Stable liquid formulation containing glucagon-like peptide 1 and its use

Abstract

Provided are stable liquid formulations of GLP-1 and GLP-1 analogs and methods of using such formulations in the treatment of disorders or conditions.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the priority of British Patent Specification No. 1917723.7 filed on December 4, 2019.

[0002] This disclosure relates to formulations of GLP - 1 and its GLP - 1 analogs and methods of using such formulations.

Background Art

[0003] Native glucagon - like peptide 1 (native GLP - 1) is a 37 - amino acid peptide secreted from intestinal L cells in response to feeding. It has been found that when insulin secretion is stimulated, insulin causes cells to take up glucose and lower blood glucose concentration (Mojsov, S., 1992). Native GLP - 1 is susceptible to proteolytic cleavage, thereby generating two biologically active peptides, GLP - 1(7 - 37) and GLP - 1(7 - 36)NH2.

[0004] However, these biologically active peptides are rapidly metabolically degraded by ubiquitously present peptidyl dipeptidase - 4 (DPP - 4), so they have a very short half - life (<2 minutes).

[0005] ROSE - 010 (Val8 - GLP - 1) is a GLP - 1 analog that has been made resistant to DPP - 4 - mediated cleavage by substituting the alanine residue at position 8 with valine. ROSE - 010 is a potent receptor agonist with very high sequence homology to the native GLP - 1(7 - 37) peptide.

[0006] Clinical trials have shown that ROSE-010 reduces acute exacerbations of irritable bowel syndrome (IBS) (Hellstroem PM, et al., 2009). In constipation-predominant irritable bowel syndrome (IBS-C), ROSE-010 delayed gastric emptying of solid contents, and 30 and 100 μg of ROSE-010 accelerated colonic transit after 48 hours, suggesting its potential to alleviate constipation in IBS-C (Camilleri, M et al., 2012). [Overview of the project] [Problems that the invention aims to solve]

[0007] However, ROSE-010 forms non-covalent aggregates in solution (Doyle, BD et al, 2005), making it difficult to develop a liquid formulation. [Means for solving the problem]

[0008] This specification describes stable liquid formulations of GLP-1 and GLP-1 analogs such as ROSE-010. [Modes for carrying out the invention]

[0009] overview This specification describes liquid formulations of glucagon-like peptide-1 or GLP-1 analogs.

[0010] In certain aspects and embodiments described herein, the liquid pharmaceutical formulations of the Disclosure may include GLP-1 or a GLP-1 analog, which is an agonist of the GLP-1 receptor. Pharmaceutical formulations of glucagon-like peptide-1 (GLP-1(7-37)) or a GLP-1 analog such as ROSE-010 are provided.

[0011] In other embodiments and models described herein, the pharmaceutical formulation may be aqueous and may contain ROSE-010 in the solution. The pharmaceutical formulations of this disclosure can be advantageously stored for long periods of time. For example, the pharmaceutical formulations of this disclosure can advantageously have a stable shelf life of at least three months.

[0012] The pharmaceutical formulations of this disclosure are advantageously able to withstand physical stress such as freeze-thaw cycles, mechanical stress, and / or high temperatures. The pharmaceutical formulations of this disclosure may be suitable for injection. In certain aspects and embodiments described herein, the pharmaceutical formulations may be provided in pre-filled syringes. In other aspects and embodiments described herein, the pharmaceutical formulations may be provided in single-dose or multi-dose containers.

[0013] In the embodiments and examples described herein, the pharmaceutical formulation may be aqueous, and GLP-1 or a GLP-1 analog may be included in the solution to obtain a liquid pharmaceutical formulation of GLP-1 or a GLP-1 analog.

[0014] The GLP-1 or GLP-1 analogs of this disclosure have, for example, the amino acid sequence shown in SEQ ID NO: 1, but are not limited thereto.

[0015] A preferred embodiment of GLP-1 or a GLP-1 analog is a biologically active peptide GLP-1 (7-37) comprising the amino acid sequence shown in SEQ ID NO: 2 (H-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-OH). The GLP-1 analog of this disclosure may have one or more amino acid substitutions compared to the wild-type GLP-1 peptide. Examples of amino acid substitutions include conservative amino acid substitutions. Examples of amino acid substitutions include modifications of amino acid residue 1, amino acid residue 2, amino acid residue 15, amino acid residue 21, amino acid residue 31, and combinations thereof.

[0016] Preferred embodiments of the GLP-1 analogs of this disclosure include, but are not limited to, a GLP-1 analog lacking a C-terminal glycine residue (H-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 (GLP-1(7-36)NH2; SEQ ID NO: 4)).

[0017] Further preferred embodiments of the analogs described herein include, for example, those in which the first amino acid residue is a modified histidine residue, such as, but not limited to, L-histidine, D-histidine, desaminohistidine, 2-aminohistidine, β-hydroxyhistidine, homohistidine, α-fluoromethylhistidine, or α-methylhistidine.

[0018] Other preferred embodiments of the analogs described herein include those in which the second amino acid is alanine, valine, glycine, threonine, isoleucine, or α-methyl-Ala. The disclosure includes the ROSE-010 peptide (H-HVEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-OH (SEQ ID NO: 3)) which contains a valine residue instead of the second alanine residue. The C-terminal glycine residue of SEQ ID NO: 3 may be deleted to form a shorter peptide (H-HVEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 (SEQ ID NO: 5)).

[0019] Further GLP-1 analogs of this disclosure include, for example, those in which the amino acid residue at position 15 (relating to SEQ ID NO: 2) is glutamic acid, glutamine, alanine, threonine, serine, or glycine.

[0020] Further GLP-1 analogs of this disclosure include, for example, those in which the amino acid residue at position 21 (relating to SEQ ID NO: 2) is glutamic acid, glutamine, alanine, threonine, serine, or glycine.

[0021] As other GLP-1 analogs of the present disclosure, for example, the amino acid residue at position 31 (relating to SEQ ID NO: 2) may be deleted, or those which are Gly-NH2 or Gly-OH can be cited.

[0022] As GLP-1 analogs of the present disclosure, for example, those having one or more of the amino acid substitutions exemplified in various substituents of the present specification or SEQ ID NO: 3 can also be cited.

[0023] The GLP-1 and GLP-1 analogs of the present disclosure can be formulated as a stable liquid formulation or a stable liquid pharmaceutical formulation. The liquid pharmaceutical formulation can be water-based (i.e., an aqueous formulation).

[0024] In one embodiment, the pharmaceutical formulation of the present disclosure can include, for example, the GLP-1(7-37) peptide (SEQ ID NO: 2) or the GLP-1(7-36)NH2 peptide (SEQ ID NO: 4).

[0025] In other embodiments, the liquid pharmaceutical formulation of the present disclosure can include, for example, a GLP-1 analog including or consisting of the amino acid sequence shown in SEQ ID NO: 3.

[0026] In other preferred embodiments, the GLP-1 analog includes an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to SEQ ID NO: 3 in which the amino acid at position 2 is valine.

[0027] Other GLP-1 analogs are described in U.S. Patent No. 6,583,111, U.S. Patent No. 8,642,548, International Publication No. 2007 / 028394, and International Publication No. 91 / 11457, and the entire contents of the said specification are incorporated herein by reference.

[0028] The liquid pharmaceutical preparation of the present disclosure can contain, for example, but not limited to these, GLP-1 or a GLP-1 analog at a concentration in the range of about 10 μg / ml to about 1 mg / ml, a concentration in the range of about 50 μg / ml to about 750 μg / ml, a concentration in the range of about 100 μg / ml to about 500 μg / ml, a concentration in the range of about 200 μg / ml to about 500 μg / ml, a concentration of at least 300 μg / ml ± 20%, a concentration of 300 μg / ml ± 20%, a concentration of 300 μg / ml ± 10%, etc.

[0029] A preferred embodiment of the provided pharmaceutical preparation contains the ROSE-010 peptide (SEQ ID NO: 3) at a concentration of, for example, about 10 μg / ml to about 1 mg / ml, about 50 μg / ml to about 750 μg / ml, about 100 μg / ml to about 500 μg / ml, about 200 μg / ml to about 500 μg / ml, a concentration of at least 300 μg / ml ± 10%, a concentration of 300 μg / ml ± 10%, a concentration of at least 300 μg / ml ± 20%, a concentration of 300 μg / ml ± 20%, etc.

[0030] It should be understood herein that the peptide concentration in a given preparation can change over time depending on the stress conditions to which it is exposed. When the initial peptide concentration is 0.300 mg / ml, a variation of ±0.05 mg / ml (i.e., about ±17%) can be considered within the quality control target range. Depending on specific conditions, larger variations may also be tolerated. 0.300 ± 0.05 mg / ml of the peptide concentration represents, for example, a range of 0.250 mg / ml to 0.350 mg / ml.

[0031] In this specification, the expression "approximately 10 μg / ml to approximately 1 mg / ml" includes all individual values ​​(including fractions) that fall within the range of 10 μg / ml to 1 mg / ml (including the boundary value), for example, 10 μg / ml, 15 μg / ml, 20 μg / ml, 30 μg / ml, 40 μg / ml, 50 μg / ml, 60 μg / ml, 70 μg / ml, 80 μg / ml, 90 μg / ml, 100 μg / ml, 125 μg / ml, 150 μg / ml, 175 μg / ml, 200 μg / ml, 225 μg / ml, 250 μg / ml, 275 μg / ml, 300 μg / ml, 325 μg / ml, 35 0μg / ml, 375μg / ml, 400μg / ml, 425μg / ml, 450μg / ml, 475μg / ml, 500μg / ml, 525μg / ml, 550μg / ml, 575μg / ml, 600μg / ml, 625μg / ml, 650μg / ml, 675μg / ml, 700μ g / ml, 725 μg / ml, 750 μg / ml, 775 μg / ml, 800 μg / ml, 825 μg / ml, 850 μg / ml, 875 μg / ml, 900 μg / ml, 925 μg / ml, 950 μg / ml, 975 μg / ml, and 1 mg / ml.

[0032] The expression "approximately 10 μg / ml to approximately 1 mg / ml" in this specification should be understood to also include all individual subranges (including fractions) that fall within the range of approximately 10 μg / ml to approximately 1 mg / ml (including boundary values), such as "approximately 110 μg / ml to approximately 490 μg / ml", "approximately 205 μg / ml to approximately 999 μg / ml", "approximately 225 μg / ml to approximately 875 μg / ml", "approximately 200 μg / ml to approximately 750 μg / ml", and similar ranges.

[0033] The same applies to similar expressions, for example, but not limited to, "approximately 200 μg / ml to approximately 500 μg / ml", "approximately 100 μg / ml to approximately 500 μg / ml", and "approximately 50 μg / ml to approximately 750 μg / ml", as well as expressions of the same kind, which include all individual values ​​(and fractions) that fall within such values ​​(including boundary values) and all individual subranges (and fractions) that fall within such ranges (including boundary values).

[0034] According to one embodiment of this disclosure, the stock solution and the formulation contain water. The type of water used in the preparation of the stock solution and the formulation may be such as highly purified water, ultrapure water, and similar types, and may be such as highly purified water, ultrapure water, and similar types. According to one embodiment of this disclosure, the formulation may be prepared using water for injection.

[0035] In the first embodiment, a liquid pharmaceutical formulation comprising GLP-1 or a GLP-1 analog and a buffering agent is provided.

[0036] The buffers described herein may be a single type of buffer. The buffers described herein may be suitable for injection in mammals (e.g., subcutaneous, intravenous, intradermal, intramuscular). The buffers disclosed herein may be aqueous-based and may be selected, for example, to avoid undesirable interactions with the active ingredient. The buffers disclosed herein may enable the formulation to maintain a stable pH, particularly in the pH range of 6.0 to 8.0, for example, in the pH range of 6.0 to 7.5 ± 0.15, more specifically in the pH range of 6.5 to 7.0 ± 0.15. In a preferred embodiment, the pH range is between 6.5 ± 0.5 and 7.0 ± 0.5.

