Glp-1 compositions and uses thereof

Abstract

The present invention relates to pharmaceutical compositions of the GLP-1 peptide semaglutide comprising not more than 0.1% (w / w) of phenol and more than 6.4 mg / ml of sodium chloride, their preparation, kits comprising such compositions and their use.

Description

[0001] The present invention relates to the field of pharmaceutical compositions comprising the GLP-1 peptide semaglutide. BACKGROUND

[0002] Marketed liquid pharmaceutical compositions comprising the GLP-1 peptide semaglutide contain a preservative and are intended for multiple uses. In order to further improve ease of use and convenience for the patient, there is a need to develop compositions comprising the GLP-1 peptide for single dose administration. These compositions should be stable and comfortably administered to a patient in need thereof.

[0003] US2019388502 reports mild pain injection upon subcutaneous injection of a phenol-free pharmaceutical composition comprising the GIP / GLP1 co-agonist peptide Tirzepatide and propylene glycol or sodium chloride. SUMMARY

[0004] In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising semaglutide, not more than 0.1% (w / w) of phenol and more than 6.4 mg / ml of sodium chloride. In some embodiments, the present invention relates to a kit comprising a pharmaceutical composition as defined herein. In some embodiments, the present invention relates to a pharmaceutical composition as defined herein for medical use. DETAILED DESCRIPTION

[0005] The present invention relates to a liquid pharmaceutical composition comprising semaglutide, not more than 0.1% (w / w) of phenol and more than 6.4 mg / ml of sodium chloride. Surprisingly, the present inventors found that such compositions have improved properties in terms of injection pain experience. In some embodiments, the liquid pharmaceutical composition comprises not more than 0.09%, or 0.08%, or 0.07%, or 0.06%, or 0.05%, or 0.04%, or 0.03%, or 0.02%, or 0.01% (w / w) of phenol. In some embodiments, the liquid pharmaceutical composition does not comprise phenol. In some embodiments, the liquid pharmaceutical composition comprises 5.0-7.0 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises about 6.4 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 6.4-7.9 mg / mL of sodium chloride, such as 6.4-7.5 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises more than 7.0 mg / ml, or more than 7.2 mg / ml, or more than 7.5 mg / ml, or more than 7.7 mg / ml, or more than 8 mg / ml, or more than 8.2 mg / ml, or more than 8.25 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 6.5-12 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 7-12 mg / ml, or 7.5-12 mg / ml, or 8-12 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 7-9.5 mg / ml, or 7-9 mg / ml, or 7-8.25 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 7-10 mg / ml, or 7-9.5 mg / ml, or 8-9 mg / ml, or 8.1-8.9 mg / ml, or 8.1-8.8 mg / ml, or 8.2-8.7 mg / ml, or 8.2-8.6 mg / ml, or 8.2-8.5 mg / ml, or 8.2-8.4 mg / ml, or 8.2-8.3 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition comprises 8.25 mg / ml of sodium chloride. In some embodiments, the liquid pharmaceutical composition

[0006] a. is for parenteral administration;

[0007] b. is an aqueous solution comprising at least 60% w / w of water; or

[0008] c. further comprises a buffer.

[0009] In some embodiments, the liquid pharmaceutical composition comprises a) semaglutide, such as 0.01-3.5 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) an isotonicity agent, d) a buffer, e) at least 60% water, and f) histidine. In some embodiments, the isotonicity agent is sodium chloride. In some embodiments, the isotonicity agent is sodium chloride.

[0010] In some embodiments, the liquid pharmaceutical composition comprises a) semaglutide, such as 0.01-3.5 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride as isotonicity agent, d) a buffer, e) at least 60% water, and f) histidine. In some embodiments, the liquid pharmaceutical composition comprises a) semaglutide, such as 0.01-3.5 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 2-12 mg / ml sodium chloride, such as 3-12 mg / ml, such as 4-12 mg / l, such as 5-12 mg / ml, such as 6-12 mg / ml, such as 7-12 mg / ml, such as 8-12 mg / ml, such as 8.1-12 mg / ml, such as 8.2-12 mg / ml, d) a buffer, e) at least 60% water, and f) histidine.

[0011] In some embodiments, the liquid pharmaceutical composition comprises a) semaglutide, such as 0.01-3.5 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 5.0-5.0 mg / ml sodium chloride, such as 5.4 or 6.7 mg / ml, d) a buffer, e) at least 60% water, and f) histidine.

[0012] In some embodiments, the liquid pharmaceutical composition comprises a) semaglutide, such as 0.01-3.5 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride, d) a phosphate, e) water for injection, f) histidine, and optionally NaOH / HCl to achieve a pH of 7-8, such as pH 7.4.

[0013] In some embodiments, the liquid pharmaceutical composition comprises a) semaglutide, such as 0.1-10 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) about 6.4 mg / ml sodium chloride, such as 6.7-12 mg / ml, such as 6.72-12 mg / l sodium chloride, d) a buffer, e) at least 60% water, and f) histidine.

[0014] In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-8.9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-8.9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8.In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) 3.2 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 97% water, optionally f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.25 mg / ml sodium chloride, d) a buffer, e) at least 97% water (such as 97-99%), optionally f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8.

[0015] In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, f) histidine, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt) such as sodium acetate or acetic acid, and the composition optionally has a pH of 6-10, such as 7-8.

[0016] In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 6.5-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 7-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 7.5-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8.In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.2-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.2-9.5 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.2-9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-8.9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of: a) 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-8.9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8.In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of a) 3.2 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the liquid pharmaceutical composition consists of or consists essentially of a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 97% water (such as 97-99%), optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8. In some embodiments, the present application relates to a kit comprising a liquid pharmaceutical composition consisting of or consisting essentially of a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), and the composition optionally has a pH of 6-10, such as 7-8, and an injection device comprising a needle for administering the composition to a subject, such as a pre-filled syringe.

