatic agent or a preservative, having sufficient antimicrobial activity to meet the European Pharmacopoeia (Ph.Eur.), Japanese Pharmacopoeia (JP), and United States Pharmacopoeia (USP) standards. In one embodiment, the bacteriostatic agent or preservative allows the pharmaceutical to be stored and used for repeated administration. In one embodiment, the bacteriostatic agent or preservative is setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) does not reduce the solubility and also does not reduce the transparency of the pharmaceutical, such as the transparency of the solution. In one embodiment, the bacteriostatic agent or preservative constituting the pharmaceutical is selected from phenol, benzoic acid, chlorobutanol, benzalkonium chloride, m-cresol, p-cresol, benzyl alcohol, or other phenolic preservatives. In one embodiment, the bacteriostatic agent or preservative is used at a concentration at which it is effective. In one embodiment, the bacteriostatic agent or preservative constituting the pharmaceutical is pharmaceutically acceptable for use by injection administration.

[0209] In one embodiment, the pharmaceutical described herein optionally contains an antimicrobial agent or a microbial growth inhibitor in addition to an antioxidant or a chemical or physical stabilizer, such as EDTA.

[0210] In one embodiment, the setmelanotide described herein; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P A pharmaceutical containing (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) does not require additional preservatives, antibacterial agents, or microbial growth inhibitors, such as bacteriostatic or bactericidal agents, to provide a multi-use format. In one embodiment, the pharmaceutical contains setmelanotide.

[0211] In one embodiment, the pharmaceutical described herein is setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P It provides a preservation effect and pharmaceutical stability with acceptable stability for (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) and can be used for single-dose as well as repeated-dose use. In one embodiment, the pharmaceutical contains setmelanotide.

[0212] In one embodiment, the pharmaceutical described in this specification for a multi-use format is setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) and a citrate buffer containing ethanol and optionally disodium edetate, alone or in any combination, in a concentration sufficient to maintain the stability of the pharmaceutical and at the same time impart a preservative effect. In one embodiment, the pharmaceutical contains setomeranotide.

[0213] Method of manufacture - in the order specified Setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) The order in which the pharmaceutical ingredients are combined is, for example, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) By reducing the time taken to solubilize it, the manufacturing method can be optimized. In one embodiment, the pharmaceutical contains setomeranotide.

[0214] In one embodiment, the corresponding portions of component a, b, or both a and b, for example all, are setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is contacted with alcohol and added, for example, after being dissolved or dispersed therein. In one embodiment, setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is dissolved or dispersed in alcohol, such as ethanol. Setomeranotide; setomeranotide as the sole pharmaceutical active ingredient formulated for injection; setomeranotide as the sole active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PWhen all or a part of (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), for example, at least 50, 70, 80, 90, 95, or 99% is dissolved or dispersed in ethanol, a corresponding part of component a, b, or both a and b, for example, all, is added to the mixture. In one embodiment, the mixture is, for example, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P When (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is dissolved or dispersed in alcohol, for example, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P When at least 50, 70, 80, 90, 95, or 99% of (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is dissolved or dispersed in ethanol, component d, for example, a polar solvent, for example, citrate buffer, may also be included. In one embodiment, the pharmaceutical contains setomeranotide.

[0215] In one embodiment, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is contacted with one or more of components a, b, and d after being dissolved or dispersed in alcohol. In one embodiment, the pharmaceutical comprises setmelanotide.

[0216] Method of manufacture - control of the amount of ethanol It may be important to have a bioactive moiety, such as setomelanotide, in a pharmaceutical product that contains alcohol at a predetermined or specified level, e.g., a level that optimizes the viscosity of the pharmaceutical product prior to injection and the release profile after injection. The manufacturing process may allow for uncontrolled or unpredictable levels of alcohol loss, e.g., by evaporation, during manufacture, and this loss can prevent the ability to have a controlled and repeatable level of alcohol in the formulation. Setomelanotide having a controlled and repeatable level of alcohol, e.g., ethanol; setomelanotide as the only pharmaceutical active ingredient formulated for injection; setomelanotide as the only active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) are provided herein. The level of alcohol affects both the viscosity prior to delivery and the release profile after delivery. Alcohol generally promotes a decrease in viscosity, but if present in too great an amount, it can undesirably affect the release profile, e.g., by an increase in C max and can undesirably affect the release profile. Therefore, a controlled and repeatable level of alcohol is desirable.

[0217] The methods described herein control the level of alcohol in a finished pharmaceutical product, e.g., a pharmaceutical product containing setomelanotide. Loss of added alcohol by evaporation can result in variability in the level of alcohol present in the pharmaceutical product. In one embodiment, the method includes manufacturing the pharmaceutical product by the addition of a controlled amount of ethanol in a closed system or container. Use of a closed system or container can minimize loss of alcohol by evaporation.

[0218] In one embodiment, the present disclosure provides a method of manufacturing a pharmaceutical described herein with a controlled or predetermined amount of alcohol, such as ethanol. In one embodiment, the amount of alcohol, such as ethanol, in the pharmaceutical is a predetermined amount, such as 10%. The method of the present disclosure includes adding a measured amount of alcohol, such as ethanol, also referred to herein as the "added amount", which results in a pharmaceutical having a predetermined amount of alcohol, such as ethanol, after manufacture under the manufacturing conditions. Generally, the added amount will be more than the predetermined amount present after manufacture, for example due to evaporation of the alcohol during manufacture. In one embodiment, the added amount is added as a single portion, and in other embodiments, multiple portions are added to provide the added amount. In embodiments, the method includes additional measures to reduce alcohol evaporation, such as performing one or more stages of the manufacturing process under conditions that reduce alcohol evaporation, such as controlling the temperature or performing one stage of the process in a sealed container.

[0219] In one embodiment, the alcohol, such as ethanol, can be provided to the pharmaceutical in one or more amounts or portions, such as 1, 2, 3, or 4 amounts or portions. In one embodiment, the method of manufacturing the pharmaceutical comprises a first amount or portion of alcohol, such as ethanol, and setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P(For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), which includes dissolving or dispersing the peptide. In one embodiment, the method for manufacturing a pharmaceutical product comprises dissolving or dispersing the corresponding portions of components a, b, and d, or all of components a, b, and d, in cetomelatonin dissolved or dispersed in ethanol; cetomelatonin as the only pharmaceutical active ingredient formulated for injection; cetomelatonin as the only active ingredient; cetomelatonin as a pharmaceutical active ingredient; cetomelatonin as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), and further comprises applying to a mixture thereof. In one embodiment, the pharmaceutical product comprises cetomelatonin

[0220] In one embodiment, the method for manufacturing a pharmaceutical product comprises applying to the mixture an alcohol, such as ethanol, in the following amount or portion, for example, the second, third, or fourth amount or portion, thereby resulting in cetomelatonin containing 10% by weight of alcohol, such as ethanol; cetomelatonin as the only pharmaceutical active ingredient formulated for injection; cetomelatonin as the only active ingredient; cetomelatonin as a pharmaceutical active ingredient; cetomelatonin as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PFurther comprising manufacturing a pharmaceutical product of (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0221] Method of treatment by formulation The method of administering the pharmaceutical product described herein is described, for example, in WO 2013 / 102047 pamphlet, WO 2014 / 144842 pamphlet, and WO 2017 / 059076 pamphlet, and the entire contents of all of them are incorporated herein by reference in their entirety.