[0037] In this specification, it should be understood that the pH of a given formulation may change over time while maintaining an acceptable range. For example, the pH of a formulation batch may be set to an initial pH of 7.0, but the pH measured after storage for 1 month, 3 months, and 6 months may vary between 6.0 and 8.0.

[0038] Furthermore, while the target pH of the formulation batch may be set to 7.0±0.5, in this specification, a pH range of 6.5±0.5 to 7.5±0.5 is understood to be within the specified range.

[0039] Unless otherwise specified, pH measurements are generally performed at room temperature (e.g., approximately 20–25°C, more specifically 22–24°C). Buffers described herein include, but are not limited to, acetates, carbonates, citrates, histidines, maleates, phosphates, succinates, tartrates, tromethamines, and similar substances, as well as combinations thereof. Other buffers may also be suitable.

[0040] In some embodiments of this disclosure, the pharmaceutical formulation may include, for example, an acetate (e.g., sodium acetate) as a buffer.

[0041] In other embodiments of this disclosure, the pharmaceutical formulation may include, for example, a citrate (e.g., sodium citrate) as a buffering agent.

[0042] In further embodiments of the present disclosure, the pharmaceutical formulation may include, for example, histidine (e.g., histidine-HCl) as a buffer.

[0043] In further embodiments of the present disclosure, the pharmaceutical formulation may include, for example, a maleate (e.g., sodium maleate) as a buffering agent.

[0044] In further embodiments described herein, the pharmaceutical formulation may include, for example, phosphates as buffering agents. Preferred embodiments of the phosphate buffer include, but are not limited to, sodium phosphate, potassium phosphate, and phosphate-buffered saline (PBS).

[0045] In other embodiments of this disclosure, the pharmaceutical formulation includes, for example, succinate as a buffering agent.

[0046] In other embodiments of the present disclosure, the pharmaceutical formulation includes, for example, a tartrate (e.g., sodium potassium tartrate) as a buffering agent.

[0047] In other embodiments of the present disclosure, the pharmaceutical formulation includes, for example, tromethamine as a buffering agent.

[0048] In some embodiments of this disclosure, the concentration of the buffer can be in the range of about 1 mM to about 50 mM; about 2 mM to about 20 mM; about 5 mM to about 20 mM; about 5 mM to about 15 mM; or about 7.5 mM to about 12.5 mM. The concentration of the buffer can be, for example, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, or 15 mM. However, it should be understood that the concentration of the buffer can be higher or lower depending on the specific conditions.

[0049] In this specification, the expression "approximately 1 mM to approximately 50 mM" includes all individual values ​​(including fractions) that fall within the range of 1 mM to 50 mM (including boundary values). For example, "approximately 1 mM to approximately 50 mM" includes 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, and 19 mM. It should be understood that this includes 20mM, 21mM, 22mM, 23mM, 24mM, 25mM, 26mM, 27mM, 28mM, 29mM, 30mM, 31mM, 32mM, 33mM, 34mM, 35mM, 36mM, 37mM, 38mM, 39mM, 40mM, 41mM, 42mM, 43mM, 44mM, 45mM, 46mM, 47mM, 48mM, 49mM, and 50mM.

[0050] In this specification, the expression "approximately 1mM to approximately 50mM" should also be understood to include all individual subranges (including fractions) that fall within the range of "approximately 1mM to approximately 50mM" (including boundary values), such as "approximately 2mM to approximately 50mM", "approximately 2mM to approximately 49mM", "approximately 5mM to approximately 50mM", "approximately 15mM to approximately 40mM", "approximately 15mM to approximately 20mM", "approximately 15mM to approximately 30mM", "approximately 26mM to approximately 30mM", "approximately 32mM to approximately 49mM", and similar ranges.

[0051] The same applies to all similar expressions, for example, but not limited to, "approximately 0.5mM to approximately 250mM", "approximately 5mM to approximately 15mM", "approximately 7.5mM to approximately 12.5mM", "approximately 25mM to approximately 75mM", "approximately 50mM to approximately 150mM", "approximately 165mM to approximately 275mM", "approximately 150mM to approximately 300mM", etc., which include all individual values ​​(and fractions) that fall within such values ​​(including boundary values) and all individual subranges (and fractions) that fall within such ranges (including boundary values).

[0052] Preferred embodiments of the pharmaceutical formulations described herein, for example, may include a buffer at a concentration of about 10 mM ± 10%.

[0053] In some embodiments described herein, the pharmaceutical formulation may contain an acetate buffer (e.g., sodium acetate) at a concentration of 10 mM ± 10%.

[0054] In other embodiments described herein, the pharmaceutical formulation may contain a citrate buffer (e.g., sodium citrate) at a concentration of 10 mM ± 10%.

[0055] In some embodiments of this disclosure, the pharmaceutical formulation may contain a histidine buffer (e.g., histidine-HCl) at a concentration of 10 mM ± 10%.

[0056] In further embodiments described herein, the pharmaceutical formulation may contain a maleate buffer (e.g., sodium maleate) at a concentration of 10 mM ± 10%.

[0057] In other embodiments described herein, the pharmaceutical formulation may contain a phosphate buffer (e.g., sodium phosphate) at a concentration of 10 mM ± 10%.

[0058] In further embodiments described herein, the pharmaceutical formulation may contain a succinate buffer at a concentration of 10 mM ± 10%.

[0059] In further embodiments described herein, the pharmaceutical formulation may contain a tartrate buffer (e.g., sodium potassium tartrate) at a concentration of 10 mM ± 10%.

[0060] In other embodiments described herein, the pharmaceutical formulation may contain a tromethamine buffer at a concentration of 10 mM ± 10%.

[0061] In another embodiment, a liquid pharmaceutical formulation comprising GLP-1 or a GLP-1 analog, a buffer, and an isotonic agent is provided.

[0062] Isotonic agents can contribute to the gravimetric osmolality of a solution. The gravimetric osmolality of the pharmaceutical formulations described herein can be adjusted to maximize the stabilization of the active ingredient and / or minimize patient discomfort during administration. The isotonic agents described herein can make the formulation isotonic with blood and / or serum.

[0063] The gravimetric osmolality of the pharmaceutical formulations described herein can vary between, for example, 250–400 mOsmol / kg; approximately 275–375 mOsmol / kg; approximately 276–369 mOsmol / kg; and approximately 290–370 mOsmol / kg, but are not limited to these ranges. The gravimetric osmolality of the liquid pharmaceutical formulations described herein can vary within the range of approximately 275–299 mOsmol / kg (the gravimetric osmolality of blood). However, it should be understood that the gravimetric osmolality can be higher or lower depending on specific conditions.

[0064] In some embodiments, the isotonic agent may include sugar-based isotonic agents, such as sugars and polyols. Preferred embodiments of the isotonic agent include, but are not limited to, mannitol, sucrose, glucose, dextrose, trehalose, and the like.

[0065] Preferred embodiments of the isotonic agents of this disclosure include, but are not limited to, dextrose, glucose, glycerin, glycerol, mannitol, potassium chloride, sodium chloride, sodium sulfate, sorbitol, sucrose, trehalose, and similar substances, as well as combinations thereof. Other isotonic agents may also be suitable.

[0066] In some embodiments, the formulation may contain glycerol. The concentration of glycerol can be varied in the following ranges, for example, but not limited to: about 0.5% (v / v) to about 5% (v / v); about 1% (v / v) to about 5% (v / v); about 1.5% (v / v) to about 4.5% (v / v); about 1% (v / v) to about 5% (v / v); about 2% (v / v) to about 4% (v / v); about 1.5% (v / v) to about 4.5% (v / v); about 1% (v / v) to about 5% (v / v). In some embodiments, the concentration of glycerol can be varied in the following ranges, for example, but not limited to: about 2.5% (v / v) to about 3.5% (v / v). In other embodiments, the concentration of glycerol can be, for example, 2.5% ± 10% (or 275 mM ± 10%). However, it should be understood that the glycerol concentration can be higher or lower depending on specific conditions.

[0067] In further embodiments of the present disclosure, the pharmaceutical formulation may contain glycerol at a concentration of about 165 mM ± 10%, for example, but not limited to these embodiments.

[0068] In other embodiments of the present disclosure, the pharmaceutical formulation may contain glycerol at a concentration of about 275 mM ± 10%, for example, but not limited to these embodiments.

[0069] In other embodiments of this disclosure, the pharmaceutical formulation may contain mannitol. The concentration of mannitol in the formulation may be in the range of, for example, about 10 mM to about 500 mM, about 50 mM to about 400 mM, about 100 mM to about 400 mM; about 150 mM to about 350 mM, about 150 mM to about 300 mM, etc. In some embodiments, the concentration of mannitol may be in the range of about 165 mM ± 10% to about 275 mM ± 10%. However, it should be understood that the concentration of mannitol may be higher or lower depending on the specific conditions. The concentration of mannitol may also be expressed herein as a percentage by weight per volume (w / v).

[0070] In further embodiments of this disclosure, the pharmaceutical formulation may contain mannitol at a concentration of about 165 mM ± 10%, for example, but not limited to these. A mannitol concentration of 165 mM also corresponds to about 3%.

[0071] In further embodiments of this disclosure, the pharmaceutical formulation may contain mannitol at a concentration of about 275 mM ± 10%, for example, but not limited to these. A mannitol concentration of 275 mM also corresponds to about 5%.

[0072] In other embodiments of this disclosure, the pharmaceutical formulation may contain sodium chloride (NaCl). The concentration of sodium chloride used in the formulation can be determined, for example, based on a desired administration method. In some embodiments, the concentration of sodium chloride may be, for example, 0.9% (w / v) ± 10% to be isotonic with blood. In other embodiments, the concentration of sodium chloride can be varied in the range of, for example, about 1 mM to about 250 mM; about 10 mM to about 200 mM; about 25 mM to about 200 mM; about 40 mM to about 175 mM; about 50 mM ± 10% to about 150 mM ± 10%, etc. The concentration of sodium chloride can be, for example, 50 mM ± 10%, 130 mM ± 10%, 150 mM ± 10%, etc., for example. However, it should be understood that the concentration of sodium chloride may be higher or lower depending on specific conditions. The concentration of sodium chloride may also be expressed in this specification as a percentage of weight per unit volume (w / v).

[0073] In some embodiments of this disclosure, the pharmaceutical formulation may contain sodium chloride at a concentration of about 50 mM ± 10%, for example, but not limited to these embodiments. A concentration of 50 mM NaCl also corresponds to about 0.3%.

[0074] In other embodiments of this disclosure, the pharmaceutical formulation may contain sodium chloride at a concentration of about 130 mM ± 10%, for example, but not limited to these. A concentration of 130 mM NaCl also corresponds to about 0.7%.

[0075] In other embodiments of this disclosure, the pharmaceutical formulation may contain sodium chloride at a concentration of about 150 mM ± 10%, for example, but not limited to these. A concentration of 150 mM NaCl also corresponds to about 0.9%.

[0076] In further embodiments of this disclosure, the pharmaceutical formulation may include, for example, sucrose. The concentration of sucrose in the formulation is expressed in w / v % and can range from about 1% (w / v) to 20% (w / v); about 2% to 18%; about 3% to 15%; about 5% to 15%, etc. The concentration of sucrose in the formulation can be, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, etc. In some embodiments, the concentration of sucrose can range from, for example, about 8% ± 10% to about 10% ± 10%. However, it should be understood that the concentration of sucrose can be higher or lower depending on specific conditions.

[0077] In some embodiments of this disclosure, the pharmaceutical formulation may contain sucrose at a concentration of about 5% ± 10%, for example, but not limited to these embodiments.

[0078] In some embodiments of this disclosure, the pharmaceutical formulation may contain sucrose at a concentration of about 8% ± 10%, for example, but not limited to these embodiments.

[0079] In other embodiments of the present disclosure, the pharmaceutical formulation may contain sucrose at a concentration of about 10% ± 10%, for example, but not limited to these embodiments.