[0017] In some embodiments, the concentration of semaglutide is 0.5-10 mg / ml or 0.01-3.5 mg / ml of the liquid pharmaceutical composition. In some embodiments, the concentration of semaglutide is 0.5 mg / ml, or 1 mg / ml, or 1.5 mg / ml, or 2 mg / ml, or 2.5 mg / ml, or 3 mg / ml, or 3.5 mg / ml. In some embodiments, the concentration of semaglutide is 3.2 mg / ml of the liquid pharmaceutical composition. In some embodiments, the semaglutide is in the form of a pharmaceutically acceptable salt. In some embodiments, the liquid pharmaceutical composition is an aqueous solution comprising at least 60% w / w water, such as at least 70% w / w water or at least 80% w / w water. In some embodiments, the liquid pharmaceutical composition is an aqueous solution comprising at least 97% w / w water, such as at least 98% w / w water. In some embodiments, the liquid pharmaceutical composition is an aqueous solution comprising 97-99% w / w water. In some embodiments, the liquid pharmaceutical composition is an aqueous solution comprising 97-98% w / w water. In some embodiments, the liquid pharmaceutical composition comprises a buffering agent. In some embodiments, the buffering agent is present in a concentration of 0.01-50 mM of the composition. In some embodiments, the buffering agent is a phosphate buffer. In some embodiments, the phosphate buffer is selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium phosphate. In some embodiments, the phosphate buffer is disodium hydrogen phosphate dihydrate. In some embodiments, the concentration of the phosphate buffer is 1-2 mg / ml, or 1.1-1.9 mg / ml, or 1.2-1.7 mg / ml, or 1.3-1.6 mg / ml, or 1.4-1.5 mg / ml. In some embodiments, the concentration of the phosphate buffer is 1.42 mg / ml. In some embodiments, the liquid pharmaceutical composition comprises one or more agents for adjusting the pH, such as HC1, NaOH or acetic acid (salt), such as sodium acetate or acetic acid. In some embodiments, the liquid pharmaceutical composition does not comprise a preservative. In some embodiments, the pH of the liquid pharmaceutical composition is in the range of 6.0-10.0 or 7-8. In some embodiments, the pH of the liquid pharmaceutical composition is 7.4. In some embodiments, the liquid pharmaceutical composition is for parenteral administration. In some embodiments, the liquid pharmaceutical composition is for subcutaneous administration. In some embodiments, the liquid pharmaceutical composition is for use in an injection device. In some embodiments, the liquid pharmaceutical composition has a pain intensity of slight or very slight pain when administered to a patient by injection. In some embodiments, the liquid pharmaceutical composition has a pain intensity of very slight pain when administered to a patient by injection.In some embodiments, the liquid pharmaceutical composition has a VAS score of less than 33 or less than 16 when administered to a patient by injection. In some embodiments, the liquid pharmaceutical composition has a VAS score of less than 20, or less than 15, or less than 10 when administered to a patient by injection.

[0018] In some embodiments, the present application relates to a liquid pharmaceutical composition further comprising histidine. In some embodiments, the concentration of histidine is 0.5-100 mM, or 0.5-50 mM, or 0.5-20 mM, or 0.5-15 mM, or 0.5-10 mM. In some embodiments, the concentration of histidine is 2-100 mM, or 2-50 mM, or 2-20 mM, or 2-15 mM, or 2-10 mM. In some embodiments, the concentration of histidine is 5-100 mM, or 5-50 mM, or 5-20 mM, or 5-15 mM, or 5-10 mM. In some embodiments, the concentration of histidine is 10-100 mM, or 10-50 mM, or 10-20 mM, or 10-15 mM. In some embodiments, the present application relates to a liquid pharmaceutical composition wherein less impurities are generated during storage. In some embodiments, the present application relates to a liquid pharmaceutical composition wherein less HMWP are generated during storage. In some embodiments, the present application relates to a liquid pharmaceutical composition wherein less hydrophobic impurity 1 is generated during storage. In some embodiments, the present application relates to a liquid pharmaceutical composition wherein less hydrophobic impurity 2 is generated during storage. In some embodiments, the present application relates to a liquid pharmaceutical composition wherein the composition obtains improved chemical stability.

[0019] In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, not exceeding 0.1% (w / w) of phenol, more than 6.4 mg / ml of sodium chloride, and 1-2 mg / ml of phosphate buffer. In some embodiments, the present invention relates to a substantially phenol-free liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, not exceeding 0.1% (w / w) of phenol, more than 6.4 mg / ml of sodium chloride, and 1-2 mg / ml of phosphate buffer. In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, not exceeding 0.1% (w / w) of phenol, 7-9 mg / ml of sodium chloride, and 1-2 mg / ml of phosphate buffer. In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, not exceeding 0.1% (w / w) of phenol, more than 6.4 mg / ml of sodium chloride, 0.5-10 mM histidine, and 1-2 mg / ml of phosphate buffer. In some embodiments, the present invention relates to a substantially phenol-free liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, more than 6.4 mg / ml of sodium chloride, 0.5-10 mM histidine, and 1-2 mg / ml of phosphate buffer. In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, not exceeding 0.1% (w / w) of phenol, 7-9 mg / ml of sodium chloride, 0.5-10 mM histidine, and 1-2 mg / ml of phosphate buffer. In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, not more than 0.1% (w / w) phenol, 7-9 mg / ml sodium chloride, and 1-2 mg / ml disodium hydrogen phosphate dihydrate. In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, not more than 0.1% (w / w) phenol, 7-9 mg / ml sodium chloride, 0.5-10 mM histidine, and 1-2 mg / ml disodium hydrogen phosphate dihydrate. In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising 0.5-3.5 mg / ml semaglutide, not more than 0.1% (w / w) phenol, 8.25 mg / ml sodium chloride, and 1.42 mg / ml disodium hydrogen phosphate dihydrate. In some embodiments, the present invention relates to a liquid pharmaceutical composition comprising 0.5-3.5 mg / ml smegglutide, not more than 0.1% (w / w) phenol, 8.25 mg / ml sodium chloride, 0.5-10 mM histidine, and 1.42 mg / ml disodium hydrogen phosphate dihydrate.

[0020] In some embodiments, the present invention relates to a kit comprising a liquid pharmaceutical composition according to the invention and instructions for use. In some embodiments, the present invention relates to a kit comprising a liquid pharmaceutical composition according to the invention and an injection device for administering the composition to a subject. In some embodiments, the injection device is selected from durable injection pens and pre-filled injection pens. In some embodiments, the present invention relates to a kit comprising a liquid pharmaceutical composition according to the invention and an injection device including a needle, such as a pre-filled syringe, for administering the composition to a subject.

[0021] In some embodiments, the present invention relates to liquid pharmaceutical compositions for medical use. In some embodiments, the present invention relates to liquid pharmaceutical compositions for treating and / or preventing diabetes, obesity, NASH, Alzheimer's disease, and / or cardiovascular disease. In some embodiments, the present invention relates to methods for preventing or treating diabetes or obesity, wherein the liquid pharmaceutical composition according to the present invention is administered to a subject in need.

[0022] Pharmaceutical Composition

[0023] The terms “pharmaceutical composition” and “composition” are used interchangeably herein and refer to a pharmaceutical composition suitable for administration to a subject in need.

[0024] In some embodiments, the composition comprises 0.01-100 mg / ml of semaglutide. In some embodiments, the composition comprises 0.1-50 mg / ml, such as 0.5-25 mg / ml or 1-15 mg / ml of semaglutide. In some embodiments, the composition comprises 0.1-10 mg / ml, such as 0.5-3.5 mg / ml or 1-2 mg / ml of semaglutide, such as 0.5 to 2 mg / ml. In some embodiments, the composition comprises 0.01-10 mg / ml, such as 0.01-3.5 mg / ml of semaglutide. In some embodiments, the composition comprises no more than 9 mg / ml, such as no more than 8 mg / ml or no more than 7 mg / ml of semaglutide. In some embodiments, the composition comprises no more than 6 mg / ml, such as no more than 5 mg / ml or no more than 4 mg / ml of semaglutide. In some embodiments, the composition contains no more than 3 mg / ml, such as no more than 2 mg / ml or no more than 1 mg / ml of semaglutide. In some embodiments, the composition contains at least 0.01 mg / ml, such as at least 0.02 mg / ml or at least 0.05 mg / ml of semaglutide. In some embodiments, the composition contains 1.34 mg / ml of semaglutide. In some embodiments, the composition contains 3.2 mg / ml of semaglutide.