[0222] In an embodiment, setmelanotide described herein; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P (For example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) The pharmaceutical product containing is a polypeptide of the pharmaceutical product, for example, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection PIt is administered to a subject having a disease or disorder that responds to the pharmacological activity possessed by (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). In one embodiment, the pharmaceutical comprises setmelanotide.

[0223] In one embodiment, the disease to be treated responds to the modulation of MC4R in a subject in need of treatment. The method comprises administering to the subject an MC4R modulator, such as setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection. P It comprises administering an effective amount of a pharmaceutical comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) as a polypeptide. In one embodiment, the pharmaceutical comprises setmelanotide.

[0224] In one embodiment, diseases that respond to the modulation of MC4R include type 1 diabetes, type 2 diabetes, obesity, insulin resistance, metabolic syndrome, male erectile dysfunction, female sexual dysfunction, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, substance use disorders including alcohol dependence, eating disorders, cachexia, inflammation, and anxiety. In one embodiment, the disease is obesity, type 1 diabetes, or type 2 diabetes. In one embodiment, the disease is obesity or an obesity-related condition. In one embodiment, the disease is Prader-Willi syndrome. In one embodiment, the disease is Bardet-Biedl syndrome. In one embodiment, the disease is Alström syndrome.

[0225] In one embodiment, the disease to be treated includes type 1 diabetes, type 2 diabetes, obesity, Prader-Willi syndrome, insulin resistance, metabolic syndrome, male erectile dysfunction, female sexual dysfunction, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, substance use disorders including alcohol dependence, eating disorders, cachexia, inflammation, anxiety, Bardet-Biedl syndrome, or Alström syndrome. In one embodiment, the disease is obesity, type 1 diabetes, or type 2 diabetes. In one embodiment, the disease is obesity or an obesity-related disorder. In one embodiment, the disease is Prader-Willi syndrome. In one embodiment, the disease is Bardet-Biedl syndrome. In one embodiment, the disease is Alström syndrome. In one embodiment, the disease to be treated includes a disease associated with or resulting from one or more mutations in a gene related to the leptin-melanocortin pathway or the POMC-MC4R pathway, such as leptin, the leptin receptor, proopiomelanocortin (POMC), prohormone convertase (e.g., PCSK1), or α-MSH.

[0226] Definitions As used herein, "naturally derived" refers to both compounds isolated from natural sources and compounds that are wholly or partially synthetically produced with the same or substantially the same structure as compounds found in nature.

[0227] The compositions and methods disclosed herein include polypeptides and nucleic acids having an explicit sequence or a sequence that is substantially identical or similar to the explicit sequence, e.g., a sequence that is at least 85%, 90%, 95% or more identical to the explicit sequence. In the context of amino acid sequences, the term "substantially identical" means that, such that the first and second amino acid sequences may have a common structural domain and / or a common functional activity, i) is identical to the second amino acid sequence, or ii) the first amino acid containing a sufficient or minimum number of amino acid residues that are conservative substitutions of contiguous amino acid residues in the second amino acid sequence, as used herein. For example, an amino acid sequence containing a common structural domain having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., a sequence provided herein.

[0228] Formulation The pharmaceutical product contains the pharmaceutical products and buffers described herein, e.g., setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11). The pH of the formulation is generally pH 5.5 - 7.0.

[0229] In one embodiment, the pharmaceutical is a liquid formulation having a low viscosity. In one embodiment, the pharmaceutical is formulated to be directly injected, for example, without further addition or pre-injection adjustment. In one embodiment, the pharmaceutical is stored as a liquid in a device, such as a syringe, such as the syringe described herein. In one embodiment, the syringe can be selected from a manual syringe, a syringe including a needle (e.g., a needle having a suitable diameter, e.g., a 27-gauge needle), a single-use syringe, a multi-use syringe, or a spring-loaded syringe (e.g., an autoinjector).

[0230] In one embodiment, the components of the pharmaceutical can be prepared as separate liquids or solids, such as lyophilized formulations, and stored separately. In one embodiment, the components of the pharmaceutical can be prepared as at least two, such as two, three, four, or five separate components. In one embodiment, the components, such as at least two components that make up the pharmaceutical, can be combined, mixed, dissolved, or dispersed immediately prior to injection. In one embodiment, the components, such as at least two components that make up the pharmaceutical, are prepared and stored in separate containers, such as at least two separate containers, such as the containers described herein, and the components, such as at least two components, are mixed by combining them in one container, such as the container described herein. In one embodiment, the components, such as at least two components that make up the pharmaceutical, are combined in a receptacle (such as the receptacle described herein, such as a receptacle having two or more chambers, such as at least two chambers), which separates the components, such as at least two components, by a pharmaceutically acceptable seal that keeps the components, such as at least two components, in separate chambers within one receptacle, such as the receptacle described herein. In one embodiment, the seal can be manipulated, such as opened or removed, to mix the components, such as at least two components that make up the pharmaceutical, to form a single solution or suspension within the receptacle. In one embodiment, the solution or suspension of the pharmaceutical can be filled into a syringe, such as the syringe described herein. In one embodiment, the solution or suspension of the pharmaceutical can be administered, for example, in an effective amount (such as a therapeutically effective amount), to a subject in need thereof, such as the subject described herein.

[0231] In one embodiment, the container can be selected from a syringe (such as a manual syringe, a syringe including a needle (such as a needle having a suitable diameter, such as a 27-gauge needle), a single-use syringe, a multi-use syringe, or a spring-loaded syringe (such as an auto-injector)); a vial (a single-use vial, or a multi-use vial); or other pharmaceutically acceptable containers.

[0232] In one embodiment, the containers described herein include, but are not limited to, a Vetter Lyo-ject® dual-chamber syringe, a Vetter V-LK® dual-chamber cartridge, a Credence Companion® dual-chamber, or other dual-chamber devices, such as a cartridge or a syringe.

[0233] Buffer solution As used herein, the term "buffer solution" refers to an excipient that stabilizes the pH of a pharmaceutical composition. Examples of buffer solutions include histidine buffer solution, citrate buffer solution, succinate buffer solution, acetate buffer solution, and phosphate buffer solution, or mixtures thereof. In one embodiment, the buffer solution of the pharmaceutical product includes citrate, L-histidine, or a mixture of L-histidine and L-histidine hydrochloride. In one embodiment, the buffer solution of the pharmaceutical product is an acetate buffer solution. Apart from the buffer solution used, the pH can be adjusted with an acid or a base, such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, and citric acid, sodium hydroxide and potassium hydroxide.

[0234] The pH of the pharmaceutical described in this specification is generally between pH 5.0 and 7.5, for example, between pH 5.5 and 6.5, pH 5.5 and 6.0, pH 6.0 and 6.5, pH 6.5 and 7.0, pH 5.5, pH 6.0, pH 6.5, or pH 7.0. In one embodiment, a buffer solution capable of maintaining the solution at pH 5.5 to pH 7.0 is used in the preparation of the pharmaceutical. In one embodiment, the buffers used in the preparation of the pharmaceutical include, without limitation, citric acid, HEPES, histidine, arginine, potassium acetate, potassium citrate, potassium phosphate (K2HPO4), sodium acetate, sodium bicarbonate, sodium citrate, sodium phosphate (NaH2PO4), tris base, and tris-HCl. In one embodiment, the concentration of the buffer solution is between 5 mM and 100 mM, for example, between 5 mM and 50 mM. In one embodiment, the sodium phosphate buffer solution is used at a concentration of 25 nM. In one embodiment, the sodium citrate buffer solution is used at a concentration of 10 mM or 25 mM. In one embodiment, the histidine buffer solution is used at a concentration of 25 mM. In one embodiment, the arginine buffer solution is used at a concentration of 25 mM.