[0080] In other embodiments, the formulation may contain trehalose. The concentration of trehalose can vary, for example, in the range of approximately 5%(w / v) to approximately 25%(w / v); approximately 7.5%(w / v) to approximately 15%(w / v); and approximately 7.5%(w / v) to approximately 10%(w / v), but is not limited to these. In some embodiments, the concentration of trehalose can be approximately 10%(w / v) ± 10%. However, it should be understood that the concentration of trehalose can be higher or lower depending on specific conditions.

[0081] In some embodiments of this disclosure, the pharmaceutical formulation may contain trehalose at a concentration of about 5% ± 10%, for example, but not limited to these embodiments.

[0082] In some embodiments of this disclosure, the pharmaceutical formulation may contain trehalose at a concentration of about 8% ± 10%, for example, but not limited to these embodiments.

[0083] In other embodiments of the present disclosure, the pharmaceutical formulation may contain trehalose at a concentration of about 10% ± 10%, for example, but not limited to these embodiments.

[0084] In this specification, the expression "from about 5% to about 15%" refers to all individual values ​​(including fractions) within and including 5.0% and 15.0%, such as 5%, 5.25%, 5.5%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 9.8%, 9.9%, 10%, 1%. It should be understood that this includes percentages such as 0.25%, 10.5%, 10.75%, 11.0%, 11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 4.25%, 14.5%, 14.75%, 14.8%, 15.0%, etc.

[0085] The expression "approximately 5% to approximately 15%" in this specification should also be understood to include all individual subranges (including fractions) that fall within that range (including boundary values), such as "approximately 5.0% to approximately 15.0%", "approximately 5.0% to approximately 10.0%", "approximately 5.0% to approximately 8.0%", "approximately 8.0% to approximately 10.0%", "approximately 6.0% to approximately 7.5%", and similar ranges.

[0086] The same applies to all similar expressions, for example, but not limited to, “approximately 8% to approximately 10%” or “approximately 0.01% to approximately 0.03%,” which include all individual values ​​(and fractions) that fall within such values ​​(including boundary values) and all individual subranges (and fractions) that fall within such ranges (including boundary values). The expression “±10%” in this specification with respect to a given number should be understood to include all individual values ​​such as +0%, +1%, +2%, +3%, +4%, +5%, +6%, +7%, +8%, +9%, +10%, -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10%, etc. For example, the expression “0.3 mg / ml ± 10%” includes all individual values ​​(including fractions and ranges) that fall within 0.27 mg / ml and 0.33 mg / ml.

[0087] The same applies to all similar expressions, for example, “10%(v / v)±10%”, which includes values ​​such as 9%, 10%, and 11%, as well as any fractions or ranges between them, such as 9.2%, 9.5%, 10.5%, etc.

[0088] In other embodiments and models provided, the pharmaceutical formulation may further include pharmaceutical excipients.

[0089] Examples of pharmaceutical additives described herein include stabilizers, surfactants, and combinations thereof. However, it should be understood that other pharmaceutical additives may also be used.

[0090] Preferred embodiments of the stabilizer include, but are not limited to, amino acids (e.g., L-amino acids or D-amino acids). Examples of amino acid stabilizers include, but are not limited to, alanine, arginine, glutamate, glycine, isoleucine, leucine, methionine, proline, and the same, as well as combinations thereof. Preferred embodiments of the amino acid stabilizer include, for example, L-alanine, L-arginine, L-glutamate, L-glycine, L-isoleucine, L-leucine, L-methionine, L-proline, etc.

[0091] The amino acid content in the pharmaceutical formulations disclosed herein can vary within ranges such as approximately 0.5 mM to approximately 300 mM; approximately 1 mM to approximately 200 mM; approximately 5 mM to approximately 150 mM; approximately 5 mM to approximately 100 mM; approximately 7.5 mM to approximately 100 mM; approximately 7.5 mM to approximately 75 mM; approximately 7.5 mM to approximately 50 mM; and approximately 10 mM to approximately 50 mM. The concentrations of amino acids in the pharmaceutical formulations disclosed herein may, for example, be 0.5 mM ± 10%, 1 mM ± 10%, 2 mM ± 10%, 3 mM ± 10%, 4 mM ± 10%, 5 mM ± 10%, 10 mM ± 10%, 15 mM ± 10%, 20 mM ± 10%, 25 mM ± 10%, 30 mM ± 10%, 35 mM ± 10%, 40 mM ± 10%, 45 mM ± 10%, or 50 mM ± 10%, but it should be understood that the amino acid concentrations may be higher or lower depending on specific conditions.

[0092] In certain embodiments of this disclosure, the liquid pharmaceutical formulation may contain alanine (e.g., L-alanine) at a concentration of about 1 mM to about 250 mM ± 10%. In some embodiments of this disclosure, the pharmaceutical formulation may contain alanine at a concentration of about 5 mM to about 15 mM ± 10%. In other embodiments of this disclosure, the pharmaceutical formulation may contain alanine at a concentration of about 10 mM ± 10%.

[0093] In other embodiments of the present disclosure, the liquid pharmaceutical formulation may contain arginine (e.g., L-arginine) at a concentration of about 1 mM to about 250 mM ± 10%. In some embodiments of the present disclosure, the liquid pharmaceutical formulation may contain arginine at a concentration of about 100 mM ± 10% or 150 mM ± 10%.

[0094] In other embodiments of the present disclosure, the liquid pharmaceutical formulation may contain glycine (e.g., L-glycine) at a concentration of about 1 mM to about 250 mM ± 10%. In some embodiments of the present disclosure, the liquid pharmaceutical formulation may contain glycine at a concentration of about 50 mM ± 10% or 150 mM ± 10%.

[0095] In other embodiments of the present disclosure, the liquid pharmaceutical formulation may contain isoleucine (e.g., L-isoleucine) at a concentration of about 1 mM to about 250 mM ± 10%. In some embodiments of the present disclosure, the liquid pharmaceutical formulation may contain isoleucine at a concentration of about 100 mM ± 10% or 150 mM ± 10%.

[0096] In other embodiments of the present disclosure, the liquid pharmaceutical formulation may contain leucine (e.g., L-leucine) at a concentration of about 1 mM to about 250 mM ± 10%. In some embodiments of the present disclosure, the liquid pharmaceutical formulation may contain leucine at a concentration of about 100 mM ± 10% or 150 mM ± 10%.

[0097] In certain embodiments of this disclosure, the liquid pharmaceutical formulation may contain methionine (e.g., L-methionine) at a concentration of about 1 mM to about 100 mM ± 10%. In some embodiments of this disclosure, the liquid pharmaceutical formulation may contain methionine at a concentration of about 5 mM to about 15 mM ± 10%. In other embodiments of this disclosure, the liquid pharmaceutical formulation may contain methionine at a concentration of about 10 mM ± 10%.

[0098] In certain embodiments of this disclosure, the liquid pharmaceutical formulation may contain proline (e.g., L-proline) at a concentration of about 5 mM to about 300 mM ± 10%. In other embodiments of this disclosure, the liquid pharmaceutical formulation may contain proline at a concentration of about 25 mM to about 75 mM ± 10%. In other embodiments of this disclosure, the liquid pharmaceutical formulation may contain proline at a concentration of about 50 mM ± 10%.

[0099] In further embodiments provided, the pharmaceutical formulation may further include a surfactant.

[0100] Preferred embodiments of the surfactant include, but are not limited to, nonionic surfactants. Examples of surfactants described herein include polysorbate 20 (PS-20), polysorbate 40 (PS-40), polysorbate 60 (PS-60), polysorbate 65 (PS-65), polysorbate 80 (PS-80), Triton X-100, poloxamer, Pluronic® F-68, and similar surfactants, as well as combinations thereof.

[0101] The concentration of the surfactant can be approximately 0.001 to 0.1%, 0.005 to 0.05%, 0.01 to 0.05%, 0.01 to 0.04%, 0.01 to 0.03%, 0.015 to 0.025%, etc. For example, the surfactant concentration can be approximately 0.02% ± 10%. However, it should be understood that the surfactant concentration can be higher or lower depending on specific conditions. The surfactant concentration is generally expressed as weight / volume (w / v). However, in some cases, the surfactant concentration is expressed as volume / volume (v / v).

[0102] In some embodiments described herein, the pharmaceutical formulation may contain polysorbate 20 at concentrations ranging from about 0.001 to about 0.1% (w / v), about 0.005 to about 0.05%, about 0.01 to about 0.05% (w / v), about 0.01 to about 0.03% (w / v), etc. In a preferred embodiment, the concentration of polysorbate 20 may be about 0.02 (w / v) ± 10%.

[0103] In some embodiments described herein, the pharmaceutical formulation may contain polysorbate 40 at concentrations ranging from about 0.001 to about 0.1% (w / v), about 0.005 to about 0.05% (w / v), about 0.01 to about 0.05% (w / v), and about 0.01 to about 0.03% (w / v). In a preferred embodiment, the concentration of polysorbate 40 may be about 0.02 (w / v) ± 10%.

[0104] In some embodiments described herein, the pharmaceutical formulation may contain polysorbate 60 at concentrations ranging from about 0.001 to about 0.1% (w / v), about 0.005 to about 0.05% (w / v), about 0.01 to about 0.05% (w / v), about 0.01 to about 0.03% (w / v), etc. In a preferred embodiment, the concentration of polysorbate 60 may be about 0.02 (w / v) ± 10%.

[0105] In some embodiments described herein, the pharmaceutical formulation may contain polysorbate 80 at concentrations ranging from about 0.001 to about 0.1% (w / v), about 0.005 to about 0.05% (w / v), about 0.01 to about 0.05% (w / v), about 0.01 to about 0.03% (w / v), etc. In a preferred embodiment, the concentration of polysorbate 80 may be about 0.02 (w / v) ± 10%.

[0106] In some embodiments described herein, the pharmaceutical formulation may contain Triton X-100 at concentrations ranging from about 0.001 to about 0.1%, about 0.005 to about 0.05%, about 0.01 to about 0.05%, about 0.01 to about 0.03%, etc. In a preferred embodiment, the concentration of Triton X-100 may be about 0.02 (v / v) ± 10%.

[0107] In some embodiments described herein, the pharmaceutical formulation may contain, for example, Pluronic® F-68 at concentrations ranging from about 0.001 to about 0.1%, about 0.005 to about 0.05%, about 0.01 to about 0.05%, about 0.01 to about 0.03%, etc. In a preferred embodiment, Pluronic® F-68 may be present at a concentration of about 0.02 (v / v) ± 10%.

[0108] In certain aspects and embodiments of this disclosure, the pharmaceutical formulations described herein may have pH values ​​in the range of approximately 5.0 to approximately 8.0, approximately 5.0 to approximately 7.5; approximately 5.5 to approximately 7.5; approximately 6.0 to approximately 8.0; approximately 6.0 to approximately 7.5; approximately 6.0 to approximately 7.0; approximately 6.5 to approximately 7.5; approximately 7.0 to approximately 7.5, etc. The pH of the pharmaceutical preparation can be, for example, approximately 6.0±0.15, 6.1±0.15, 6.2±0.15, 6.3±0.15, 6.4±0.15, 6.5±0.15, 6.6±0.15, 6.7±0.15, 6.8±0.15, 6.9±0.15, 7.0±0.15, 7.1±0.15, 7.2±0.15, 7.3±0.15, 7.4±0.15, or 7.5±0.15.

[0109] In a preferred embodiment, the pH of the pharmaceutical formulation can be, for example, about 6.5 ± 0.5.

[0110] In a preferred embodiment, the pH of the pharmaceutical formulation can be, for example, about 7.0 ± 0.5.

[0111] In a preferred embodiment, the pH of the pharmaceutical formulation can be, for example, about 7.5 ± 0.5.