[0025] In some embodiments, the pH of the compositions of the present invention is in the range of 3-10, such as pH 6-10 or 6-9. In some embodiments, the pH of the compositions of the present invention is in the range of pH 6.5-8.5, such as pH 7.0-8.2 or 7.0-7.8. In some embodiments, the pH is measured at 25°C.

[0026] In some embodiments, the compositions of the present invention comprise one or more pharmaceutically acceptable excipients.

[0027] In some embodiments, the compositions of the present invention comprise an isotonic agent, such as propylene glycol or sodium chloride. In some embodiments, the isotonic agent is propylene glycol and / or sodium chloride. In some embodiments, the isotonic agent is not propylene glycol.

[0028] In some embodiments, the compositions of the present invention do not contain propylene glycol.

[0029] In some embodiments, the compositions of the present invention do not contain other isotonic agents.

[0030] In some embodiments, the compositions of the present invention comprise 6.5-12 mg / ml, or 7-12 mg / ml, or 7.5-12 mg / ml, or 8-12 mg / ml, or 8.2-12 mg / ml, or 8.25-12 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention comprise 6.5-9.5 mg / ml, or 7-9.5 mg / ml, or 7.5-9.5 mg / ml, or 8-9.5 mg / ml, or 8.2-9.5 mg / ml, or 8.25-9.5 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention comprise 6.5-9 mg / ml, or 7-9 mg / ml, or 7.5-9 mg / ml, or 8-9 mg / ml, or 8.2-9 mg / ml, or 8.25-9 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention comprise 6.5-8.5 mg / ml, or 7-8.5 mg / ml, or 7.5-8.5 mg / ml, or 8-8.5 mg / ml, or 8.2-8.5 mg / ml, or 8.25-8.5 mg / ml of sodium chloride.

[0031] In some embodiments, the compositions of the present invention contain 6.5-12 mg / ml, such as 7-12 mg / ml or 7.5-12 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention contain 8-12 mg / ml, such as 8.2-12 mg / ml or 8.25-12 mg / ml of sodium chloride.

[0032] In some embodiments, the compositions of the present invention contain 6.5-9.5 mg / ml, such as 7-9.5 mg / ml or 7.5-9.5 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention contain 8-9.5 mg / ml, such as 8.2-9.5 mg / ml or 8.25-9.5 mg / ml of sodium chloride.

[0033] In some embodiments, the compositions of the present invention contain 6.5-9 mg / ml, such as 7-9 mg / ml or 7.5-9 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention contain 8-9 mg / ml, such as 8.2-9 mg / ml or 8.25-9 mg / ml of sodium chloride.

[0034] In some embodiments, the compositions of the present invention contain 6.5-8.5 mg / ml, such as 7-8.5 mg / ml or 7.5-8.5 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention contain 8-8.5 mg / ml, such as 8.2-8.5 mg / ml or 8.25-8.5 mg / ml of sodium chloride.

[0035] In some embodiments, the compositions of the present invention contain 5-6.2 mg / ml, such as 5.2-6.2 mg / ml or 5.3-6.2 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention contain 5-6 mg / ml, such as 5.2-6 mg / ml or 5.3-6 mg / ml of sodium chloride.

[0036] In some embodiments, the compositions of the present invention contain 6.5-7.9 mg / ml, such as 6.6-7.9 mg / ml or 6.7-7.9 mg / ml of sodium chloride. In some embodiments, the compositions of the present invention contain 6.5-7.8 mg / ml, such as 6.6-7.8 mg / ml or 6.7-7.8 mg / ml of sodium chloride.

[0037] In some embodiments, the compositions of the present invention contain 5.4 mg / ml or 6.72 mg / ml of sodium chloride.

[0038] In some embodiments, the compositions of the present invention comprise a buffer, such as a phosphate buffer or TRIS, or do not comprise a buffer. In some embodiments, the phosphate buffer is a sodium salt buffer of phosphate, such as disodium hydrogen phosphate.

[0039] In some embodiments, the compositions of the present invention do not contain preservatives. In some embodiments, the compositions of the present invention are substantially preservative-free.

[0040] The compositions of the present invention are in the form of liquid pharmaceutical compositions. In some embodiments, the liquid pharmaceutical composition is a solution or suspension. In some embodiments, the compositions of the present invention are in solution form, such as an aqueous solution. In some embodiments, the term "aqueous solution" as used herein refers to a solution containing at least 60% w / w water. In some embodiments, the aqueous solution contains 60-99% w / w water. In some embodiments, the aqueous solution contains at least 75% w / w water, such as at least 80% w / w water or at least 85% w / w water. In some embodiments, the aqueous solution contains at least 90% w / w water, such as at least 92% w / w water or at least 94% w / w water. In some embodiments, the aqueous solution contains at least 97% w / w water, such as at least 98% w / w water. In some embodiments, the aqueous solution contains 97-98% w / w water. In some embodiments, the liquid pharmaceutical composition is prepared by dissolving a powder, such as a freeze-dried or spray-dried powder.

[0041] Smegglutide

[0042] GLP-1 peptide smegglutinin can be prepared as described in Example 4 of WO2006 / 097537. Smegglutinin is also known as N6,26-{18-[N-(17-carboxyheptadecyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecyl}-[8-(2-amino-2-propionic acid),34-L-arginine] human glucagon-like peptide 1 (7-37), see WHO Drug Information Vol.24, No.1, 2010. In some embodiments, smegglutinin may be present in the composition in its fully or partially ionized form; for example, one or more carboxylic acid groups (-COOH) may be deprotonated to carboxylate groups (-COO). - And / or one or more amino groups (-NH2) can be protonated to -NH3. + Group. In some embodiments, semaglutide is added to the composition in the form of a salt. In some embodiments, semaglutide can be generated by recombination. In some embodiments, semaglutide can be generated synthetically.

[0043] Dosage and kit

[0044] In some embodiments, the compositions of the present invention are used for parenteral administration. In some embodiments, the compositions are used for subcutaneous administration.

[0045] In some embodiments, the compositions of the present invention are used for weekly administration. In some embodiments, the compositions of the present invention are used for daily administration, every two days, or every three days.

[0046] In some embodiments, the present invention relates to a kit comprising a pharmaceutical composition as defined herein and instructions for use. In some embodiments, the instructions for use include a package insert for the pharmaceutical product.

[0047] In some embodiments, the present invention relates to a kit comprising a pharmaceutical composition and an injection device as defined herein. In some embodiments, the injection device is selected from durable pens and prefilled pens. An example of a durable pen is... 4 or 5 (all from NovoNordisk A / S, Denmark). Examples of pre-filled injection pens are: (Novo Nordisk A / S, Denmark).