[0235] Numbered embodiments The present invention will be further described with reference to the following numbered embodiments.

[0236] 1. A composition or formulation, such as a pharmaceutical composition, comprising: a) Neutral diacyl lipid and / or tocopherol; b) Phospholipid; c) Alcohol; d) Optionally, a polar solvent, such as a buffer solution optionally containing an antioxidant; and e) Setomelatonin, for example, setomelatonin as the only pharmaceutical active ingredient formulated for injection; setomelatonin as the only active ingredient; setomelatonin as a pharmaceutical active ingredient; setomelatonin as a pharmaceutical active ingredient for injection; or, for example, MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0237] 2. A composition or formulation, e.g., a pharmaceutical composition, comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent, e.g., a buffer optionally containing an antioxidant; and e) setomelanotide.

[0238] 3. A composition or formulation, e.g., a pharmaceutical composition, comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent, e.g., a buffer optionally containing an antioxidant; and e) setomelanotide as the sole pharmaceutical active ingredient formulated for injection.

[0239] 4. A composition or formulation, e.g., a pharmaceutical composition, comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) optionally, a polar solvent, e.g., a buffer optionally containing an antioxidant; and e) setomelanotide as a pharmaceutical active ingredient.

[0240] 5. A composition or formulation, e.g., a pharmaceutical composition, comprising: a) a neutral diacyl lipid and / or tocopherol; b) a phospholipid; c) an alcohol; d) Optionally, a polar solvent, such as a buffer solution optionally containing an antioxidant; and e) Setomelotide as an active pharmaceutical ingredient for injection.

[0241] 6. A composition or formulation, such as a pharmaceutical composition, comprising: a) Neutral diacyl lipid and / or tocopherol; b) Phospholipid: c) Alcohol; d) Optionally, a polar solvent, such as a buffer solution optionally containing an antioxidant; and e) MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0242] 7. A composition or formulation, such as a pharmaceutical composition, comprising: a) Neutral diacyl lipid and / or tocopherol; b) Phospholipid: c) Alcohol; d) Optionally, a polar solvent, such as a buffer solution optionally containing an antioxidant; and e) MC4RA as the sole active ingredient P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0243] 8. A composition or formulation, such as a pharmaceutical composition, comprising: a) Neutral diacyl lipid and / or tocopherol; b) Phospholipid: c) Alcohol; d) Optionally, a polar solvent, such as a buffer solution optionally containing an antioxidant; and e) MC4RA as the sole active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0244] 9. A composition or formulation, e.g., a pharmaceutical composition, comprising: a) Neutral diacyl lipids and / or tocopherol; b) Phospholipids; c) Alcohol; d) Optionally, a polar solvent, e.g., a buffer optionally containing an antioxidant; and e) MC4RA as a pharmaceutical active ingredient P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0245] 10. A composition or formulation, e.g., a pharmaceutical composition, comprising: a) Neutral diacyl lipids and / or tocopherol; b) Phospholipids; c) Alcohol; d) Optionally, a polar solvent, e.g., a buffer optionally containing an antioxidant; and e) MC4RA as a pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0246] 11. The composition according to any one of the foregoing embodiments, comprising a neutral diacyl lipid.

[0247] 12. The composition according to embodiment 11, wherein the neutral diacyl lipid comprises diacylglycerol.

[0248] 13. The composition according to any one of embodiments 11 to 12, wherein the neutral diacyl lipid comprises glycerol dioleate (GDO).

[0249] 14. The composition according to any one of the foregoing embodiments, wherein the phospholipid comprises phosphatidylcholine.

[0250] 15. The composition according to any one of the foregoing embodiments, wherein the phospholipid comprises soy phosphatidylcholine.

[0251] 16. The composition according to any one of the foregoing embodiments, wherein the alcohol comprises ethanol.

[0252] 17. The composition according to any one of the foregoing embodiments, wherein ethanol is provided in an amount sufficient to provide a solubility of at least 10 mg / g, 20 mg / g, or 30 mg / g of setomelanotide.

[0253] 18. The composition according to embodiment 17, wherein the amount by weight % of ethanol exceeds 1% by weight, for example, is between 1 and 20% by weight.

[0254] 19. The composition according to any one of embodiments 17 to 18, wherein the amount of ethanol is sufficiently low such that injection can be easily and comfortably performed by operation of a device, such as a syringe, by a subject, for example, a subject described herein.

[0255] 20. The composition according to any one of embodiments 17 to 19, wherein the amount of ethanol by weight % is less than 20%, 15%, or 10%.

[0256] 21. The composition according to any one of embodiments 17 - 20, wherein the composition has a viscosity low enough to be comfortably delivered by a device, such as a syringe having a thin needle, such as a 27 - gauge needle, and has a sufficient amount of ethanol.

[0257] 22. At the time of injection, the initial burst of the drug after subcutaneous injection, e.g., the initial release, is less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), the ratio of the highest concentration (C max ) in plasma before the next dose is administered to the lowest concentration (C min ) in plasma, and the amount of ethanol is sufficiently low for this ratio. The composition according to any one of embodiments 17 - 21.

[0258] 23. At the time of injection, the pharmaceutical is setomelotide; setomelotide as the only pharmaceutically active ingredient formulated for injection; or MC4RA P (e.g., BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11), and the amount of ethanol is sufficiently low to give a low initial release. The composition according to any one of embodiments 17 - 22.

[0259] 24. The low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 6 hours) after administration, and is less than 10% or less of the area under the drug concentration - time curve for a 7 - day steady - state dosing interval. The composition according to embodiment 23.

[0260] 25. The low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 12 hours) after administration, and is less than 10 - 20% or less of the area under the drug concentration - time curve for a 7 - day steady - state dosing interval. The composition according to embodiment 23.

[0261] 26. The composition according to embodiment 23, wherein the low initial release is less than 20 to 30% or less of the area under the drug concentration-time curve at a steady-state dosing interval of 7 days, as measured by the partial area under the drug concentration curve during the first few hours (e.g., the first 24 hours) after administration.

[0262] 27. The composition according to embodiment 19, wherein the device may be a single-use device or a multi-use device.

[0263] 28. The composition according to embodiment 19, wherein the device is selected from a manual syringe (e.g., a syringe containing a needle (e.g., a needle having a suitable diameter, e.g., a 27-gauge needle)), or an auto-injector (e.g., a spring-loaded syringe, or a pen-type syringe).

[0264] 29. The composition according to any one of the foregoing embodiments, wherein the polar solvent, e.g., the buffer solution, contains a citrate buffer, and optionally the pH of the buffer solution is 6.4.

[0265] 30. The composition according to any one of the foregoing embodiments, wherein the polar solvent, e.g., the buffer solution, contains citric acid monohydrate.

[0266] 31. The composition according to any one of the foregoing embodiments, wherein the polar solvent, e.g., the buffer solution, contains additional components, e.g., an antioxidant or a chemical or physical stabilizer.

[0267] 32. The composition according to embodiment 31, wherein the antioxidant is EDTA.

[0268] 33. The composition according to any one of the foregoing embodiments, wherein the polar solvent, e.g., the buffer solution, contains citric acid monohydrate, disodium EDTA, and water.