[0112] The pH of the pharmaceutical formulations disclosed herein may be between 6.0±0.15 and 7.5±0.15. Alternatively, the pH of the pharmaceutical formulations disclosed herein may be between 6.5±0.15 and 7.0±0.15. Preferred embodiments disclosed herein include pharmaceutical formulations with a pH between 6.0±0.15. Other preferred embodiments disclosed herein include pharmaceutical formulations with a pH of 6.5±0.15. Even more preferred embodiments disclosed herein include pharmaceutical formulations with a pH of 7.0±0.15. Even more preferred embodiments disclosed herein include pharmaceutical formulations with a pH of 7.5±0.15.

[0113] In a preferred embodiment, the pharmaceutical formulations described herein may have a pH of approximately 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0 at room temperature (e.g., approximately 23°C).

[0114] In other preferred embodiments, the pharmaceutical formulations described herein may have pH values ​​of approximately 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, and 7.7 at room temperature (e.g., approximately 23°C).

[0115] In yet another preferred embodiment, the pharmaceutical formulations described herein may have a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5 at room temperature (e.g., about 23°C).

[0116] The liquid pharmaceutical formulations of this disclosure can be stable under stress conditions. For example, the liquid formulations can be stable under mechanical stress and / or freeze-thaw conditions.

[0117] Preferred embodiments and aspects of the present disclosure relate to pharmaceutical formulations that can be stable for at least one month under refrigerated conditions (e.g., including 2-8°C, 3°C, 4°C, 5°C, 6°C, and 7°C). Preferred embodiments of the present disclosure relate to pharmaceutical formulations that can be stable for at least two months; at least three months, or at least six months under refrigerated conditions. Preferred embodiments of the present disclosure also relate to pharmaceutical formulations that can be stable for at least twelve months under refrigerated conditions. Preferred embodiments of the present disclosure also relate to pharmaceutical formulations that can be stable for at least eighteen months under refrigerated conditions.

[0118] Further preferred embodiments and aspects of the present disclosure relate to pharmaceutical formulations that can be stable for at least one month, at least two months, and at least three months at room temperature (e.g., 15°C to 30°C, including 25°C). Further preferred embodiments and aspects of the present disclosure relate to pharmaceutical formulations that can be stable for at least six months at room temperature. Other preferred embodiments and aspects of the present disclosure relate to pharmaceutical formulations that can be stable for at least twelve months at room temperature.

[0119] Furthermore, further preferred embodiments and aspects of this disclosure relate to pharmaceutical formulations that can be stable for at least one month, at least two months, or at least three months at high temperatures (at least 40°C).

[0120] In a further embodiment, a liquid pharmaceutical formulation is provided comprising glucagon-like peptide 1 (GLP-1) or a GLP-1 analog, a buffer, an isotonic agent, and an optional pharmaceutical excipient and / or surfactant.

[0121] In further embodiments, liquid pharmaceutical formulations are provided comprising glucagon-like peptide 1 (GLP-1) or a GLP-1 analog, a buffer, an isotonic agent, a pharmaceutical additive, and an optional surfactant.

[0122] In further embodiments, a liquid pharmaceutical formulation is provided comprising glucagon-like peptide 1 (GLP-1) or a GLP-1 analog, a buffer, an isotonic agent, a surfactant, and an optional pharmaceutical excipient.

[0123] In yet another embodiment, a liquid pharmaceutical formulation is provided comprising glucagon-like peptide 1 (GLP-1) or a GLP-1 analog, a buffer, an isotonic agent, a pharmaceutical additive, and a surfactant.

[0124] Numerous non-limiting embodiments of the pharmaceutical formulations of this disclosure are shown below.

[0125] In some embodiments, the pharmaceutical formulation has a pH of approximately 6.0 ± 0.5 to 7.5 ± 0.5 and contains GLP-1 or a GLP-1 analog, a buffer, and an isotonic agent in a concentration sufficient to be isotonic with blood and / or serum.

[0126] In some embodiments, the pharmaceutical formulation has a pH of approximately 6.0 ± 0.15 to 7.5 ± 0.15 and contains GLP-1 or a GLP-1 analog, a buffer, and an isotonic agent in a concentration sufficient to be isotonic with blood and / or serum.

[0127] In further embodiments, the pharmaceutical formulation has a pH of approximately 6.0 ± 0.5 to 7.5 ± 0.5 and comprises a GLP-1 analog containing or consisting of the amino acid sequence shown in SEQ ID NO: 3; a buffer; and an isotonic agent in a concentration sufficient to be isotonic with blood and / or serum.

[0128] In further embodiments, the pharmaceutical formulation has a pH of approximately 6.0 ± 0.15 to 7.5 ± 0.15 and comprises a GLP-1 analog containing or consisting of the amino acid sequence shown in SEQ ID NO: 3; a buffer; and an isotonic agent in a concentration sufficient to be isotonic with blood and / or serum.

[0129] In further embodiments, the pharmaceutical formulation has a pH of approximately 6.0 ± 0.15 to 7.5 ± 0.5 and comprises a GLP-1 analog containing or consisting of the amino acid sequence shown in SEQ ID NO: 3; a buffer; and an isotonic agent in a concentration sufficient to be isotonic with blood and / or serum.

[0130] In further embodiments, the pH of the pharmaceutical formulation is approximately 6.5±0.15 to 7.0±0.15 and contains a GLP-1 analog comprising or consisting of the amino acid sequence shown in SEQ ID NO: 3, a buffer, and an isotonic agent in a concentration sufficient to make it isotonic with blood and / or serum.

[0131] In further embodiments, the pH of the pharmaceutical formulation is approximately 6.5±0.5 to 7.0±0.5 and contains a GLP-1 analog comprising or consisting of the amino acid sequence shown in SEQ ID NO: 3, a buffer, and an isotonic agent in a concentration sufficient to be isotonic with blood and / or serum.

[0132] The pharmaceutical preparation may further contain pharmaceutical excipients and / or surfactants. The surfactant may be nonionic and may include, for example, polysorbates (e.g., PS-20, PS-40, PS-60, PS-80, and the like). The pharmaceutical excipient may be an amino acid excipient.

[0133] In the embodiments and examples described herein, the pharmaceutical formulation comprises a GLP-1 analog having the amino acid sequence shown in SEQ ID NO: 3, the pH of the liquid pharmaceutical formulation is between 6.5±0.15 and 7.0±0.15, and includes histidine-HCl as a buffer, sucrose or mannitol as an isotonic agent, methionine or proline as a pharmaceutical additive, and a surfactant.

[0134] In some embodiments, the liquid pharmaceutical formulation contains a GLP-1 analog at a concentration of approximately 50 μg / ml to approximately 2 mg / ml.

[0135] In some embodiments, the liquid pharmaceutical formulation contains a GLP-1 analog at a concentration of approximately 50 μg / ml to approximately 1 mg / ml.

[0136] In some embodiments, the liquid pharmaceutical formulation contains a GLP-1 analog at a concentration of approximately 100 μg / ml to approximately 1 mg / ml.

[0137] In some embodiments, the liquid pharmaceutical formulation contains a GLP-1 analog at a concentration of approximately 100 μg / ml to approximately 500 μg / ml.

[0138] In some embodiments, the surfactant is polysorbate-20.

[0139] In some embodiments, the liquid pharmaceutical formulation contains a GLP-1 analog at a concentration of approximately 300 μg / ml ± 20%.

[0140] In some embodiments, the pH of the liquid pharmaceutical formulation is 6.5 ± 0.5.

[0141] In some embodiments, the pH of the liquid pharmaceutical formulation is 7.0 ± 0.5.

[0142] In some embodiments, the pH of the liquid pharmaceutical formulation is 7.0 ± 0.15.

[0143] In some embodiments, the pH of the liquid pharmaceutical formulation is 7.5 ± 0.5.

[0144] In the embodiments and models described herein, the pharmaceutical formulation has a pH of approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15 and comprises: a) a GLP-1 analog containing or consisting of the amino acid sequence shown in SEQ ID NO: 3 at a concentration of approximately 10 μg / ml to approximately 1 mg / ml; b) a citrate buffer at a concentration of approximately 1 mM to approximately 50 mM; and c) a concentration of approximately 10 mM to approximately 500 mM. It contains glycerol, mannitol at a concentration of approximately 10 mM to 500 mM, sucrose at a concentration of approximately 1% to 20%, trehalose at a concentration of approximately 1% to 20%, or NaCl at a concentration of approximately 50 mM to 150 mM, and d) an optional concentration of approximately 0.001% to 0.1% (w / v) of polysorbate, and e) an optional concentration of approximately 0.5 mM to 300 mM of a pharmaceutical additive amino acid.

[0145] In the embodiments and settings described herein, the pharmaceutical formulation has a pH of approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15 and comprises: a) a GLP-1 analog containing or consisting of the amino acid sequence shown in SEQ ID NO: 3 at a concentration of approximately 10 μg / ml to approximately 1 mg / ml; b) a histidine buffer at a concentration of approximately 1 mM to approximately 50 mM; and c) a concentration of approximately 10 mM to approximately 500 mM. It contains glycerol, mannitol at a concentration of approximately 10 mM to 500 mM, sucrose at a concentration of approximately 1% to 20%, trehalose at a concentration of approximately 1% to 20%, or NaCl at a concentration of approximately 50 mM to 150 mM, and d) an optional concentration of approximately 0.001% to 0.1% (w / v) of polysorbate, and e) an optional concentration of approximately 0.5 mM to 300 mM of a pharmaceutical additive amino acid.

[0146] In further embodiments and examples described herein, the pH of the pharmaceutical formulation is approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15, and comprises: a) a GLP-1 analog containing or consisting of the amino acid sequence shown in SEQ ID NO: 3 at a concentration of approximately 10 μg / ml to approximately 1 mg / ml; b) a phosphate buffer at a concentration of approximately 1 mM to approximately 50 mM; and c) a phosphate buffer at a concentration of approximately 10 mM to approximately 500 mM. It contains glycerol, mannitol at concentrations of approximately 10 mM to 500 mM, sucrose at concentrations of approximately 1% to 20%, trehalose at concentrations of approximately 1% to 20%, or NaCl at concentrations of approximately 50 mM to 150 mM, and d) an optional concentration of approximately 0.001% to 0.1% (w / v) of polysorbate, and e) an optional concentration of approximately 0.5 mM to 300 mM of a pharmaceutical additive amino acid.

[0147] In further embodiments and examples described herein, the pharmaceutical formulation has a pH of approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15 and comprises: a) a GLP-1 analog containing or consisting of the amino acid sequence shown in SEQ ID NO: 3 at a concentration of approximately 10 μg / ml to approximately 1 mg / ml; b) a maleate buffer at a concentration of approximately 1 mM to approximately 50 mM; and c) approximately 10 mM to approximately 500 mM It contains glycerol at a concentration of approximately 10 mM to 500 mM, sucrose at a concentration of approximately 1% to 20%, trehalose at a concentration of approximately 1% to 20%, or NaCl at a concentration of approximately 50 mM to 150 mM, and d) an optional concentration of approximately 0.001% to 0.1% (w / v) of polysorbate, and e) an optional concentration of approximately 0.5 mM to 300 mM of a pharmaceutical additive amino acid.

[0148] In further embodiments and examples, the pharmaceutical formulation comprises GLP-1 or a GLP-1 analog having a pH of about 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15 and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml; citrate at a concentration of about 7.5 mM to about 12.5 mM ± 10%; glycerol at a concentration of about 150 mM to about 300 mM ± 10%; mannitol at a concentration of about 150 mM to about 300 mM ± 10%; sucrose at a concentration of about 5% to about 15% ± 10%; or trehalose at a concentration of about 5% to about 15% ± 10%.

[0149] In further embodiments and examples, the pharmaceutical formulation comprises GLP-1 or a GLP-1 analog having a pH of about 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15 and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml; histidine-HCl at a concentration of about 7.5 mM to about 12.5 mM ± 10%; glycerol at a concentration of about 150 mM to about 300 mM ± 10%; mannitol at a concentration of about 150 mM to about 300 mM ± 10%; sucrose at a concentration of about 5% to about 15% ± 10%; or trehalose at a concentration of about 5% to about 15% ± 10%.