[0048] Indications

[0049] In some embodiments, the compositions of the present invention are used in medicine. In some embodiments, the compositions of the present invention can be used for the following medical treatments:

[0050] (i) Prevention and / or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (mature-onset diabetes in young adults), gestational diabetes, and / or for reducing HbA1c.

[0051] (ii) Delay or prevent the progression of diabetes, such as type 2 diabetes, delay the progression of impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delay the progression of insulin-free type 2 diabetes to insulin-requiring type 2 diabetes.

[0052] (iii) For example, by reducing food intake, losing weight, suppressing appetite, inducing satiety to prevent and / or treat eating disorders such as obesity; treat or prevent bulimia, bulimia nervosa and / or obesity induced by antipsychotic or steroid administration; reduce gastric motility; and / or delay gastric emptying.

[0053] (iv) Prevention and / or treatment of cardiovascular disease, such as delaying or reducing major adverse cardiovascular events (MACE) selected from cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, hospitalization due to unstable angina, and hospitalization due to heart failure.

[0054] The development of.

[0055] (v) Prevention and / or treatment of NASH.

[0056] (vi) Prevention and / or treatment of Alzheimer's disease.

[0057] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In yet another particular aspect, the indication is (iii). In yet another particular aspect, the indication is (iv). In yet another particular aspect, the indication is (v). In yet another particular aspect, the indication is (vi). In some embodiments, the indication is type 2 diabetes and / or obesity.

[0058] In some embodiments, the method or use includes the prevention, treatment, reduction, and / or induction of one or more diseases or conditions as defined herein. In some embodiments, the indications are (i) and (iii). In some embodiments, the indications are (ii) and (iii). In some embodiments, the invention includes the administration of an effective amount of GLP-1 peptide. In some embodiments, the invention relates to the administration of an effective amount of GLP-1 peptide.

[0059] Typically, all subjects suffering from obesity are also considered overweight. In some embodiments, the present invention relates to methods for treating or preventing obesity. In some embodiments, the present invention relates to the use of the composition in the treatment or prevention of obesity. In some embodiments, the subjects suffering from obesity are persons, such as adults or pediatric patients (including infants, children, and adolescents). Body Mass Index (BMI) is a measure of body fat based on height and weight. The calculation formula is BMI = weight in kilograms / height in meters. 2 Human subjects suffering from obesity may have a BMI ≥30; such subjects may also be referred to as obese. In some embodiments, human subjects suffering from obesity may have a BMI ≥35 or a BMI in the range of ≥30 to <40. In some embodiments, the obesity is severe obesity or morbid obesity, wherein the human subject may have a BMI ≥40.

[0060] In some embodiments, the present invention relates to methods for treating or preventing overweight in the presence of at least one weight-related comorbidity. In some embodiments, the present invention relates to the use of the composition for treating or preventing overweight in the presence of at least one weight-related comorbidity. In some embodiments, the overweight subject is a person, such as an adult or a pediatric patient (including infants, children, and adolescents). In some embodiments, the overweight human subject may have a BMI ≥25, such as a BMI ≥27. In some embodiments, the overweight human subject has a BMI in the range of 25 to <30 or a BMI in the range of 27 to <30. In some embodiments, the weight-related comorbidity is selected from hypertension, diabetes (such as type 2 diabetes), dyslipidemia, high cholesterol, and obstructive sleep apnea.

[0061] In some embodiments, the present invention relates to a method of weight loss. In some embodiments, the present invention relates to the use of the composition in weight loss. A person who will undergo weight loss according to the present invention may have a BMI ≥25, such as a BMI ≥27 or a BMI ≥30. In some embodiments, a person who will undergo weight loss according to the present invention may have a BMI ≥35 or a BMI ≥40. The term "weight loss" may include the treatment or prevention of obesity and / or overweight.

[0062] In some implementations, as used herein, a specific value given with respect to a number or range can be understood as that specific value or approximately that specific value (e.g., that specific value plus or minus 10%).

[0063] Embodiments of the present invention

[0064] The following are non-limiting embodiments of the present invention:

[0065] 1. A liquid pharmaceutical composition comprising smegglutide, not more than 0.1% (w / w) of phenol and more than 6.4 mg / ml of sodium chloride.

[0066] 2. A liquid pharmaceutical composition comprising smegglutide, not more than 0.1% (w / w) of phenol and more than 6.4 mg / ml of sodium chloride, and optionally further comprising histidine.

[0067] 3. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0068] 4. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0069] 5. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at 8.1-8.9 mg / ml, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0070] 6. A liquid pharmaceutical composition comprising essentially the following substances: a) 0.5-10 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0071] 7. A liquid pharmaceutical composition comprising essentially the following substances: a) 0.5-10 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-8.9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0072] 8. A liquid pharmaceutical composition comprising essentially the following substances: a) 3.2 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0073] 9. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 97% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0074] 10. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.25 mg / ml sodium chloride, d) a buffer, e) at least 97% water (e.g., 97-99%), optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0075] 11. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt) such as sodium acetate or acetic acid, and said composition optionally having a pH of 6-10, such as 7-8.

[0076] 12. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0077] 13. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0078] 14. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at 8.1-8.9 mg / ml, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0079] 15. A liquid pharmaceutical composition comprising essentially the following substances: a) 0.5-10 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0080] 16. A liquid pharmaceutical composition comprising essentially the following substances: a) 0.5-10 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-8.9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0081] 17. A liquid pharmaceutical composition comprising essentially the following substances: a) 3.2 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0082] 18. A liquid pharmaceutical composition comprising essentially the following substances: a) smegglutide, optionally b) not more than 0.1% (w / w) of phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 97% water (e.g., 97-99%), optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0083] 19. A liquid pharmaceutical composition comprising: a) smegglutinin, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0084] 20. A liquid pharmaceutical composition comprising: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0085] 21. A liquid pharmaceutical composition comprising: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at 8.1-8.9 mg / ml, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0086] 22. A liquid pharmaceutical composition comprising: a) 0.5-10 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0087] 23. A liquid pharmaceutical composition comprising: a) 0.5-10 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-8.9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0088] 24. A liquid pharmaceutical composition comprising: a) 3.2 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0089] 25. A liquid pharmaceutical composition comprising: a) smegglutinin, optionally b) not more than 0.1% (w / w) of phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 97% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0090] 26. A liquid pharmaceutical composition comprising: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.25 mg / ml sodium chloride, d) a buffer, e) at least 97% water (e.g., 97-99%), optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0091] 27. A liquid pharmaceutical composition comprising: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt) such as sodium acetate or acetic acid, and said composition optionally having a pH of 6-10, such as 7-8.