[0269] 34. Setomeranotide; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P The composition according to any one of the foregoing embodiments, wherein (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is present as a chloride salt.

[0270] 35. The composition according to any one of the foregoing embodiments, wherein the pharmaceutical optionally contains an antibacterial agent or a microbial growth inhibitor, such as a bacteriostatic agent or a preservative.

[0271] 36. The composition according to any one of the foregoing embodiments, wherein the weight ratio of a:b is from 70:30 to 40:60.

[0272] 37. The composition according to any one of the foregoing embodiments, wherein the weight ratio of a:b is 70:30, 65:45, 60:40, 55:45, 50:50, 45:55, or 40:60.

[0273] 38. The composition according to any one of the foregoing embodiments, wherein component a is 20 to 80%, 30 to 70%, 33 to 60%, or 38 to 43% by weight of the total weight of components a, b, and c solution.

[0274] 39. The composition according to any one of the foregoing embodiments, wherein component b is 20 to 80%, 30 to 70%, 33 to 60%, or 38 to 43% by weight of the total weight of components a, b, and c solution.

[0275] 40. The composition according to any one of the foregoing embodiments, wherein component c, for example ethanol, is 0.5 to 50%, 2 to 30%, or 5 to 20% by weight of the total weight of components a, b, and c solution.

[0276] 41. The neutral diacyl lipid contains glycerol dioleate; The phospholipid contains phosphatidylcholine; The alcohol contains ethanol; and The composition according to any one of the foregoing embodiments, wherein the polar solvent, for example the buffer solution, contains a citrate buffer solution.

[0277] 42. The neutral diacyl lipid contains glycerol dioleate; The phospholipid contains soy phosphatidylcholine; The alcohol contains ethanol; and The composition according to any one of the foregoing embodiments, wherein the polar solvent, for example the buffer solution, contains a citrate buffer solution at pH 6.4 containing EDTA.

[0278] 43. Per milliliter of the composition: 420 ± 20% mg of glycerol dioleate (GDO); 420 ± 20% mg of soy phosphatidylcholine; 105 ± 20% mg of ethanol; 20 ± 20% mg of citrate buffer; and 30 ± 20% mg of setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or setmelanotide as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection of MC4RA P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) The composition according to any one of the foregoing embodiments, comprising

[0279] 44. Per milliliter of the composition: 420 ± 10% mg of glycerol dioleate (GDO); 420 ± 10% mg of soy phosphatidylcholine; 105 ± 10% mg of ethanol; 20 ± 10% mg of citrate buffer; and 30 ± 10% mg of setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) The composition according to any one of the foregoing embodiments, comprising

[0280] 45. Per milliliter of the composition: 420 ± 5% mg of glycerol dioleate (GDO); 420 ± 5% mg of soy phosphatidylcholine; 105 ± 5% mg of ethanol; 20 ± 5% mg of citrate buffer; and 30 ± 5% mg of setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) The composition according to any one of the foregoing embodiments, comprising

[0281] 46. Per milliliter of the composition: 420 ± 2% mg of glyceryl dioleate (GDO); 420 ± 2% mg of soy phosphatidylcholine; 105 ± 2% mg of ethanol; 20 ± 2% mg of citrate buffer; and 30 ± 2% mg of setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) The composition according to any one of the foregoing embodiments, comprising

[0282] 47. Per milliliter of the composition 419.8 mg of glyceryl dioleate (GDO); 419.8 mg of soy phosphatidylcholine; 105 mg of ethanol; 20 mg of citrate buffer; and 30 mg of setmelanotide The composition according to any one of the foregoing embodiments, comprising

[0283] 48. A neutral diacyl lipid of component a in an amount of 20-80%, 30-70%, 33-60%, or 38-43% by weight of components a, b, and c; or components a, b, c, d, and e of the composition; 20-80%, 30-70%, 33-60%, or 38-43% by weight of the phospholipids of component b of the composition; the alcohol of component c being from 0.1 to 35%, from 5 to 20%, from 8 to 15%, or from 9 to 11% by weight of components a, b, c, d, and e of the composition; components a, b, and c of the composition; components a, b, c, and d; or 0.5 to 10%, 1 to 5%, or 1 to 3% by weight of components a, b, c, d, and e of component d, a polar solvent, such as a buffer; and 0.1-10%, 0.2-8%, 0.5-6%, 1-4% by weight of cetomelanotide of components a, b, and c; components a, b, c, d, and e of the composition; cetomelanotide as the sole active pharmaceutical ingredient formulated for injection; cetomelanotide as the sole active ingredient; cetomelanotide as the active pharmaceutical ingredient; cetomelanotide as the active pharmaceutical ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as the active pharmaceutical ingredient, or as the active pharmaceutical ingredient for injection. P (e.g. BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) The composition of any one of the preceding embodiments, comprising:

[0284] 49. 42%±10, 42%±5, 42%±2, or 42%±1 neutral diacyl lipid by weight of components a, b, and c; components a, b, c, and d; or components a, b, c, d, and e of the composition; Component a, b, and c of the composition; component a, b, c, and d; or phospholipids of 42% ± 10, 42% ± 5, 42% ± 2, or 42% ± 1 by weight of component a, b, c, d, and e; Component a, b, and c of the composition; component a, b, c, and d; or alcohol of 10% ± 8, 10% ± 6, 10% ± 5, or 10% ± 1 by weight of component a, b, c, d, and e; Component a, b, and c of the composition; component a, b, c, and d; or polar solvents of 2% ± 1, 2% ± 0.5, 2% ± 0.25, or 2% ± 0.1 by weight of component a, b, c, d, and e, such as buffer; and Component a, b, and c of the composition; component a, b, c, and d; or setomeranotide or MC4RA of 3% ± 1.5, 3% ± 1, or 3% ± 0.5 by weight of component a, b, c, d, and e P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) The composition according to any one of the foregoing embodiments, comprising

[0285] 50. The composition according to any one of the foregoing embodiments, which forms or is capable of forming at least one liquid crystal structure upon contact with an aqueous environment, such as injection, for example, subcutaneous injection into a subject.

[0286] 51. The viscosity is (i) low enough to be comfortably delivered by a device, such as a syringe having a thin needle, such as a 27-gauge needle; (ii) at the time of injection, setomeranotide or MC4RA P(e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) having an initial burst, e.g., initial release, from the drug product after subcutaneous injection of less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or less) of peak concentration in plasma before the next dose is administered (C max ) in plasma (C min ) is sufficiently low to give a ratio to (iii) At the time of injection, the drug is cetomelanotide or MC4RA P The composition of any one of the preceding embodiments, wherein the initial release of MC4R-11 is sufficiently low to provide a low initial release of MC4R-11 (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0287] 52. When injected into the subject i) Setomelanotide or MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) having an initial burst, e.g., initial release, from the drug product after subcutaneous injection of less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or less) of peak concentration in plasma before the next dose is administered (C max ) in plasma (C min ) or ii) The drug is setomelanotide or MC4RA PA composition according to any one of the preceding embodiments, which gives a low initial release (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0288] 53. A composition according to embodiment 51 or 52, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 6 hours) after administration, which is less than 10% or less of the area under the drug concentration-time curve for a 7-day steady-state dosing interval.

[0289] 54. A composition according to embodiment 51 or 52, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 12 hours) after administration, which is less than 10 - 20% or less of the area under the drug concentration-time curve for a 7-day steady-state dosing interval.