[0150] In other embodiments and designs, the pharmaceutical formulation comprises GLP-1 or a GLP-1 analog having a pH of about 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15 and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml; sodium phosphate at a concentration of about 7.5 mM to about 12.5 mM ± 10%; glycerol at a concentration of about 150 mM to about 300 mM ± 10%; mannitol at a concentration of about 150 mM to about 300 mM ± 10%; sucrose at a concentration of about 5% to about 15% ± 10%; or trehalose at a concentration of about 5% to about 15% ± 10%.

[0151] In other embodiments and designs, the pharmaceutical formulation comprises GLP-1 or a GLP-1 analog having a pH of about 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15 and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml; calcium phosphate at a concentration of about 7.5 mM to about 12.5 mM ± 10%; glycerol at a concentration of about 150 mM to about 300 mM ± 10%; mannitol at a concentration of about 150 mM to about 300 mM ± 10%; sucrose at a concentration of about 5% to about 15% ± 10%; or trehalose at a concentration of about 5% to about 15% ± 10%.

[0152] In further embodiments and examples, the pharmaceutical formulation comprises GLP-1 or a GLP-1 analog having a pH of about 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15 and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml; maleate at a concentration of about 7.5 mM to about 12.5 mM ± 10%; glycerol at a concentration of about 150 mM to about 300 mM ± 10%; mannitol at a concentration of about 150 mM to about 300 mM ± 10%; sucrose at a concentration of about 5% to about 15% ± 10%; or trehalose at a concentration of about 150 mM to about 300 mM ± 10%.

[0153] In a further embodiment, the pharmaceutical formulation further comprises an amino acid which is a surfactant and / or a pharmaceutical additive. For example, the pharmaceutical formulation contains a polysorbate and / or an amino acid which is a pharmaceutical additive in a concentration of about 0.005 to about 0.05% (w / v) ± 10%.

[0154] In a further embodiment, the pharmaceutical formulation includes an amino acid which is a pharmaceutical additive, for example, methionine at a concentration of about 5 mM to about 25 mM ± 10%, proline at a concentration of about 25 mM to about 75 mM ± 10%, glycine at a concentration of about 50 mM to about 150 mM ± 10%, and / or arginine at a concentration of about 50 mM to about 150 mM ± 10%.

[0155] In some embodiments, the pH of a pharmaceutical formulation containing a histidine buffer can be approximately 6.5±0.5 to 7.5±0.5. In other embodiments, the pH of a pharmaceutical formulation containing a phosphate buffer can be approximately 6.5±0.5 to 7.5±0.5. In other embodiments, the pH of the pharmaceutical formulation is approximately 6.5±0.15 to 7.0±0.15. In further embodiments, the pH of a pharmaceutical formulation containing a citrate buffer is approximately 6.5±0.15. In other embodiments, the pH of a pharmaceutical formulation containing a histidine buffer is approximately 7.0±0.15. In further embodiments, the pH of a pharmaceutical formulation containing a maleate buffer is approximately 7.0±0.15. In further embodiments, the pH of a pharmaceutical formulation containing a phosphate buffer is approximately 6.5±0.15.

[0156] In further embodiments, the concentration of the GLP-1 analog shown in SEQ ID NO: 3 in the pharmaceutical formulation is approximately 10 μg / ml to approximately 1 mg / ml. In further embodiments, the concentration of the GLP-1 analog shown in SEQ ID NO: 3 is approximately 100 μg / ml to approximately 500 μg / ml. In yet another embodiment, the concentration of the GLP-1 analog shown in SEQ ID NO: 3 is approximately 0.3 mg / ml ± 20%. In yet another embodiment, the concentration of the GLP-1 analog shown in SEQ ID NO: 3 is approximately 0.3 mg / ml ± 10%.

[0157] In a further embodiment, the pharmaceutical formulation has a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and contains or comprises a GLP-1 analog having the amino acid sequence shown in SEQ ID NO: 3 at a concentration of about 100 μg / ml to about 500 μg / ml, sodium citrate at a concentration of about 10 mM ± 10%, and an isotonic agent, for example, glycerol at a concentration of about 165 mM to about 275 mM ± 10%, at a concentration of about 5% to about 15%. It contains sucrose at a concentration of %, trehalose at a concentration of approximately 5% to 15%, or NaCl at a concentration of approximately 50 mM to 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid that is a pharmaceutical additive such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0158] In a further embodiment, the pharmaceutical formulation has a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and contains or comprises a GLP-1 analog comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine HCl at a concentration of approximately 10 mM ± 10%, and an isotonic agent, for example, glycerol at a concentration of approximately 165 mM to approximately 275 mM ± 10%, approximately 5% to approximately 15%. It contains sucrose at a concentration of approximately 5% to 15% trehalose, or NaCl at a concentration of approximately 50 mM to 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid that is a pharmaceutical additive such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0159] In a further embodiment, the pharmaceutical formulation has a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and contains or comprises a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine HCl at a concentration of approximately 10 mM±10%, and an isotonic agent, for example, approximately 165 mM±10% to approximately 275 mM± It contains mannitol at a concentration of 10% or sucrose at a concentration of approximately 5%±10% to approximately 15%±10%, a surfactant, for example, polysorbate-20 at a concentration of approximately 0.005±10% to 0.05%±10% (w / v)±10%, and an amino acid, which is a pharmaceutical additive, for example, methionine at a concentration of approximately 5mM±10% to approximately 25mM±10% or proline at a concentration of approximately 25mM±10% to approximately 75mM±10%.

[0160] In a further embodiment, the pharmaceutical formulation has a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and contains or comprises a GLP-1 analog having the amino acid sequence shown in SEQ ID NO: 3 at a concentration of about 100 μg / ml to about 500 μg / ml, a maleate at a concentration of about 10 mM ± 10%, and an isotonic agent, for example, glycerol at a concentration of about 165 mM to about 275 mM ± 10%, at a concentration of about 5% to about 15%. It contains sucrose at a concentration of approximately 5% to 15% trehalose, or NaCl at a concentration of approximately 50 mM to 150 mM; a surfactant, such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%; and an amino acid, which is a pharmaceutical additive, such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0161] In a further embodiment, the pharmaceutical formulation has a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and contains or comprises a GLP-1 analog having the amino acid sequence shown in SEQ ID NO: 3 at a concentration of about 100 μg / ml to about 500 μg / ml, sodium phosphate at a concentration of about 10 mM ± 10%, and an isotonic agent, for example, glycerol at a concentration of about 165 mM to about 275 mM ± 10%, at a concentration of about 5% to about 15%. It contains sucrose at a concentration of %, trehalose at a concentration of approximately 5% to 15%, or NaCl at a concentration of approximately 50 mM to 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid that is a pharmaceutical additive such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0162] In a further embodiment, the pharmaceutical formulation has a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and contains or comprises a GLP-1 analog having the amino acid sequence shown in SEQ ID NO: 3 at a concentration of about 100 μg / ml to about 500 μg / ml, potassium phosphate at a concentration of about 10 mM ± 10%, and an isotonic agent, for example, glycerol at a concentration of about 165 mM to about 275 mM ± 10%, at a concentration of about 5% to about 15%. It contains sucrose at a % concentration, trehalose at a concentration of approximately 5% to 15%, or NaCl at a concentration of approximately 50 mM to 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid that is a pharmaceutical additive such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0163] An exemplary embodiment is a pharmaceutical formulation comprising a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM to approximately 275 mM±10%, sucrose at a concentration of approximately 5% to approximately 15%±10%, or trehalose at a concentration of approximately 5% to approximately 15%±10%.

[0164] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM to approximately 275 mM±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0165] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 275 mM±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0166] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0167] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 275 mM±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0168] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; mannitol at a concentration of approximately 165 mM±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0169] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; mannitol at a concentration of approximately 275 mM±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0170] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0171] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 5% to approximately 15%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0172] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 8%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0173] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 10%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0174] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 8%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0175] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 10%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0176] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 8%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0177] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 10%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0178] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 5% to approximately 15%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0179] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 8%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0180] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 10%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0181] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 8%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0182] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 10%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0183] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 8%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0184] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; trehalose at a concentration of approximately 10%±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0185] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml, sodium phosphate at a concentration of about 10 mM±10%, mannitol at a concentration of about 165 mM to about 275 mM±10%, sucrose at a concentration of about 5% to about 15%±10%, or trehalose at a concentration of about 5% to about 15%±10%.

[0186] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; mannitol at a concentration of approximately 165 mM to approximately 275 mM ± 10%; and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%.

[0187] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 275 mM±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0188] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0189] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 275 mM±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0190] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0191] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM±10%; mannitol at a concentration of approximately 275 mM±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0192] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM±10%; mannitol at a concentration of approximately 165 mM±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0193] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml, sodium phosphate at a concentration of about 10 mM±10%, sucrose at a concentration of about 5% to about 15%±10%, and polysorbate-20 at a concentration of about 0.01 to 0.03% (w / v)±10%.

[0194] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, sucrose at a concentration of 8%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0195] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, sucrose at a concentration of 10%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0196] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 8%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0197] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, sucrose at a concentration of 10%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0198] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml, sodium phosphate at a concentration of about 10 mM ± 10%, sucrose at a concentration of about 8% ± 10%, polysorbate-20 at a concentration of about 0.01 to 0.03% (w / v) ± 10%, and proline at a concentration of about 25 mM to about 75 mM ± 10%.

[0199] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM ± 10%, sucrose at a concentration of approximately 10% ± 10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%, and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0200] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 5% to approximately 15%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0201] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, trehalose at a concentration of 8%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0202] In other embodiments, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, trehalose at a concentration of 10%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0203] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM ± 10%, trehalose at a concentration of approximately 8% ± 10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%.

[0204] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, trehalose at a concentration of 10%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0205] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 8%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0206] In a further embodiment, the pharmaceutical formulation comprises a GLP-1 analog having a pH of 6.5±0.5 to 7.5± (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of about 100 μg / ml to about 500 μg / ml, sodium phosphate at a concentration of about 10 mM±10%, trehalose at a concentration of about 10%±10%, polysorbate-20 at a concentration of about 0.01 to 0.03% (w / v)±10%, and proline at a concentration of about 25 mM to about 75 mM±10%.

[0207] The pharmaceutical formulations of this disclosure can be used for the treatment of irritable bowel syndrome (IBS). In preferred embodiments, the pharmaceutical formulations can be used for the relief of pain in IBS and / or constipation in IBS-C. The pharmaceutical formulations can be used for the treatment of IBS-C, diarrhea-predominant irritable bowel syndrome (IBS-D), or mixed or alternating IBS (IBS-M). Prevention of pain in IBS, IBS-C, IBS-D, and / or IBS-M is also envisioned.

[0208] Alternatively, the formulations of this disclosure may be used to treat other diseases or conditions in mammals requiring treatment, including but not limited to diabetes, ischemia, tissue injury due to reperfusion, dyslipidemia, diabetic cardiomyopathy, myocardial infarction, acute coronary syndrome, obesity, postoperative catabolic changes, hyperglycemia, irritable bowel syndrome, stroke, neurodegenerative disorders, memory and learning disorders, islet transplantation, functional dyspepsia, and / or regenerative therapy.

[0209] In the context of this disclosure, the term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those requiring treatment include not only those who already have a disability, but also those who are prone to developing a disability or who should be prevented from developing a disability.

[0210] Accordingly, in certain aspects and embodiments, the Disclosure provides a stable liquid formulation for use in the manufacture of a stable pharmaceutical formulation, comprising a liquid formulation having a pH between 6.0 ± 0.15 and 7.5 ± 0.15 and comprising glucagon-like peptide 1 (GLP-1) or its GLP-1 analog, a buffer, and an optional isotonic agent, a pharmaceutical additive, and / or a surfactant. For example, a stable pharmaceutical formulation can be obtained by adding the isotonic agents and / or pharmaceutical additives described herein to this type of stable liquid formulation.