[0092] 28. A liquid pharmaceutical composition comprising: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0093] 29. A liquid pharmaceutical composition comprising: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0094] 30. A liquid pharmaceutical composition comprising: a) smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at 8.1-8.9 mg / ml, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0095] 31. A liquid pharmaceutical composition comprising: a) 0.5-10 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0096] 32. A liquid pharmaceutical composition comprising: a) 0.5-10 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) 8.1-8.9 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0097] 33. A liquid pharmaceutical composition comprising: a) 3.2 mg / ml smegglutide, optionally b) not more than 0.1% (w / w) phenol, c) more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0098] 34. A liquid pharmaceutical composition comprising: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 97% water (e.g., 97-99%), optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and said composition optionally having a pH of 6-10, such as 7-8.

[0099] 35. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising not more than 0.09%, or 0.08%, or 0.07%, or 0.06%, or 0.05%, or 0.04%, or 0.03%, or 0.02%, or 0.01% (w / w) of phenol.

[0100] 36. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the liquid composition is substantially free of phenol.

[0101] 37. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein it does not contain phenol.

[0102] 38. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising sodium chloride at a concentration of more than 7.0 mg / ml, or more than 7.2 mg / ml, or more than 7.5 mg / ml, or more than 7.7 mg / ml, or more than 8 mg / ml, or more than 8.2 mg / ml, or more than 8.25 mg / ml.

[0103] 39. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising 7-12 mg / ml, or 7.5-12 mg / ml, or 8-12 mg / ml of sodium chloride.

[0104] 40. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising 7-9.5 mg / ml, or 7-9 mg / ml, or 7-8.25 mg / ml of sodium chloride.

[0105] 41. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising 7-10 mg / ml, or 7-9.5 mg / ml, or 8-9 mg / ml, or 8.1-8.9 mg / ml, or 8.1-8.8 mg / ml, or 8.2-8.7 mg / ml, or 8.2-8.6 mg / ml, or 8.2-8.5 mg / ml, or 8.2-8.4 mg / ml, or 8.2-8.3 mg / ml.

[0106] 42. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising 7-10 mg / ml, such as 7-9.5 mg / ml or 8-9 mg / ml of sodium chloride.

[0107] 43. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising 8.1-8.9 mg / ml, such as 8.1-8.8 mg / ml or 8.2-8.7 mg / ml of sodium chloride.

[0108] 44. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising 8.2-8.6 mg / ml or 8.2-8.5 mg / ml of sodium chloride.

[0109] 45. The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising 8.2-8.4 mg / ml or 8.2-8.3 mg / ml of sodium chloride.

[0110] 46. ​​The liquid pharmaceutical composition according to any one of the foregoing embodiments, comprising 8.25 mg / ml of sodium chloride.

[0111] 47. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition

[0112] a. For parenteral administration;

[0113] b. is an aqueous solution containing at least 60% w / w water; or

[0114] c. Further includes a buffer.

[0115] 48. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the concentration of smegglutide is 0.5-10 mg / ml or 0.01-3.5 mg / ml of the composition.

[0116] 49. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the concentration of smegglutide is 0.5 mg / ml, or 1 mg / ml, or 1.5 mg / ml, or 2 mg / ml, or 2.5 mg / ml, or 3 mg / ml, or 3.5 mg / ml.

[0117] 50. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the concentration of smegglutide is 3.2 mg / ml.

[0118] 51. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the smegglutinin is in the form of a pharmaceutically acceptable salt.

[0119] 52. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition is an aqueous solution containing at least 60% w / w water, such as at least 70% w / w water or at least 80% w / w water.

[0120] 53. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition is an aqueous solution containing at least 97% w / w water, such as at least 98% w / w water.

[0121] 54. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition is an aqueous solution containing 97-99% w / w water.

[0122] 55. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the liquid pharmaceutical composition comprises a buffer.

[0123] 56. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the buffer is present at a concentration of 0.01-50 mM of the composition.

[0124] 57. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the buffer is a phosphate buffer.

[0125] 58. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the phosphate buffer is selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate.

[0126] 59. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the phosphate buffer is disodium hydrogen phosphate dihydrate.

[0127] 60. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the concentration of the phosphate buffer is 1-2 mg / ml, or 1.1-1.9 mg / ml, or 1.2-1.7 mg / ml, or 1.3-1.6 mg / ml, or 1.4-1.5 mg / ml.

[0128] 61. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the concentration of the phosphate buffer is 1.42 mg / ml.

[0129] 62. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition comprises one or more reagents for adjusting pH, such as HCl, NaOH or acetic acid (salt).

[0130] 63. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition does not contain a preservative.

[0131] 64. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the pH of the composition is in the range of 6.0-10.0 or 7-8.

[0132] 65. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the pH of the composition is 7.4.

[0133] 66. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition is for parenteral administration.

[0134] 67. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition is for subcutaneous administration.

[0135] 68. The liquid pharmaceutical composition according to any one of the foregoing embodiments, used in an injection device.

[0136] 69. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition has a slight or very slight pain intensity when administered to a patient by injection.

[0137] 70. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition has a very mild pain intensity when administered to a patient by injection.

[0138] 71. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition has a VAS score of less than 33 or less than 16 when administered to a patient by injection.

[0139] 72. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition has a VAS score of less than 20, less than 15, or less than 10 when administered to a patient by injection.

[0140] 73. The liquid pharmaceutical composition according to any one of the foregoing embodiments further comprises histidine.

[0141] 74. The liquid pharmaceutical composition according to embodiment 73, wherein the concentration of histidine is 0.5-100 mM, or 0.5-50 mM, or 0.5-20 mM, or 0.5-15 mM, or 0.5-10 mM.

[0142] 75. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein fewer impurities are generated during storage.

[0143] 76. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein less HMWP is generated during storage.

[0144] 77. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein fewer hydrophobic impurities 1 are generated during storage.

[0145] 78. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein fewer hydrophobic impurities 2 are generated during storage.

[0146] 79. The liquid pharmaceutical composition according to any one of the foregoing embodiments, wherein the composition achieves improved chemical stability.

[0147] 80. A liquid pharmaceutical composition comprising 0.5-3.5 mg / ml of smegglutide, not exceeding 0.1% (w / w) of phenol, 7-9 mg / ml of sodium chloride, and 1-2 mg / ml of phosphate buffer.

[0148] 81. A liquid pharmaceutical composition comprising 0.5-3.5 mg / ml of smegglutide, not exceeding 0.1% (w / w) of phenol, 7-9 mg / ml of sodium chloride, 0.5-10 mM of histidine, and 1-2 mg / ml of phosphate buffer.

[0149] 82. A liquid pharmaceutical composition comprising 0.5-3.5 mg / ml of smegglutide, not exceeding 0.1% (w / w) of phenol, 7-9 mg / ml of sodium chloride, and 1-2 mg / ml of disodium hydrogen phosphate dihydrate.

[0150] 83. A liquid pharmaceutical composition comprising 0.5-3.5 mg / ml of smegglutide, not exceeding 0.1% (w / w) of phenol, 7-9 mg / ml of sodium chloride, 0.5-10 mM of histidine, and 1-2 mg / ml of disodium hydrogen phosphate dihydrate.