[0290] 55. A composition according to embodiment 51 or 52, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 24 hours) after administration, which is less than 20 - 30% or less of the area under the drug concentration-time curve for a 7-day steady-state dosing interval.

[0291] 56. A composition according to any one of the preceding embodiments, which contains setmelanotide.

[0292] 57. A composition according to any one of embodiments 1 - 55, which contains setmelanotide as the only pharmaceutical active ingredient formulated for injection.

[0293] 58. A composition according to any one of embodiments 1 - 55, which contains setmelanotide as the only active ingredient.

[0294] 59. A composition according to any one of embodiments 1 - 55, which contains setmelanotide as a pharmaceutical active ingredient.

[0295] 60. The composition according to any one of Embodiments 1 to 55, comprising setmelanotide as a pharmaceutical active ingredient for injection.

[0296] 61. MC4RA P The composition according to any one of Embodiments 1 to 55, comprising (for example, as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection).

[0297] 62. The composition according to any one of Embodiments 1 to 55, comprising BIM-22511.

[0298] 63. The composition according to any one of Embodiments 1 to 55, comprising BIM-22287.

[0299] 64. The composition according to any one of Embodiments 1 to 55, comprising BIM-22512.

[0300] 65. The composition according to any one of Embodiments 1 to 55, comprising 001152C.

[0301] 66. The composition according to any one of Embodiments 1 to 55, comprising 001543C.

[0302] 66a. The composition according to any one of Embodiments 1 to 55, comprising 001003C.

[0303] 66b. The composition according to any one of Embodiments 1 to 55, comprising 001574C.

[0304] 66c. The composition according to any one of Embodiments 1 to 55, comprising 001555C.

[0305] 66d. The composition according to any one of Embodiments 1 to 55, comprising 001554C.

[0306] 66e. The composition according to any one of Embodiments 1 to 55, comprising 001556C.

[0307] The composition according to any one of Embodiments 1 to 55, comprising 66f.001358C.

[0308] The composition according to any one of Embodiments 1 to 55, comprising 66g.001576C.

[0309] The composition according to any one of Embodiments 1 to 55, comprising 66h.001364C.

[0310] The composition according to any one of Embodiments 1 to 55, comprising 66i.001258C.

[0311] The composition according to any one of Embodiments 1 to 55, comprising 66j.MC4R-11.

[0312] 67. A unit dosage form comprising the composition according to any one of Embodiments 1 to 76.

[0313] 68. The unit dosage form according to Embodiment 67, comprising at least 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, or 0.2 mL of the composition.

[0314] 69. The unit dosage form according to any one of Embodiments 67 to 68, disposed in a liquid tight enclosure, such as a vial or a cartridge.

[0315] 70. The unit dosage form according to any one of Embodiments 67 to 69, disposed in an injection device, such as a single-use device or a multi-use device.

[0316] 71. The unit dosage form according to Embodiment 70, wherein the device is selected from a manual syringe, (e.g., a syringe comprising a needle (e.g., a needle having a suitable diameter, e.g., a 27-gauge needle), or an auto-injector (e.g., a spring-loaded syringe, or a pen-type syringe).

[0317] Setomeranotide at 72.10 - 70; 20 - 60, 25 - 50; 25 - 40; 25 - 35 mg; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A unit dosage form according to any of embodiments 67 - 71, comprising (for example, BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11).

[0318] Setomeranotide at 73.50 ± 20%; 40 ± 20%; or 30 ± 20% mg; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A unit dosage form according to any of embodiments 67 - 71, comprising (for example, BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11).

[0319] Setomeranotide at 74.50 ± 10%; 40 ± 10%; or 30 ± 10% mg; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A unit dosage form according to any of embodiments 67 - 71, comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11)

[0320] Setomeranotide at 75.50 ± 5%; 40 ± 5%; or 30 ± 5% mg; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A unit dosage form according to any of embodiments 67 - 71, comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11)

[0321] Setomeranotide at 76.40, 35, or 30 mg; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injectionP (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), a unit dosage form according to any of embodiments 67-71.

[0322] 77. A unit dosage according to any of embodiments 67-76, wherein the composition is suitable for injection, such as subcutaneous or intramuscular injection.

[0323] 78. The viscosity is i) low enough to be comfortably delivered by a device, such as a syringe with a fine needle, such as a 27-gauge needle; ii) at the time of injection, cetomelanotide; or MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), the initial burst, e.g., initial release, from the pharmaceutical after subcutaneous injection is less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), the ratio of the highest concentration (C max ) in plasma to the lowest concentration (C min ) in plasma before the next dose is administered; or iii) at the time of injection, the pharmaceutical gives a low initial release of cetomelanotide or MC4RA P (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), a unit dosage form according to any of embodiments 67-77.

[0324] 79. When injected into a subject: i) The initial burst, e.g., initial release, from a pharmaceutical after subcutaneous injection of setomeranotide or MC4RA P (e.g., BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11), such that the highest concentration (C max ) in plasma before the next dose is administered is less than 8 (e.g., less than 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, or lower), gives a ratio to the lowest concentration (C min ) in plasma; or ii) The pharmaceutical gives a low initial release of setomeranotide or MC4RA P (e.g., BIM - 22511, BIM - 22287, BIM - 22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R - 11), and is a unit dosage form according to any of embodiments 67 - 77.

[0325] 80. The unit dosage form according to embodiment 78 or 79, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 6 hours) after administration, which is less than 10% or less of the area under the drug concentration - time curve for a 7 - day steady - state dosing interval.

[0326] 81. The unit dosage form according to embodiment 78 or 79, wherein the low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 12 hours) after administration, which is less than 10 - 20% or less of the area under the drug concentration - time curve for a 7 - day steady - state dosing interval.

[0327] 82. An embodiment 78 or 79 unit dosage form, wherein low initial release is measured by the area under the drug concentration curve during the first few hours (e.g., the first 24 hours) after administration and is less than 20-30% or less of the area under the drug concentration-time curve for a 7-day steady-state dosing interval.

[0328] 83. Setmelanotide; setmelanotide as the sole pharmaceutical active ingredient formulated for injection; setmelanotide as the sole active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the sole active ingredient, as the sole active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A method for producing a formulation or composition, such as a pharmaceutical composition, such as a formulation or composition having a controlled level of EtOH, comprising component (e) containing (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), i) Setmelanotide or MC4RA P Component (e) containing (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), a first amount of EtOH, and one or more of the following components: a) Neutral diacyl lipids and / or tocopherol; b) Phospholipids; c) Alcohol; and d) A polar solvent, such as a buffer Providing a mixture of; and ii) Adding a second amount of EtOH, Thereby, setomeranotide; setomeranotide as the only pharmaceutical active ingredient formulated for injection; setomeranotide as the only active ingredient; setomeranotide as a pharmaceutical active ingredient; setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, as the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A method for producing a formulation or composition, such as a pharmaceutical composition, comprising ingredient (e) comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0329] 84. The method according to embodiment 83, wherein providing comprises forming a mixture.

[0330] 85. The method according to any one of embodiments 83 to 84, wherein the addition of the second amount of EtOH results in an amount of EtOH that meets a reference value, for example, falls within a range of values, for example, a lower limit value and an upper limit value, for example, an upper limit value and a lower limit value of wt% EtOH, for example, falls within a range defined by 10 to 0.5 wt%.