[0211] In other aspects and embodiments, the Disclosure provides a method for producing a stable pharmaceutical formulation, which includes adding a pharmaceutical additive and / or surfactant to a stable formulation to further stabilize it.

[0212] Further scope, applicability, and benefits will become apparent from the non-limiting detailed description provided below. However, it should be understood that this detailed description is illustrative only, and suggests preferred embodiments or aspects.

[0213] Detailed explanation The use of the words "a," "an," and "the" should be interpreted as encompassing both singular and plural forms, unless otherwise specified or unless the context clearly contradicts it.

[0214] Unless otherwise specified or made clear from the context, the word "or" as used herein should be understood to encompass and include both "or" and "and."

[0215] The terms "and / or" as used herein should be interpreted as specifically disclosing each of the specified features or components, whether or not they are accompanied by other features or components.

[0216] The words "comprising," "having," "including," and "containing" should be interpreted as open-ended (i.e., including but not limited to) unless otherwise specified, meaning that elements other than the constituent elements may be present. The word "consisting of" should be interpreted as closed-ended, meaning that only the elements listed as constituent elements are permitted.

[0217] The word "about" or "approximately" generally means within 20 percent, 10 percent, 5, 4, 3, 2, or 1 percent of a given value or range.

[0218] As used herein, the term “liquid” in relation to a formulation means that the peptide is dissolved in a solution and there is no significant precipitation.

[0219] As used herein, the term “stable” in relation to a formulation means a formulation in which significant aggregation and / or degradation of GLP-1 or a GLP-1 analog does not occur in the absence of stress or under one or more stress conditions.

[0220] As used herein, the phrase “no significant aggregation and / or degradation” means that aggregation and / or degradation is less than 20 percent, less than 15 percent, less than 10 percent, less than 5 percent, less than 3 percent, or less than 2 percent. For example, a formulation can be considered stable if degradation is less than 5% after storage at 5°C for 1 to 3 months, less than 10 percent after storage at 25°C for 3 months, and / or less than 20 percent after storage at 40°C for 3 months. A formulation can be considered stable if degradation is less than 10 percent, or even less than 5 percent, after freeze-thaw cycles and / or mechanical stress.

[0221] As used herein, the term "one or more stress conditions" refers to long-term storage (e.g., under refrigerated conditions), accelerated storage conditions (e.g., ambient temperature and / or high temperature, e.g., 40°C), mechanical stress, freeze-thaw cycles, or a combination thereof.

[0222] As used herein, the term “high concentration of subvisible particles” includes, for example, a cumulative particle count measured by microflow imaging at T0, T-1m_25°C, and / or T-1m_40°C of an unstressed formulation, where there are more than 1,000 particles ≥2 μm, more than 500 particles ≥5 μm, more than 100 particles ≥10 μm, and / or more than 10 particles ≥25 μm.

[0223] As used herein, the term “low concentration of subvisible particles” includes, for example, a cumulative number of particles measured by microflow imaging at T-1m_25°C and / or T-1m_40°C, where there are 1000 or fewer particles ≥2 μm, 275 or fewer particles ≥5 μm, 100 or fewer particles ≥10 μm, and / or 30 or fewer particles ≥25 μm. As used herein, the term “low concentration of subvisible particles” also includes a cumulative number of particles measured by microflow imaging at T-3m_5°C and / or T-3m_25°C, where there are 500 or fewer particles ≥2 μm, 200 or fewer particles ≥5 μm, 50 or fewer particles ≥10 μm, and 10 and / or fewer than 10 particles ≥25 μm.

[0224] The term "sugar" refers to monosaccharides, disaccharides, and polysaccharides. Examples of sugars, though not limited to these, include sucrose, glucose, and dextrose.

[0225] The term "long-term storage" (or "prolonged storage") is understood to mean storing for at least one month, at least three months, at least six months, and / or at least one year.

[0226] The term "mammal" is not limited to these, but it does include humans.

[0227] The terms "pharmaceutical composition" and "pharmaceutical preparation" are used interchangeably.

[0228] Liquid pharmaceutical formulations of GLP-1 or its GLP-1 analogs are provided. The liquid pharmaceutical formulations of this disclosure are resistant to physical stress such as freeze-thaw cycles, mechanical stress, high temperatures, and / or long-term storage.

[0229] In several examples, liquid pharmaceutical formulations containing GLP-1 or a GLP-1 analog, a buffer, and an isotonic agent have been found to be stable even without the presence of pharmaceutical additives or surfactants. Therefore, liquid pharmaceutical formulations containing GLP-1 or its GLP-1 analog, a buffer, an isotonic agent, and optional pharmaceutical additives and / or surfactants are provided.

[0230] In other examples, the disclosure relates to liquid pharmaceutical formulations comprising GLP-1 or GLP-1 analogs, buffers, isotonic agents, surfactants, and pharmaceutical additives.

[0231] Embodiments disclosed herein relate to liquid pharmaceutical formulations containing ROSE-010 (Val8-GLP-1). The formulations of this disclosure may contain ROSE-010 peptide at concentrations such as approximately 10 μg / ml to approximately 2 mg / ml, approximately 50 μg / ml to approximately 2 mg / ml, approximately 100 μg / ml to approximately 2 mg / ml, approximately 10 μg / ml to approximately 1 mg / ml, approximately 100 μg / ml to approximately 1 mg / ml, approximately 50 μg / ml to approximately 750 μg / ml, approximately 100 μg / ml to approximately 500 μg / ml, approximately 200 μg / ml to approximately 500 μg / ml, at least 1 mg / ml, at least 750 μg / ml, at least 500 μg / ml, at least 300 μg / ml, and 300 μg / ml ± 20% or 300 μg / ml ± 10%.

[0232] This pharmaceutical formulation appears to be stable even at higher pH levels (e.g., pH 6.5±0.5 to 7.5±0.5, pH 6.0±0.15 to 7.5±0.15). For example, a pH of 6.5±0.5 to 7.5±0.5 (including, for example, 6.5±0.15 to 7.0±0.15) may be advantageous for peptide stability. In a preferred embodiment, a histidine buffer can be used to impart a pH of 6.5±0.5, 7.0±0.5 (e.g., 7.0±0.15), or 7.5±0.5. In another preferred embodiment, a sodium phosphate buffer or a potassium phosphate buffer can be used to impart a pH of 6.5±0.5 (e.g., 6.5±0.15), 7.0±0.5, or 7.5±0.5.

[0233] The stability of the formulation appears to be unaffected by the isotonic agent. However, pharmaceutical formulations containing an isotonic agent are included in this disclosure. The isotonic agent may be a sugar or a simpler and less reactive isotonic agent. However, other isotonic agents may also be used. The formulation can be given greater stability by adding a surfactant and / or a pharmaceutical additive, or both.

[0234] Thus, surfactants can be advantageous to the stability of the pharmaceutical formulations disclosed herein. Nonionic surfactants such as polysorbates (e.g., PS-20, PS-40, PS-60, PS-65, PS-80, etc.), Triton X-100, Poloxamer, Pluronic® F-68, and similars, and combinations thereof, can be added to the pharmaceutical formulations to protect GLP-1 or GLP-1 analogs from decomposition and / or aggregation.

[0235] Pharmaceutical formulations containing polysorbate appear to protect GLP-1 or GLP-1 analogs under mechanical stress. Therefore, polysorbate can help stabilize ROSE-010 against mechanical stress during shipping and product handling.

[0236] Pharmaceutical preparations containing small amounts of amino acids as pharmaceutical additives appear to be more stable.

[0237] Exemplary embodiments of the pharmaceutical formulations disclosed herein are stable under common stress conditions such as freeze-thaw stress and / or mechanical stress. The purity of the preferred pharmaceutical formulations disclosed herein, as determined by RP-UPLC after storage at 25°C for at least 3 months, is approximately 95%. The preferred pharmaceutical formulations disclosed herein also appear to be stable when stored at temperatures of 2–8°C (for example, for at least 3 months).

[0238] The liquid formulations of this disclosure may be suitable for injection. In certain embodiments and forms described herein, the liquid formulations may be provided in pre-filled syringes. In other embodiments and forms described herein, the liquid formulations may be provided in single-dose or multi-dose containers. In yet other embodiments and forms described herein, the liquid formulations may be suitable for long-term storage.

[0239] In preferred embodiments, single-dose or multi-dose containers include, for example, vials (e.g., glass vials), syringes (e.g., pre-filled syringes), cartridges, injectors (e.g., pen-type or other types of automatic injectors), and the like.

[0240] The formulation may also be made suitable for parenteral delivery. In certain embodiments, the formulation may be encapsulated for oral or mucosal (e.g., nasal) delivery.

[0241] The formulations of this disclosure may contain GLP-1 or a GLP-1 analog in doses of at least 20 μg, at least 30 μg, at least 50 μg, at least 75 μg, at least 100 μg, at least 150 μg, at least 200 μg, at least 300 μg, at least 500 μg, or at least 1 mg. The dose contained in each vial or syringe will vary depending on the needs of the patient population.

[0242] Liquid formulations containing GLP-1 or a GLP-1 analog, a buffer, and an isotonic agent have been shown to be stable even without the inclusion of pharmaceutical additives or surfactants. Therefore, liquid formulations containing these components (e.g., stock solutions) can be prepared and stored for at least one week (i.e., at least two weeks, at least three weeks, at least one month, at least two months, at least three months, etc.). The pharmaceutical composition can then be reconstituted by adding other components to make it suitable for longer-term storage.

[0243] In addition to the embodiments described and provided herein, the following non-limiting embodiments are specifically envisioned.

[0244] 1. Pharmaceutical formulations comprising GLP-1 or a GLP-1 analog, buffers, isotonic agents, and optional pharmaceutical excipients and / or surfactants.

[0245] 2. Pharmaceutical formulations containing GLP-1 or a GLP-1 analog, buffers, isotonic agents, pharmaceutical additives and / or nonionic surfactants.

[0246] 3. Pharmaceutical preparations containing GLP-1 or GLP-1 analogs, as individually or collectively listed in Table 1A.

[0247] 4. Pharmaceutical preparations containing GLP-1 or GLP-1 analogs, as individually or collectively listed in Table 1B.

[0248] 5. Pharmaceutical preparations containing GLP-1 or GLP-1 analogs, as individually or collectively listed in Table 1C.

[0249] 6. Pharmaceutical preparations containing GLP-1 or GLP-1 analogs, as individually or collectively listed in Table 1D.

[0250] 7. Pharmaceutical preparations containing GLP-1 or GLP-1 analogs, as individually or collectively listed in Table 1E.

[0251] 8. Pharmaceutical preparations containing GLP-1 or GLP-1 analogs, as individually or collectively listed in Table 4.

[0252] 9. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is GLP-1(7-37) and comprises the amino acid sequence shown in SEQ ID NO: 2.

[0253] 10. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is ROSE-010 and comprises the amino acid sequence shown in SEQ ID NO: 3.

[0254] 11. A pharmaceutical formulation according to any one of the prior embodiments, wherein the GLP-1 analog comprises an amino acid sequence at least 90% identical to SEQ ID NO: 3, and the amino acid at position 2 is valine.

[0255] 12. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is formulated to provide the user with a dose of approximately 50 μg.

[0256] 13. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is formulated to provide the user with a dose of approximately 100 μg.

[0257] 14. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is formulated to provide the user with a dose of approximately 150 μg.

[0258] 15. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is formulated to provide the user with a dose of approximately 200 μg.

[0259] 16. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is formulated to provide the user with a dose of approximately 300 μg.

[0260] 17. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is formulated to provide the user with a dose of approximately 400 μg.

[0261] 18. A pharmaceutical formulation according to any one of the prior embodiments, wherein GLP-1 or its analog is formulated to provide the user with a dose of approximately 500 μg.

[0262] 19. A pharmaceutical preparation according to any one of the preceding embodiments, wherein the concentration of GLP-1 or its analog is between 10 μg / ml and 2 mg / ml.