[0151] 84. A liquid pharmaceutical composition comprising 0.5-3.5 mg / ml of smegglutide, not exceeding 0.1% (w / w) of phenol, 8.25 mg / ml of sodium chloride, and 1.42 mg / ml of disodium hydrogen phosphate dihydrate.

[0152] 85. A liquid pharmaceutical composition comprising 0.5-3.5 mg / ml of smegglutide, not exceeding 0.1% (w / w) of phenol, 8.25 mg / ml of sodium chloride, 0.5-10 mM of histidine, and 1.42 mg / ml of disodium hydrogen phosphate dihydrate.

[0153] 86. A kit comprising a liquid pharmaceutical composition according to any one of the foregoing embodiments and instructions for use.

[0154] 87. A kit comprising a liquid pharmaceutical composition according to any one of embodiments 1-85 and an injection device for administering the composition to a subject.

[0155] 88. The kit according to embodiment 87, wherein the injection device is selected from durable injection pens and pre-filled injection pens.

[0156] 89. A kit comprising a liquid pharmaceutical composition as defined in any of the foregoing embodiments and an injection device including a needle, such as a pre-filled syringe, for administering the composition to a subject.

[0157] 90. A kit comprising a liquid pharmaceutical composition and an injection device including a needle, such as a pre-filled syringe, for administering the composition to a subject, the liquid pharmaceutical composition comprising essentially the following substances: a) semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH, or acetic acid (salt), and the composition optionally having a pH of 6-10, such as 7-8.

[0158] 91. A kit comprising a liquid pharmaceutical composition and an injection device including a needle, such as a pre-filled syringe, for administering the composition to a subject, the liquid pharmaceutical composition comprising: a) smegglutinin, optionally b) not more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and the composition optionally having a pH of 6-10, such as 7-8.

[0159] 92. The liquid pharmaceutical composition according to any one of embodiments 1-85, for use in medicine.

[0160] 93. The liquid pharmaceutical composition according to any one of embodiments 1-85, for the treatment and / or prevention of diabetes, obesity, Alzheimer's disease, NASH and / or cardiovascular disease.

[0161] 94. The liquid pharmaceutical composition according to any one of embodiments 1-85, for the treatment and / or prevention of Alzheimer's disease.

[0162] 95. The liquid pharmaceutical composition according to any one of embodiments 1-85, for the treatment and / or prevention of Alzheimer's disease, NASH and / or cardiovascular disease.

[0163] 96. A method for the prevention or treatment of diabetes or obesity, wherein a liquid pharmaceutical composition according to any one of embodiments 1-85 is administered to a subject in need.

[0164] 97. A method for the prevention or treatment of Alzheimer's disease, NASH and / or cardiovascular disease, wherein a liquid pharmaceutical composition according to any one of embodiments 1-85 is administered to a subject in need.

[0165] Example

[0166] List of Abbreviations

[0167] SDD: Single-Dose Device

[0168] VAS: Visual Analog Scale

[0169] WFI: Water for Injection

[0170] qs: sufficient quantity

[0171] General Methods

[0172] Preparation of semaglutide compositions for clinical studies

[0173] The semaglutide composition is prepared as follows: a buffer (disodium hydrogen phosphate dihydrate), an isotonic agent (propylene glycol or sodium chloride), and phenol (optionally) are dissolved in water. The pH of the buffer solution is adjusted to 7.4 by adding sodium hydroxide and / or hydrochloric acid. Semaglutide is dissolved in the buffer solution, the pH is adjusted to 7.4 using sodium hydroxide and / or hydrochloric acid, and the composition is finally sterilized by filtration through a 0.22 μm sterile filter. The semaglutide composition is then filled into pre-filled syringes or cartridges. All semaglutide compositions exhibit acceptable stability during storage and under use conditions.

[0174] Design of clinical studies

[0175] The tested compositions were prepared as described in the section “Preparation of Smegglutinin Compositions for Clinical Studies”.

[0176] A single-center, crossover, randomized, double-blind study was conducted in healthy men and women to compare injection site pain experience with designated products (see Tables 2 and 4) when 0.25 mg semaglutide was delivered subcutaneously using two different products. Subjects were uniformly randomized to four sequential products and injection sides using a 2×2 protocol, as shown in Table 1.

[0177] Table 1: Products and abdominal injection sites for each treatment

[0178] FORM B: Formulation B as specified in Tables 2 and 4. FORM C / D: Formulation C or D as specified in Table 2 or Table 4.

[0179]

[0180] Instruct staff to select the injection site on the designated side of the midline, based on their judgment of the area with the greatest subcutaneous fat thickness, using visual inspection and palpation. Injections of FORM C / D products should be performed as described in the instructions for the DV3396 pen injector, i.e., without lifting skin folds. Injections of FORM B products should be performed as described in the instructions for the PDS290 pen injector and the instructions for the Ypsomed Clickfine AutoProtect, 8mm x 29G needle.

[0181] Subjects received two (2) single doses of smegglutide 0.25 mg on one (1) day. The two (2) products were administered at least 30 minutes apart on the anterior abdominal wall on opposite sides of the midline.

[0182] The first dose was administered as follows. An informed staff member in the study room started a timer, while another informed staff member began the injection. The timer was placed out of the subjects' sight. Uninformed staff members were not in the study room during the administration. Immediately after administration, the informed group left the study room, and the uninformed group took over. This occurred within one minute of the injection.

[0183] The injection site pain intensity VAS was completed by the subject starting one (1) minute after each injection of the study drug to report the intensity of pain experienced in the first minute after injection. The subject was instructed to draw a vertical line on the VAS (100 mm); the endpoints were “no pain” and “unbearable pain”. The VAS is shown below. The distance (mm) between the endpoint “no pain” and the vertical line on the VAS was recorded. The VAS is a well-validated tool for assessing injection site pain (Williamson A1, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs. 2005 Aug; 14(7):798-804.).

[0184]

[0185] At least 30 minutes after the first injection, once the subject has confirmed that the pain has completely subsided (so as not to affect the rating of the last injection), the timer is reset and the last injection is given. For each subject, the two (2) semaglutide injections are administered by the same staff. If the pain has not subsided after 30 minutes, another attempt is made at 60 minutes. If the pain is still present at this time, no further attempts are made.

[0186] After the final injection, the same measurements as after the first injection, as described above, are performed. Subjects are not allowed to review their previous ratings.

[0187] A total of 100 subjects were tested, and the VAS score is shown as the average of the obtained VAS scores. Using data from actual trials and statistical information, the pain category that best matches a given VAS score was calculated, as shown below. The "very severe" category and VAS scores higher than 83 were not used and could not be characterized.

[0188]

[0189] Preparation of semaglutide compositions for stability studies

[0190] Unless otherwise specified, the composition of semaglutide is prepared as follows: a buffer (disodium hydrogen phosphate dihydrate), an isotonic agent (sodium chloride), and optionally a stabilizer (histidine) are dissolved in water. Semaglutide is dissolved therein. The pH is adjusted to 7.4 using sodium hydroxide and / or hydrochloric acid, and the composition is finally sterilized by filtration through a 0.22 μm sterile filter. The composition containing semaglutide and optionally histidine is added to a pre-filled syringe (Ompi#7600002.8506).