[0331] 86. The method according to embodiment 85, wherein the reference value is a value within the range of 5 to 20; 8.5 to 12.5; and 9 to 11 wt% EtOH, for example, 10 wt%.

[0332] 87. The method according to embodiment 85, wherein the reference value is a value within the range of 9 to 11 wt% EtOH, for example, 10 wt%.

[0333] 88. The method according to any one of embodiments 83 to 87, comprising measuring the amount of EtOH in the mixture by a suitable analytical measurement.

[0334] 89. The method according to embodiment 88, comprising selecting the amount of EtOH to be added to the mixture, for example, the amount that achieves the reference value, according to the measurement.

[0335] 90. The method according to embodiment 89, comprising adding a selected amount of EtOH to the mixture to form an EtOH-supplemented mixture.

[0336] 91. The method according to embodiment 90, wherein the selected amount is added to the mixture as a single portion or as a plurality of portions of the same or different amounts.

[0337] 92. The method according to any one of embodiments 83 to 91, wherein less than 48 hours, less than 24 hours, or less than 4 hours elapses between the formation of the mixture and the measurement of the amount of EtOH in the mixture, the selection of the amount of EtOH to be added, or the addition of a second amount.

[0338] 93. The method according to any one of embodiments 83 to 91, comprising providing the amount of components added to the mixture.

[0339] 94. The method according to embodiment 93, wherein providing comprises measuring the amount of components added to the mixture.

[0340] 95. The method according to any one of embodiments 83 to 94, comprising providing a value of the amount of EtOH in the mixture and determining the amount of EtOH that needs to be added to meet a criterion for the amount of EtOH.

[0341] 96. The method according to any one of embodiments 83 to 95, wherein after forming the mixture, EtOH is lost from the mixture, for example by evaporation, for example by evaporation into the headspace of a container, for example a mixing container.

[0342] 97. The method according to any one of embodiments 83 to 96, comprising measuring the amount of EtOH in the EtOH-supplemented mixture after adding a second amount to the mixture.

[0343] 98. The method according to embodiment 97, comprising selecting the amount of EtOH to be added to the EtOH-supplemented mixture according to the measurement.

[0344] The method according to embodiment 98, comprising adding a selected amount of EtOH to the mixture replenished with EtOH to form a twice-replenished mixture.

[0345] 100. Setomeranotide; Setomeranotide as the only pharmaceutical active ingredient formulated for injection; Setomeranotide as the only active ingredient; Setomeranotide as a pharmaceutical active ingredient; Setomeranotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P The method according to any one of embodiments 83 to 99, further comprising providing a second formulation or composition, such as a pharmaceutical, comprising component (e) comprising (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0346] 101. Comprising producing a mixture comprising component (e) comprising setomeranotide, EtOH, neutral diacyl lipid and / or tocopherol, and phospholipid, wherein one or both of the neutral diacyl lipid and / or tocopherol and the phospholipid is setomeranotide or MC4RA P (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) is added after being combined with EtOH, Thereby, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P A method according to any one of embodiments 83 to 100 for producing a component (e) composition or formulation, such as a pharmaceutical, comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0347] 102. Setmelanotide or MC4RA P Producing a mixture comprising a component (e) (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), water or a polar solvent such as a buffer, a neutral diacyl lipid and / or tocopherol, and a phospholipid, wherein one or both of the neutral diacyl lipid and / or tocopherol and the phospholipid is setmelanotide or MC4RA P added after combining a component (e) (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) with water or a polar solvent such as a buffer, Thereby, setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, as a pharmaceutical active ingredient, or as a pharmaceutical active ingredient for injection P A method according to any of embodiments 83-100 for producing a component (e) composition or formulation, for example a pharmaceutical, comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11).

[0348] 103. The order of formation of the mixture is i) setmelanotide or MC4RA P Contacting a component (e) comprising (e.g., BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11) with EtOH (and optionally water or a polar solvent, e.g., a buffer); ii) adding a phospholipid to the mixture resulting from i); iii) adding a neutral diacyl lipid and / or tocopherol to the mixture resulting from ii) A method according to any of embodiments 83-102.

[0349] 104. The method according to embodiment 83, wherein the formulation or composition comprises setmelanotide.

[0350] 105. The method according to embodiment 83, wherein the formulation or composition comprises setomeranotide as the only pharmaceutical active ingredient formulated for injection, setomeranotide as the only active ingredient, setomeranotide as a pharmaceutical active ingredient, or setomeranotide as a pharmaceutical active ingredient for injection.

[0351] 106. The method according to embodiment 83, wherein the formulation or composition comprises, for example, MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection. P as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection.

[0352] 107. The method according to embodiment 83, wherein the formulation or composition comprises BIM-22511.

[0353] 108. The method according to embodiment 83, wherein the formulation or composition comprises BIM-22287.

[0354] 109. The method according to embodiment 83, wherein the formulation or composition comprises BIM-22512.

[0355] 110. The method according to embodiment 83, wherein the formulation or composition comprises 001152C.

[0356] 111. The method according to embodiment 83, wherein the formulation or composition comprises 001543C.

[0357] 112. The method according to embodiment 83, wherein the formulation or composition comprises 001003C.

[0358] 113. The method according to embodiment 83, wherein the formulation or composition comprises 001574C.

[0359] 114. The method according to embodiment 83, wherein the formulation or composition comprises 001555C.

[0360] 115. The method according to embodiment 83, wherein the formulation or composition comprises 001554C.

[0361] 116. The method according to embodiment 83, wherein the conditioner or composition contains 001556C.

[0362] 117. The method according to embodiment 83, wherein the conditioner or composition contains 001358C.

[0363] 118. The method according to embodiment 83, wherein the conditioner or composition contains 001576C.

[0364] 119. The method according to embodiment 83, wherein the conditioner or composition contains 001364C.

[0365] 120. The method according to embodiment 83, wherein the conditioner or composition contains 001258C.

[0366] 121. The method according to embodiment 83, wherein the conditioner or composition contains MC4R-11.

[0367] 122. Setmelanotide; setmelanotide as the only pharmaceutical active ingredient formulated for injection; setmelanotide as the only active ingredient; setmelanotide as a pharmaceutical active ingredient; setmelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, a pharmaceutical active ingredient, or a pharmaceutical active ingredient for injection P A method for manufacturing a pharmaceutical product comprising component (e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), component a, component b, component d, and a predetermined amount of alcohol, (in any order) setmelanotide; or MC4RA PCombining component (e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), component a, component b, component d, and alcohol to form a mixture, and comparing the value of the alcohol content in the mixture with a reference value of the alcohol content, whereby, setomelanotide; setomelanotide as the only pharmaceutical active ingredient formulated for injection; setomelanotide as the only active ingredient; setomelanotide as a pharmaceutical active ingredient; setomelanotide as a pharmaceutical active ingredient for injection; or MC4RA as the only active ingredient, the only active ingredient for injection, the pharmaceutical active ingredient, or the pharmaceutical active ingredient for injection P A method for manufacturing a formulation of component (e) containing (for example, BIM-22511, BIM-22287, BIM-22512, 001152C, 001543C, 001003C, 001574C, 001555C, 001554C, 001556C, 001358C, 001576C, 001364C, 001258C, or MC4R-11), component a, component b, component d, and a predetermined amount of alcohol.

[0368] 123. The method according to embodiment 122, comprising increasing or decreasing the amount of alcohol in the mixture in response to the value or comparison to provide a formulation having a predetermined amount of alcohol.