[0263] 20. A pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of GLP-1 or its analog is between 50 μg / ml and 2 mg / ml.

[0264] 21. A pharmaceutical preparation according to any one of the preceding embodiments, wherein the concentration of GLP-1 or its analog is between 100 μg / ml and 1 mg / ml.

[0265] 22. A pharmaceutical preparation according to any one of the preceding embodiments, wherein the concentration of GLP-1 or its analog is between 10 μg / ml and 1 mg / ml.

[0266] 23. A pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of GLP-1 or its analog is between 50 μg / ml and 750 μg / ml.

[0267] 24. A pharmaceutical preparation according to any one of the preceding embodiments, wherein the concentration of GLP-1 or its analog is between 100 μg / ml and 500 μg / ml.

[0268] 25. A pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of GLP-1 or its analog is between 200 μg / ml and 500 μg / ml.

[0269] 26. A pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of GLP-1 or its analog is 300 μg / ml ± 20%.

[0270] 27. A pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of GLP-1 or its analog is 300 μg / ml ± 10%.

[0271] 28. A pharmaceutical formulation comprising a surfactant, as described in any one of the prior embodiments.

[0272] 29. A pharmaceutical formulation according to any one of the prior embodiments, comprising a nonionic surfactant.

[0273] 30. A pharmaceutical preparation according to any one of the prior embodiments, comprising polysorbate 20.

[0274] 31. A pharmaceutical formulation according to any one of the prior embodiments, comprising polysorbate 40.

[0275] 32. A pharmaceutical preparation containing polysorbate 60, as described in any one of the preceding statements.

[0276] 33. A pharmaceutical preparation according to any one of the prior embodiments, comprising polysorbate 65.

[0277] 34. A pharmaceutical preparation according to any one of the prior embodiments, comprising polysorbate 80.

[0278] 35. A pharmaceutical formulation according to any one of the prior embodiments, comprising Triton X-100.

[0279] 36. A pharmaceutical formulation comprising poloxamer, as described in any one of the prior embodiments.

[0280] 37. A pharmaceutical formulation according to any one of the prior embodiments, including Pluronic® F-68.

[0281] 38. A pharmaceutical preparation according to any one of the prior embodiments, wherein the buffering agent is an acetate, citrate, histidine, phosphate, succinate, maleate, or tromethamine.

[0282] 39. A pharmaceutical preparation according to any one of the prior embodiments, comprising citrate as a buffering agent.

[0283] 40. A pharmaceutical formulation according to any one of the prior embodiments, comprising histidine-HCl as a buffer.

[0284] 41. A pharmaceutical formulation according to any one of the prior embodiments, comprising sodium phosphate as a buffering agent.

[0285] 42. A pharmaceutical preparation according to any one of the prior embodiments, comprising potassium phosphate as a buffering agent.

[0286] 43. A pharmaceutical preparation according to any one of the prior embodiments, comprising maleate as a buffering agent.

[0287] 44. A pharmaceutical preparation according to any one of the prior embodiments, comprising tromethamine as a buffering agent.

[0288] 45. The pharmaceutical formulation according to any one of the preceding embodiments, wherein the isotonic agent is selected from the group consisting of dextrose, glucose, glycerin, glycerol, mannitol, sodium chloride, sodium sulfate, sorbitol, sucrose, trehalose, and potassium chloride.

[0289] 46. ​​A pharmaceutical preparation according to any one of the prior embodiments, comprising glycerol as an isotonic agent.

[0290] 47. A pharmaceutical preparation according to any one of the prior embodiments, comprising mannitol as an isotonic agent.

[0291] 48. A pharmaceutical preparation according to any one of the prior embodiments, comprising sucrose as an isotonic agent.

[0292] 49. A pharmaceutical preparation according to any one of the preceding embodiments, comprising trehalose as an isotonic agent.

[0293] 50. A pharmaceutical preparation according to any one of the preceding embodiments, comprising an amino acid as a pharmaceutical additive.

[0294] 51. A pharmaceutical preparation according to any one of the preceding embodiments, comprising alanine as a pharmaceutical additive.

[0295] 52. A pharmaceutical preparation according to any one of the preceding embodiments, comprising arginine as a pharmaceutical additive.

[0296] 53. A pharmaceutical preparation according to any one of the preceding embodiments, comprising glycine as a pharmaceutical additive.

[0297] 54. A pharmaceutical preparation according to any one of the preceding embodiments, comprising leucine as a pharmaceutical additive.

[0298] 55. A pharmaceutical preparation according to any one of the preceding embodiments, comprising methionine as a pharmaceutical additive.

[0299] ​​​​​​​​​​​​​​​​​60. A pharmaceutical preparation according to any one of the prior embodiments, wherein the pH of the pharmaceutical preparation is between 6.5±0.15 and 7.0±0.15.

[0304] 61. A pharmaceutical formulation according to any one of the prior embodiments, wherein the pH of the formulation is 6.5 ± 0.5.

[0305] 62. A pharmaceutical formulation according to any one of the prior embodiments, wherein the pH of the formulation is 6.5 ± 0.15.

[0306] 63. A pharmaceutical formulation according to any one of the prior embodiments, wherein the pH of the formulation is 7.0 ± 0.5.

[0307] 64. A pharmaceutical formulation according to any one of the prior embodiments, wherein the pH of the formulation is 7.0 ± 0.15.

[0308] 65. A pharmaceutical formulation according to any one of the prior embodiments, wherein the pH of the formulation is 7.5 ± 0.5.

[0309] 66. A pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of the buffering agent is approximately 1 mM to approximately 50 mM.

[0310] 67. A pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of the isotonic agent is approximately 10 mM to approximately 500 mM.

[0311] 68. A pharmaceutical preparation according to any one of the preceding embodiments, wherein the concentration of the isotonic agent is approximately 1% to approximately 20% (w / v).

[0312] 69. A pharmaceutical formulation according to any one of the prior embodiments, wherein the concentration of the surfactant is approximately 0.001 to approximately 0.1% (w / v).

[0313] 70. A pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of the amino acid, which is a pharmaceutical additive, is approximately 0.5 mM to approximately 300 mM.

[0314] 71. The pH is approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15, and the mixture contains a) a GLP-1 analog containing or consisting of the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 10 μg / ml to approximately 1 mg / ml, b) a citrate buffer at a concentration of approximately 1 mM to approximately 50 mM, and c) glycerol at a concentration of approximately 10 mM to approximately 500 mM. A pharmaceutical preparation comprising mannitol at a concentration of 500 mM, sucrose at a concentration of approximately 1% to 20%, trehalose at a concentration of approximately 1% to 20%, or NaCl at a concentration of approximately 50 mM to 150 mM, d) an optional concentration of polysorbate at approximately 0.001% to 0.1% (w / v), and e) an optional concentration of an amino acid, which is a pharmaceutical additive, at approximately 0.5 mM to 300 mM.

[0315] 72. The pH is approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15, and the mixture contains a) a GLP-1 analog containing or consisting of the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 10 μg / ml to approximately 1 mg / ml, b) a histidine buffer at a concentration of approximately 1 mM to approximately 50 mM, and c) glycerol at a concentration of approximately 10 mM to approximately 500 mM. A pharmaceutical preparation comprising mannitol at a concentration of 500 mM, sucrose at a concentration of approximately 1% to 20%, trehalose at a concentration of approximately 1% to 20%, or NaCl at a concentration of approximately 50 mM to 150 mM, d) an optional concentration of polysorbate at approximately 0.001% to 0.1% (w / v), and e) an optional concentration of an amino acid, which is a pharmaceutical additive, at approximately 0.5 mM to 300 mM.

[0316] 73. The pH is approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15, and the mixture contains a) a GLP-1 analog containing or consisting of the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 10 μg / ml to approximately 1 mg / ml, b) a maleate buffer at a concentration of approximately 1 mM to approximately 50 mM, and c) glycerol at a concentration of approximately 10 mM to approximately 500 mM, approximately 10 mM to A pharmaceutical preparation comprising mannitol at a concentration of approximately 500 mM, sucrose at a concentration of approximately 1% to approximately 20%, trehalose at a concentration of approximately 1% to approximately 20%, or NaCl at a concentration of approximately 50 mM to approximately 150 mM, d) an optional concentration of polysorbate at a concentration of approximately 0.001% to approximately 0.1% (w / v), and e) an optional concentration of an amino acid, which is a pharmaceutical additive, at a concentration of approximately 0.5 mM to approximately 300 mM.

[0317] 74. The pH is approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15, and the mixture contains a) a GLP-1 analog containing or consisting of the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 10 μg / ml to approximately 1 mg / ml, b) a phosphate buffer at a concentration of approximately 1 mM to approximately 50 mM, and c) glycerol at a concentration of approximately 10 mM to approximately 500 mM. A pharmaceutical preparation comprising mannitol at a concentration of 500 mM, sucrose at a concentration of approximately 1% to 20%, trehalose at a concentration of approximately 1% to 20%, or NaCl at a concentration of approximately 50 mM to 150 mM, d) an optional concentration of polysorbate at approximately 0.001% to 0.1% (w / v), and e) an optional concentration of an amino acid, which is a pharmaceutical additive, at approximately 0.5 mM to 300 mM.

[0318] 75. A pharmaceutical preparation comprising a pH of approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15, containing or comprising the amino acid sequence shown in Sequence ID No. 3, or a GLP-1 analog thereof, at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; citrate at a concentration of approximately 7.5 mM to approximately 12.5 mM ± 10%; glycerol at a concentration of approximately 150 mM to approximately 300 mM ± 10%; mannitol at a concentration of approximately 150 mM to approximately 300 mM ± 10%; sucrose at a concentration of approximately 5% to approximately 15% ± 10%; or trehalose at a concentration of approximately 5% to approximately 15% ± 10%.

[0319] 76. A pharmaceutical preparation comprising a GLP-1 or GLP-1 analog that has a pH of about 6.5 ± 0.5 to 7.5 ± 0.5 or 6.0 ± 0.15 to 7.5 ± 0.15 and contains or consists of the amino acid sequence shown in SEQ ID NO:3 at a concentration of about 100 μg / ml to about 500 μg / ml, histidine-HCl at a concentration of about 7.5 mM to about 12.5 mM ± 10%, glycerol at a concentration of about 150 mM to about 300 mM ± 10%, mannitol at a concentration of about 150 mM to about 300 mM ± 10%, sucrose at a concentration of about 5% to about 15% ± 10%, or trehalose at a concentration of about 5% to about 15% ± 10%.

[0320] 77. A pharmaceutical preparation comprising a GLP-1 or GLP-1 analog that has a pH of about 6.5 ± 0.5 to 7.5 ± 0.5 or 6.0 ± 0.15 to 7.5 ± 0.15 and contains or consists of the amino acid sequence shown in SEQ ID NO:3 at a concentration of about 100 μg / ml to about 500 μg / ml, sodium phosphate at a concentration of about 7.5 mM to about 12.5 mM ± 10%, glycerol at a concentration of about 150 mM to about 300 mM ± 10%, mannitol at a concentration of about 150 mM to about 300 mM ± 10%, sucrose at a concentration of about 5% to about 15% ± 10%, or trehalose at a concentration of about 5% to about 15% ± 10%.

[0321] 78. A pharmaceutical preparation comprising a GLP-1 or GLP-1 analog that has a pH of about 6.5 ± 0.5 to 7.5 ± 0.5 or 6.0 ± 0.15 to 7.5 ± 0.15 and contains or consists of the amino acid sequence shown in SEQ ID NO:3 at a concentration of about 100 μg / ml to about 500 μg / ml, potassium phosphate at a concentration of about 7.5 mM to about 12.5 mM ± 10%, glycerol at a concentration of about 150 mM to about 300 mM ± 10%, mannitol at a concentration of about 150 mM to about 300 mM ± 10%, sucrose at a concentration of about 5% to about 15% ± 10%, or trehalose at a concentration of about 5% to about 15% ± 10%.