[0191] Assay (I): Determination of high molecular weight protein (HMWP) content of semaglutide compositions

[0192] HMWP content was determined using size exclusion chromatography (SE-HPLC) with a Waters Insulin HMWP column and a mobile phase of sodium chloride, sodium phosphate, phosphoric acid, and isopropanol. Elution was isocratic, and detection was performed at 280 nm. The HMWP content is given as a percentage of the combined area of ​​the peak eluted earlier than the semaglutide monomer peak (i.e., the HMWP peak) relative to the total area of ​​the HMWP and semaglutide monomer peaks.

[0193] Assay (II): Determination of hydrophobic impurities 1 and 2, hydrophilic impurities and total impurities of semaglutide compositions

[0194] The determination of hydrophobic impurities 1 and 2, hydrophilic impurities, and the total impurities in the smegglutinin composition was performed using reversed-phase high-performance liquid chromatography (RP-HPLC). The RP-HPLC method was performed on a Kinetex C18 column, beginning with isocratic elution followed by a gradient elution using eluent A (90% 0.09 M phosphate buffer, pH 3.6, and 10% acetonitrile) and eluent B (60% acetonitrile and 20% isopropanol) from approximately 50:50 to 10:90, and back to approximately 50:50. Detection was performed at 210 nm.

[0195] The total impurities were calculated as the ratio of the area of ​​all semaglutide-related impurity peaks to the total area of ​​semaglutide and semaglutide-related impurity peaks, expressed as a percentage. The total impurities were further divided into three groups.

[0196] • Hydrophilic impurities are impurity peaks eluted before smegglutinin.

[0197] • Hydrophobic impurity 1 is all the peaks eluted between smegglutinin and the start of the second linear gradient in the chromatogram.

[0198] • Hydrophobic impurity 2 is all the peaks eluted between the end of the first isocratic elution and the start of the third linear gradient in the chromatogram.

[0199] These three impurity groups are expressed as a percentage of the total area of ​​all smegglutinin-related peaks.

[0200] Example 1 : Clinical studies comparing approved formulation and new SDD formulation

[0201] Objective: To test and compare the new SDD formulation with approved [product name missing]. preparation.

[0202] This study was conducted as described in the "Design of Clinical Studies" section. The following two products were compared: FORM B product (Formulation B) PDS290 and FORM C products (Formulation C, DV3396). The composition is shown in Table 2. In addition to the difference in semaglutide concentration, the preservative (phenol) was removed from Formulation C because this product is intended for single-injection use. To adjust the formulation's tensile strength after phenol removal, the propylene glycol content was adjusted from 14.0 mg / ml to 18.5 mg / ml. Compositional changes are highlighted in bold.

[0203] Table 2. Compositional changes compared to smegglutinin 1.34 mg / ml

[0204]

[0205] Table 3 VAS Scores

[0206] Formulation VAS score Intensity of pain Formulation B (PDS290) 4.4 Very slight Formulation C (DV3396) 35.1 Moderate

[0207] VAS scores were obtained and are shown in Table 3. Low VAS scores were associated with a low level of pain experience. The VAS score obtained for FORM B was 4.4 mm (very mild pain intensity), while the VAS score obtained for FORM C was 35.1 mm (moderate pain intensity). These results indicate that subjects using FORM C experienced increased injection pain compared to FORM B.

[0208] Example 2: Clinical studies comparing approved formulation and new improved SDD formulation

[0209] Objective: To test and compare the new improved SDD formulation with the approved one. preparation.

[0210] This study was conducted as described in the "Design of Clinical Studies" section. The following two products were compared: FORM B product (Formulation B) PDS290) and FORM D product (Formulation D, DV3396). A new single-dose formulation of smegglutide was developed, which showed acceptable physical and chemical stability. The optimized formulation (named Formulation D) contains sodium chloride (8.25 mg / ml for tensile strength) instead of propylene glycol. The composition is shown in Table 4.

[0211] Table 4. Compositional changes compared to smegglutinin 1.34 mg / ml

[0212]

[0213]

[0214] Table 5 VAS Scores

[0215] Formulation VAS score Intensity of pain Formulation B (PDS290) 5.7 Very slight Formulation D (DV3396) 8.3 Very slight

[0216] The VAS scores are shown in Table 5. The VAS score for FORM B was 5.7 mm (very mild pain intensity), while the VAS score for FORM D was 8.3 mm (very mild pain intensity). These results indicate that subjects using FORM D experienced similar, very mild injection pain compared to FORM B. These results suggest that the injection pain experience is independent of the device used, but different formulations containing semaglutide do affect the pain experience.

[0217] Example 3: Stability study (30°C)

[0218] Compositions containing semaglutide were prepared as described in "Preparation of Semaglutide Compositions for Stability Studies" and tested using assays (I) and (II) as described in the General Methods. The tested compositions contained semaglutide (0.5 mg / ml), sodium chloride (8.25 mg / ml), disodium hydrogen phosphate dihydrate (1.42 mg / ml), and optionally histidine (0.5, 2, and 10 mM) in an aqueous solution at pH 7.4 (as specified in Table 6). The compositions were added to pre-filled syringes with a stoked needle (fill volume 0.5 ml). The filled syringes were stored at 30°C, and chemical stability was observed over time. After storage at 30°C, chemical stability was determined by measuring the formation of HMWP as described in Assay (I); results are provided in Table 7. After storage at 30°C, the formation of semaglutide-related impurities was determined as described in Assay (II); results are provided in Tables 8-11.

[0219] Table 6. Compositions tested in Examples 3 and 4.

[0220] Composition number Description 1 0 mM Histidine 2 0.5 mM Histidine 3 2 mM Histidine 4 10 mM Histidine

[0221] Table 7. HMWP formation in the smegglutinin composition during storage at 30°C.

[0222]

[0223] The results presented in Table 7 indicate that fewer HMWPs are formed during storage when histidine is present in the composition; compared to batches produced without histidine, a reduction of approximately 50% in the maximum HMWP was observed from 31 days up to 150 days with the addition of 10 mM histidine. The lower HMWP concentration corresponds to better stability, i.e., the composition is more chemically stable in the presence of histidine.

[0224] Table 8. Formation of hydrophobic impurity 1 in the smegglutinin composition during storage at 30°C.

[0225]

[0226] The results presented in Table 8 indicate that fewer hydrophobic impurities 1 are formed during storage when histidine is present in the composition. The lower concentration of hydrophobic impurity 1 corresponds to better stability, i.e., the composition is more chemically stable in the presence of histidine.

[0227] Table 9. Formation of hydrophobic impurity 2 in the smegglutinin composition during storage at 30°C.

[0228]

[0229] The results presented in Table 9 indicate that fewer hydrophobic impurities 2 are formed during storage when histidine is present in the composition; compared to batches produced without histidine, a reduction of approximately 50% in the maximum hydrophobic impurity 2 was observed from 31 days up to 150 days with the addition of 10 mM histidine. The lower concentration of hydrophobic impurity 2 corresponds to better stability, i.e., the composition is more chemically stable in the presence of histidine.