[0369] 124. The method according to embodiment 123, comprising adding an amount of alcohol to the mixture.

[0370] 125. The method according to embodiment 124, wherein the added amount of alcohol is more than the predetermined amount of alcohol.

[0371] 126. The method according to embodiment 122, wherein the pharmaceutical contains setomelanotide.

[0372] 127. The method according to embodiment 122, wherein the pharmaceutical product is setomeranotide as the only active pharmaceutical ingredient formulated for injection, setomeranotide as the only active ingredient; setomeranotide as an active pharmaceutical ingredient, or setomeranotide as an active pharmaceutical ingredient for injection.

[0373] 128. The method according to embodiment 122, wherein the pharmaceutical product comprises, for example, MC4RA as the only active ingredient, the only active ingredient for injection, the active pharmaceutical ingredient, or the active pharmaceutical ingredient for injection. P as the only active ingredient, the only active ingredient for injection, the active pharmaceutical ingredient, or the active pharmaceutical ingredient for injection.

[0374] 129. The method according to embodiment 122, wherein the pharmaceutical product comprises BIM-22511.

[0375] 130. The method according to embodiment 122, wherein the pharmaceutical product comprises BIM-22287.

[0376] 131. The method according to embodiment 122, wherein the pharmaceutical product comprises BIM-22512.

[0377] 132. The method according to embodiment 122, wherein the pharmaceutical product comprises 001152C.

[0378] 133. The method according to embodiment 122, wherein the pharmaceutical product comprises 001543C.

[0379] 134. The method according to embodiment 122, wherein the pharmaceutical product comprises 001003C.

[0380] 135. The method according to embodiment 122, wherein the pharmaceutical product comprises 001574C.

[0381] 136. The method according to embodiment 122, wherein the pharmaceutical product comprises 001555C.

[0382] 137. The method according to embodiment 122, wherein the pharmaceutical product comprises 001554C.

[0383] 138. The method according to embodiment 122, wherein the pharmaceutical product comprises 001556C.

[0384] 139. The method according to embodiment 122, wherein the pharmaceutical product comprises 001358C.

[0385] 140. The method according to...

Claims

1. a) glycerol dioleate (GDO); b) phosphatidylcholine; c) alcohol; and d) setomeranotide A composition for injection comprising the same.

2. e) A composition for injection according to claim 1, comprising a polar solvent.

3. The composition for injection according to claim 1, wherein the phosphatidylcholine comprises soy phosphatidylcholine.

4. The composition for injection according to claim 1, wherein the alcohol comprises ethanol.

5. The composition for injection according to claim 4, wherein the ethanol is provided in an amount sufficient to provide a solubility of at least 10 mg / g, 20 mg / g or 30 mg / g of setomeranotide.

6. The composition for injection according to claim 4, wherein the amount of ethanol by weight is more than 1% by weight.

7. The composition for injection according to claim 4, wherein the amount of ethanol is sufficiently low such that the injection can be easily and comfortably performed by the operation of the device depending on the subject.

8. The composition for injection according to claim 4, wherein the amount by weight of ethanol is less than 20%, 15%, or 10%.

9. The composition for injection according to claim 4, wherein the amount of ethanol is sufficiently large such that the composition has a viscosity sufficiently low for comfortable delivery by the device.

10. The amount of ethanol is such that, upon injection, the initial burst of the drug after subcutaneous injection is less than 8 and the ratio of the minimum concentration (C ｍａｘ ) in plasma to the maximum concentration (C ｍｉｎ ) in plasma before the next dose is administered. The injectable composition according to claim 4, wherein the amount is sufficiently small to provide the ratio.

11. The composition for injection according to claim 4, wherein the amount of ethanol is sufficiently small such that the composition for injection provides a low initial release of setomeranotide during injection.

12. The composition for injection according to claim 2, wherein the polar solvent comprises a citrate buffer.

13. The composition for injection according to claim 2, wherein the polar solvent comprises citrate hydrochloride monohydrate.

14. The composition for injection according to claim 2, wherein the polar solvent comprises an antioxidant, a chemical stabilizer or a physical stabilizer.

15. The composition for injection according to claim 14, wherein the antioxidant is EDTA.

16. The composition for injection according to claim 2, wherein the polar solvent comprises citric acid monohydrate, disodium EDTA, and water.

17. The composition for injection according to claim 1, wherein setomeranotide is present as a chloride salt.

18. The composition for injection according to claim 1, wherein the ratio of a:b by weight is 70:30, 65:45, 60:40, 55:45, 50:50, 45:55, or 40:

60.

19. The composition for injection according to claim 1, wherein component a is 20 to 80%, 30 to 70%, 33 to 60%, or 38 to 43% by weight of the total weight of the solutions of components a, b, and c.

20. The composition for injection according to claim 1, wherein component b is 20 to 80%, 30 to 70%, 33 to 60%, or 38 to 43% by weight of the total weight of the solutions of components a, b, and c.

21. The composition for injection according to claim 1, wherein component c is 0.5 to 50%, 2 to 30%, or 5 to 20% by weight of the total weight of the solutions of components a, b, and c.

22. The alcohol is ethanol; and the polar solvent is a citrate buffer solution. The composition for injection according to claim 2.

23. The alcohol is ethanol; and the polar solvent is a citrate buffer solution of pH 6.4 containing EDTA. The composition for injection according to claim 2.

24. Per milliliter of the composition: 420 ± 20% mg of glycerol dioleate (GDO); 420 ± 20% mg of soy phosphatidylcholine; 105 ± 20% mg of ethanol; 30 ± 20% mg of cetomelatide; and 20 ± 20% mg of a citrate buffer solution. The composition for injection according to claim 1.

25. 20 to 80%, 30 to 70%, 33 to 60%, or 38 to 43% by weight of component a of glycerol dioleate (GDO) of components a, b, and c; components a, b, c, and e; or components a, b, c, d, and e of the composition; 20 to 80%, 30 to 70%, 33 to 60%, or 38 to 43% by weight of component b of phosphatidylcholine of components a, b, and c; components a, b, c, and e; or components a, b, c, d, and e of the composition; 0.1 to 35%, 5 to 20%, 8 to 15%, or 9 to 11% by weight of component c of alcohol of components a, b, and c; components a, b, c, and e; or components a, b, c, d, and e of the composition; 0.1 to 10%, 0.2 to 8%, 0.5 to 6%, or 1 to 4% by weight of cetomelatide of components a, b, and c; components a, b, c, and e; or components a, b, c, d, and e of the composition; and 0.5 to 10%, 1 to 5%, or 1 to 3% by weight of component e of the polar solvent of components a, b, and c; components a, b, c, and e; or components a, b, c, d, and e of the composition. The composition for injection according to claim 2.

26. The injectable composition according to claim 1, which forms, or is capable of forming, at least one liquid crystal structure upon contact with an aqueous environment.

27. The viscosity of said composition is (i) low enough to be comfortably delivered by the device; (ii) upon injection, is the initial burst of setomelotide from the injection composition after subcutaneous injection low enough to provide a ratio to the lowest concentration (C ｍａｘ ) in plasma of the highest concentration (C ｍｉｎ ) in plasma before the next dose is administered; or (iii) low enough such that upon injection, said injectable composition provides a low initial release of setomeranotide, the injectable composition according to claim 1.