[0230] Table 10. Formation of hydrophilic impurities in the smegglutinin composition during storage at 30°C.

[0231]

[0232] The results presented in Table 10 show that the presence of histidine in the composition had little or no effect on the formation of hydrophilic impurities. Therefore, the composition is similarly stable in the presence of histidine.

[0233] Table 11. Formation of total impurities in the smegglutide composition during storage at 30°C.

[0234]

[0235] The results presented in Table 8-11 indicate that the chemical stability of smegglutide is similar to or improved when histidine is present in the composition, due to the overall formation of fewer impurities during storage. The improved stability profile (lower impurity levels) may allow for a longer shelf life and / or usage period for the pharmaceutical product.

[0236] Example 4: Stability study (5°C)

[0237] Compositions containing semaglutide were prepared as described in "Preparation of Semaglutide Compositions for Stability Studies" and tested using assays (I) and (II) as described in the General Methods. The tested compositions contained semaglutide (0.5 mg / ml), sodium chloride (8.25 mg / ml), disodium hydrogen phosphate dihydrate (1.42 mg / ml), and optionally histidine (0.5, 2, and 10 mM) in an aqueous solution at pH 7.4 (as specified in Table 6). The compositions were added to pre-filled syringes with a stoked needle (fill volume 0.5 ml). The filled syringes were stored at 5°C, and chemical stability was observed over time. After storage at 5°C, chemical stability was determined by measuring the formation of HMWP as described in Assay (I); results are provided in Table 12. After storage at 5°C, the formation of semaglutide-related impurities was determined as described in Assay (II); results are provided in Tables 13-16.

[0238] Table 12. HMWP formation in the smegglutinin composition during storage at 5°C.

[0239]

[0240] The results presented in Table 12 support the overall trend of the data obtained at 30°C shown in Table 7.

[0241] Table 13. Formation of hydrophobic impurity 1 in the smegglutinin composition during storage at 5°C.

[0242]

[0243] The results presented in Table 13 support the overall trend of the data obtained at 30°C as shown in Table 8.

[0244] Table 14. Formation of hydrophobic impurity 2 in the smegglutinin composition during storage at 5°C.

[0245]

[0246] The results presented in Table 14 support the overall trend of the data obtained at 30°C as shown in Table 9.

[0247] Table 15. Formation of hydrophilic impurities in the smegglutinin composition during storage at 5°C.

[0248]

[0249] The results presented in Table 15 support the overall trend of the data obtained at 30°C as shown in Table 10.

[0250] Table 16. Formation of total impurities in the smegglutinin composition during storage at 5°C.

[0251]

[0252] The results presented in Table 16 support the overall trend of the data obtained at 30°C as shown in Table 11.

[0253] The results presented in Tables 12-16 show that the chemical stability of smegglutide under long-term storage conditions is improved when histidine is present in the composition, consistent with results obtained at 30°C. The improved stability profile (lower impurity levels) allows for a longer shelf life (generally at least 3 years) and / or usage period for the pharmaceutical product.

[0254] While certain features of the invention have been set forth and described herein, many modifications, substitutions, alterations, and equivalents will now occur to those skilled in the art. Therefore, it should be understood that all such modifications and alterations falling within the true scope of the invention are intended to be covered by the appended claims.

Claims

1. A liquid pharmaceutical composition consisting of: a) 0.5-3.5 mg / ml semaglutide, b) 7-9.5 mg / ml sodium chloride, c) a buffer, d) at least 60% w / w water, optionally e) histidine, and optionally f) one or more agents for adjusting the pH; wherein the pH of the liquid pharmaceutical composition is in the range of 7-8.

2. The liquid pharmaceutical composition according to claim 1, wherein the f) one or more agents for adjusting the pH is HC1, NaOH, acetic acid or an acetate salt.

3. The liquid pharmaceutical composition according to any one of claims 1-2, comprising 8.2-8.9 mg / ml sodium chloride.

4. The liquid pharmaceutical composition according to claim 3, comprising 8.2-8.3 mg / ml sodium chloride.

5. The liquid pharmaceutical composition according to claim 4, comprising 8.25 mg / ml sodium chloride.

6. The liquid pharmaceutical composition according to any one of claims 1-2 and 4-5, comprising 3.2 mg / ml semaglutide.

7. The liquid pharmaceutical composition according to any one of claims 1-2 and 4-5, further comprising histidine.

8. The liquid pharmaceutical composition according to claim 7, wherein the concentration of histidine is 0.5-50 mM.

9. The liquid pharmaceutical composition according to claim 8, wherein the concentration of histidine is 0.5-15 mM.

10. The liquid pharmaceutical composition according to claim 9, wherein the concentration of histidine is 0.5-10 mM.

11. The liquid pharmaceutical composition according to any one of claims 1-2, 4-5 and 8-10, wherein the buffer is present in a concentration of 0.01-50 mM.

12. The liquid pharmaceutical composition according to claim 11, wherein the buffer is a phosphate buffer.

13. The liquid pharmaceutical composition according to claim 12, wherein the phosphate buffer is selected from the group consisting of sodium phosphate monobasic, sodium phosphate dibasic and sodium phosphate.

14. The liquid pharmaceutical composition according to claim 13, wherein the concentration of the phosphate buffer is 1-2 mg / ml.

15. The liquid pharmaceutical composition according to claim 14, wherein the concentration of the phosphate buffer is 1.42 mg / ml.

16. The liquid pharmaceutical composition according to any one of claims 1-2, 4-5, 8-10 and 12-15, wherein the pH of the liquid pharmaceutical composition is 7.

4.

17. The liquid pharmaceutical composition according to any one of claims 1-2, 4-5, 8-10 and 12-15, wherein the liquid pharmaceutical composition is for parenteral administration.

18. The liquid pharmaceutical composition according to claim 17, wherein the liquid pharmaceutical composition is for subcutaneous administration.

19. A kit comprising a liquid pharmaceutical composition according to any one of claims 1-18 and an injection device for administering the composition to a subject.

20. The kit according to claim 19, wherein the injection device comprises a needle.

21. The kit according to claim 19, wherein the injection device is a pre-filled syringe.

22. Use of a liquid pharmaceutical composition according to any one of claims 1-18 for the manufacture of a medicament, wherein the medicament is for the treatment and / or prevention of diabetes, obesity, NASH and / or cardiovascular disease.

23. Use of a liquid pharmaceutical composition according to any one of claims 1-18 for the manufacture of a medicament, wherein the medicament is for the prevention and / or treatment of hyperglycemia, type 2 diabetes, type 1 diabetes, young adult-onset diabetes, and / or gestational diabetes.

24. Use of a liquid pharmaceutical composition according to any one of claims 1-18 for the manufacture of a medicament, wherein the medicament is for the treatment and / or prevention of overweight, wherein a human subject suffering from overweight has a BMI of > 25.

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