28. When injected into a subject: (i) Whether the initial burst of setomelanotide from the injectable composition after subcutaneous injection gives a ratio of the highest concentration (C ｍａｘ ) in plasma before the next dose is administered to the lowest concentration (C ｍｉｎ ) in plasma; or (ii) said injectable composition provides a low initial release of setomeranotide, the injectable composition according to claim 1.

29. Said low initial release is measured by the area under the drug concentration curve during the first few hours after administration, which is less than 10% or less of the area under the drug concentration-time curve for a 7-day steady-state dosing interval, the injectable composition according to claim 27.

30. The injectable composition according to claim 1, which is in unit dosage form.

31. The injectable composition according to claim 30, wherein said injectable composition is a liquid of at least 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, or 0.2 mL.

32. The injectable composition according to claim 30, which is disposed in a liquid-tight housing.

33. The injectable composition according to claim 30, which is disposed in an injection device.

34. The injectable composition according to claim 33, wherein said device comprises a manual syringe or an autoinjector.

35. The injectable composition according to claim 30, which contains 10 to 70, 20 to 60, 25 to 50, 25 to 40, or 25 to 35 mg of setomeranotide.

36. The injectable composition according to claim 30, which contains 40, 35, or 30 mg of setomeranotide.

37. The injectable composition according to claim 30, wherein said composition is suitable for injection.

38. The viscosity of said composition is (i) low enough to be comfortably delivered by the device; (ii) upon injection, the initial burst of setomelanotide from the injection composition after subcutaneous injection is less than 8 times lower than the maximum concentration (C ｍａｘ ) in plasma before the next dose is administered; or the ratio to the minimum concentration (C ｍｉｎ ) in plasma; or (iii) low enough such that upon injection, said injectable composition provides a low initial release of setomeranotide, the injectable composition according to claim 30.

39. When injected into a subject, (i) Whether the initial burst of setomelanotide from the injection composition after subcutaneous injection gives a ratio of the highest concentration (C ｍａｘ ) in plasma before the next dose is administered to the lowest concentration (C ｍｉｎ ) in plasma; or (ii) said injectable composition provides a low initial release of setomeranotide, the injectable composition according to claim 30. **Claim 40**: The injectable composition according to claim 30, wherein the injectable composition provides a low initial release of setmelanotide, and the low initial release of setmelanotide is less than 10% or less thereof with respect to the area under the drug concentration-time curve at a steady-state dosing interval of 7 days, as measured by the partial area under the drug concentration curve during the first few hours after administration. **Claim 41** A method for manufacturing a formulation or composition formulated for injection and containing setmelanotide, comprising: i) providing a mixture of setmelanotide, a first amount of ethanol, glycerol dioleate (GDO); and phosphatidylcholine; and ii) adding a second amount of ethanol Thereby, a method for manufacturing a formulation or composition formulated for injection and containing setmelanotide. **Claim 42** The method according to claim 41, wherein the addition of the second amount of ethanol results in an amount of ethanol that meets a reference value. **Claim 43** The method according to claim 42, wherein the reference value is a value within the range of 5-20, 8.5-12.5, or 9-11% by weight of ethanol. **Claim 44** Including manufacturing a mixture containing setmelanotide, ethanol, glycerol dioleate (GDO), and phosphatidylcholine, wherein one or both of glycerol dioleate (GDO) and phosphatidylcholine are added after setmelanotide and ethanol are combined, Thereby, the method according to claim 41 for manufacturing a setmelanotide composition or formulation formulated for injection. **Claim 45** A method for manufacturing a pharmaceutical product formulated for injection and containing setmelanotide, glycerol dioleate (GDO), phosphatidylcholine, a polar solvent, and a predetermined amount of alcohol, comprising: combining (in any order) setmelanotide, glycerol dioleate (GDO), phosphatidylcholine, a polar solvent, and alcohol to form a mixture, and comparing the value of the alcohol content in the mixture with a reference value of the alcohol content, Thereby, a method for manufacturing a pharmaceutical product formulated for injection and containing setmelanotide, glycerol dioleate (GDO), phosphatidylcholine, a polar solvent, and a predetermined amount of alcohol. **Claim 46** The method according to claim 45, wherein the predetermined amount of alcohol is added as a single portion. **Claim 47** The method according to claim 45, wherein the predetermined amount of alcohol is added as a plurality of portions.

48. A method for manufacturing a pharmaceutical product containing setmelanotide formulated for injection, comprising the following steps: (i) providing a mixture comprising setmelanotide, an alcohol, and a polar solvent; and (ii) combining said mixture with a certain amount of glycerol dioleate (GDO), and phosphatidylcholine, or all of a certain amount of glycerol dioleate (GDO) and phosphatidylcholine; sequentially comprising, thereby, a method for manufacturing a pharmaceutical product containing setmelanotide formulated for injection.

49. An injectable composition for use in treating a disease or disorder in a subject, the injectable composition comprising setmelanotide, glycerol dioleate (GDO), phosphatidylcholine, and an alcohol.

50. The injectable composition for use according to claim 49, wherein the subject has, or is at risk of having, a disease that responds to the modulation of the melanocortin-4 receptor (MC4R).

51. The injectable composition for use according to claim 50, wherein the disease is selected from type 1 diabetes, type 2 diabetes, obesity, insulin resistance, metabolic syndrome, male erectile dysfunction, female sexual dysfunction, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, substance use disorders including alcohol dependence, eating disorders, cachexia, inflammation, or anxiety, Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome.

52. The injectable composition for use according to claim 51, wherein the disease is obesity.

53. The injectable composition for use according to claim 51, wherein the disease is type 1 diabetes.

54. The injectable composition for use according to claim 51, wherein the disease is type 2 diabetes.

55. The injectable composition for use according to claim 51, wherein the disease is Prader-Willi syndrome.

56. The injectable composition for use according to claim 51, wherein the disease is Bardet-Biedl syndrome.

57. The injectable composition for use according to claim 51, wherein the disease is Alström syndrome.

58. The injectable composition for use according to claim 49, wherein the subject is human.

59. The injectable composition for use according to claim 49, wherein the injectable composition further comprises tocopherol.

60. The injectable composition for use according to claim 49, which is in unit dosage form.

61. An injectable composition for use according to claim 60, comprising 10 to 70, 20 to 60, 25 to 50, 25 to 40, or 25 to 35 mg of setomeranotide.

62. An injectable composition for use in a method of treating a disease in a subject, a) glycerol dioleate (GDO); b) phosphatidylcholine; c) alcohol; and d) setomeranotide An injectable composition comprising the same.

63. The injectable composition for use according to claim 62, wherein the disease is selected from type 1 diabetes, type 2 diabetes, obesity, insulin resistance, metabolic syndrome, male erectile dysfunction, female sexual dysfunction, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, substance use disorders including alcohol dependence, eating disorders, cachexia, inflammation, or anxiety, Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome.

64. The injectable composition according to any one of claims 1 to 40 or the injectable composition for use according to any one of claims 49 to 63, further comprising an antibacterial agent or a microbial growth inhibitor.

65. A plurality of injectable compositions comprising setomeranotide, glycerol dioleate (GDO), phosphatidylcholine, and ethanol, wherein each of the plurality of injectable compositions has an amount of ethanol that falls within a predetermined range.

66. The injectable composition according to claim 7, wherein the device is a single-use device or a multi-use device.

67. The injectable composition according to claim 7, wherein the device comprises a manual syringe or an autoinjector.

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