[0322] 79. A pharmaceutical preparation comprising a pH of approximately 6.5±0.5 to 7.5±0.5 or 6.0±0.15 to 7.5±0.15, containing or comprising the amino acid sequence shown in Sequence ID No. 3, or a GLP-1 analog thereof, at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; a maleate salt at a concentration of approximately 7.5 mM to approximately 12.5 mM ± 10%; glycerol at a concentration of approximately 150 mM to approximately 300 mM ± 10%; mannitol at a concentration of approximately 150 mM to approximately 300 mM ± 10%; sucrose at a concentration of approximately 5% to approximately 15% ± 10%; or trehalose at a concentration of approximately 5% to approximately 15% ± 10%.

[0323] 80. A GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium citrate at a concentration of approximately 10 mM ± 10%, and an isotonic agent, such as glycerol at a concentration of approximately 165 mM to approximately 275 mM ± 10%, or sucrose at a concentration of approximately 5% to approximately 15%. A pharmaceutical preparation comprising trehalose at a concentration of approximately 5% to 15%, or NaCl at a concentration of approximately 50 mM to 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid, which is a pharmaceutical additive, such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0324] 81. A GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine HCl at a concentration of approximately 10 mM ± 10%, and an isotonic agent, such as glycerol at a concentration of approximately 165 mM to approximately 275 mM ± 10%, or sucrose at a concentration of approximately 5% to approximately 15%. A pharmaceutical preparation comprising trehalose at a concentration of approximately 5% to 15%, or NaCl at a concentration of approximately 50 mM to 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid, which is a pharmaceutical additive, such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0325] 82. A GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, a maleate at a concentration of approximately 10 mM ± 10%, and an isotonic agent, for example, glycerol at a concentration of approximately 165 mM to approximately 275 mM ± 10%, sucrose at a concentration of approximately 5% to approximately 15%, A pharmaceutical preparation comprising trehalose at a concentration of 5% to approximately 15%, or NaCl at a concentration of approximately 50 mM to approximately 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid, which is a pharmaceutical additive, such as methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%, proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to approximately 150 mM ± 10%.

[0326] 83. A GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM ± 10%, and an isotonic agent, such as glycerol at a concentration of approximately 165 mM to approximately 275 mM ± 10%, or sucrose at a concentration of approximately 5% to approximately 15%. A pharmaceutical preparation comprising trehalose at a concentration of approximately 5% to 15%, or NaCl at a concentration of approximately 50 mM to 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid, which is a pharmaceutical additive, such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0327] 84. A GLP-1 analog having a pH of 6.5±0.5 to 7.5±0.5 (e.g., 6.5±0.15 to 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, potassium phosphate at a concentration of approximately 10 mM ± 10%, and an isotonic agent, such as glycerol at a concentration of approximately 165 mM to approximately 275 mM ± 10%, or sucrose at a concentration of approximately 5% to approximately 15%. A pharmaceutical preparation comprising trehalose at a concentration of approximately 5% to 15%, or NaCl at a concentration of approximately 50 mM to 150 mM, a surfactant such as polysorbate at a concentration of approximately 0.005 to 0.05% (w / v) ± 10%, and an amino acid, which is a pharmaceutical additive, such as methionine at a concentration of approximately 5 mM to 25 mM ± 10%, proline at a concentration of approximately 25 mM to 75 mM ± 10%, or arginine at a concentration of approximately 50 mM to 150 mM ± 10%.

[0328] 85. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM to approximately 275 mM±10%, sucrose at a concentration of approximately 5% to approximately 15%±10%, or trehalose at a concentration of approximately 5% to approximately 15%±10%.

[0329] 86. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM to approximately 275 mM±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0330] 87. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 165 mM±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0331] 88. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 275 mM±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0332] 89. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, mannitol at a concentration of approximately 275 mM±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0333] 90. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; mannitol at a concentration of approximately 165 mM±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0334] 91. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; mannitol at a concentration of approximately 275 mM±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0335] 92. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; mannitol at a concentration of approximately 165 mM±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0336] 93. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 5% to approximately 15%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0337] 94. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 8%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0338] 95. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 10%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0339] 96. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 8%±10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0340] 97. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; sucrose at a concentration of approximately 10%±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0341] 98. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM ± 10%; sucrose at a concentration of approximately 8% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0342] 99. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM ± 10%; sucrose at a concentration of approximately 10% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0343] 100. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 5% to approximately 15%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0344] 101. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 8%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0345] 102. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 10%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0346] 103. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, histidine-HCl at a concentration of approximately 10 mM ± 10%, trehalose at a concentration of approximately 8% ± 10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%.

[0347] 104. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; trehalose at a concentration of approximately 10%±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM±10%.

[0348] 105. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; trehalose at a concentration of approximately 8%±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0349] 106. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 7.0±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; histidine-HCl at a concentration of approximately 10 mM±10%; trehalose at a concentration of approximately 10%±10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%; and proline at a concentration of approximately 25 mM to approximately 75 mM±10%.

[0350] 107. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM ± 10%, mannitol at a concentration of approximately 165 mM to approximately 275 mM ± 10%, sucrose at a concentration of approximately 5% to approximately 15% ± 10%, or trehalose at a concentration of approximately 5% to approximately 15% ± 10%.

[0351] 108. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; mannitol at a concentration of approximately 165 mM to approximately 275 mM ± 10%; and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%.

[0352] 109. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM ± 10%, mannitol at a concentration of approximately 165 mM ± 10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%.

[0353] 110. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM ± 10%, mannitol at a concentration of approximately 275 mM ± 10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%.

[0354] 111. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; mannitol at a concentration of approximately 275 mM ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%.

[0355] 112. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; mannitol at a concentration of approximately 165 mM ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%.

[0356] 113. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; mannitol at a concentration of approximately 275 mM ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0357] 114. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; mannitol at a concentration of approximately 165 mM ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0358] 115. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 5% to approximately 15%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0359] 116. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 8%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0360] 117. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, sucrose at a concentration of approximately 10%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0361] 118. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM ± 10%, sucrose at a concentration of approximately 8% ± 10%, polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%, and methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%.

[0362] 119. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; sucrose at a concentration of approximately 10% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%.

[0363] 120. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; sucrose at a concentration of approximately 8% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0364] 121. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; sucrose at a concentration of approximately 10% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0365] 122. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 5% to approximately 15%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0366] 123. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 8%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0367] 124. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml, sodium phosphate at a concentration of approximately 10 mM±10%, trehalose at a concentration of approximately 10%±10%, and polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v)±10%.

[0368] 125. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; trehalose at a concentration of approximately 8% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%.

[0369] 126. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; trehalose at a concentration of approximately 10% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and methionine at a concentration of approximately 5 mM to approximately 25 mM ± 10%.

[0370] 127. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; trehalose at a concentration of approximately 8% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0371] 128. A pharmaceutical preparation comprising a GLP-1 analog having a pH of approximately 6.5±0.5 to 7.5±0.5 (e.g., 7.0±0.5, 6.5±0.15, etc.) and containing or comprising the amino acid sequence shown in Sequence ID No. 3 at a concentration of approximately 100 μg / ml to approximately 500 μg / ml; sodium phosphate at a concentration of approximately 10 mM ± 10%; trehalose at a concentration of approximately 10% ± 10%; polysorbate-20 at a concentration of approximately 0.01 to 0.03% (w / v) ± 10%; and proline at a concentration of approximately 25 mM to approximately 75 mM ± 10%.

[0372] 129. A pharmaceutical preparation according to any one of the preceding embodiments, wherein the preparation is isotonic with blood and / or serum.

[0373] A pharmaceutical formulation according to any one of the preceding embodiments, wherein the peptide concentration after exposure to 130.1 or multiple stress conditions is ±20% of the initial concentration (at the time of preparation).

[0374] 131. A pharmaceutical formulation according to any one of the prior embodiments, wherein the subvisible particles of the formulation are at a low concentration.

[0375] 132. A pharmaceutical formulation according to any one of the prior embodiments, wherein the concentration (cumulative number of particles) of subvisible particles at T-1m_25℃ and / or T-1m_40℃, as measured by microflow imaging, is 1000 or less of particles ≥2μm, 275 or less of particles ≥5μm, 100 or less of particles ≥10μm, and / or 30 or less of particles ≥25μm.

[0376] 133. A pharmaceutical formulation according to any one of the prior embodiments, wherein the concentration (cumulative number of particles) of subvisible particles at T-3m_5℃ and / or T-3m_25℃, as measured by microflow imaging, is 500 or less of particles ≥2μm, 200 or less of particles ≥5μm, 50 or less of particles ≥10μm, and / or 10 or less of particles ≥25μm.

[0377] 134. A pharmaceutical formulation according to any one of the prior embodiments, wherein the monomer content measured by HP-SEC is 95% or more at T-1m_5℃, 95% or more at T-1m_25℃, 92% or more at T-1m_40℃, 95% or more at T-3m_5℃, 95% or more at T-3m_25℃, and / or 92% or more at T-3m_40℃.

[0378] A pharmaceutical formulation according to any one of the prior embodiments, wherein the monomer content, as measured by HP-SEC under 135.1 or multiple stress conditions, is at least 92%, at least 93%, at least 94%, or at least 95% or more.

[0379] 136. A pharmaceutical formulation according to any one of the prior embodiments, wherein the aggregate content measured by HP-SEC is 5% or less, 4% or less, 3% or less, 2% or less, and 1% or less at T-1m_5℃, T-1m_25℃, T-3m_5℃, and / or T-3m_25℃.

[0380] A pharmaceutical formulation according to any one of the prior embodiments, wherein the aggregate content, as measured by HP-SEC under 137.1 or multiple stress conditions, is 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less.

[0381] 138. A pharmaceutical preparation according to any one of the prior embodiments, provided in a single-dose or multi-dose container.

[0382] 139. A pharmaceutical preparation according to any one of the preceding embodiments, contained in a single-dose vial, a multi-dose vial, a cartridge, or a pre-filled syringe.

[0383] 140. A pharmaceutical formulation according to any one of the preceding embodiments, for example, in a single-dose vial, multi-dose vial, cartridge, or pre-filled syringe, containing approximately 20 μg to approximately 1 mg of GLP-1 or a GLP-1 analog or ROSE-010.

[0384] 141. For example, a pharmaceutical formulation according to any one of the preceding embodiments, in a single-dose vial, multi-dose vial, cartridge, or pre-filled syringe, comprising at least 150 μg of GLP-1 or a GLP-1 analog or ROSE-010.

[0385] 142. A pharmaceutical formulation according to any one of the prior embodiments, wherein sodium acetate is used at a concentration of 10 mM.

[0386] 143. A pharmaceutical preparation according to any one of the prior embodiments, wherein sodium citrate is used at a concentration of 10 mM.

[0387] 144. A pharmaceutical formulation according to any one of the prior embodiments, wherein histidine-HCl is used at a concentration of 10 mM.

[0388] 145. A pharmaceutical formulation according to any one of the prior embodiments, wherein sodium maleate is used at a concentration of 10 mM.

[0389] 146. A pharmaceutical formulation according to any one of the prior embodiments, wherein sodium phosphate is used at a concentration of 10 mM.

[0390] 147. A pharmaceutical formulation according to any one of the prior embodiments, wherein glycerol is used at a concentration of 165 mM.

[0391] 148. A pharmaceutical formulation according to any one of the prior embodiments, wherein glycerol is used at a concentration of 275 mM.

[0392] 149. A pharmaceutical formulation according to any one of the prior embodiments, wherein mannitol is used at a concentration of 3%.

[0393] 150. A pharmaceutical formulation according to any one of the prior embodiments, wherein mannitol is used at a concentration of 5%.

[0394] 151. A pharmaceutical preparation according to any one of the prior embodiments, wherein NaCl is used at a concentration of 50 mM.

[0395] 152. A pharmaceutical preparation according to any one of the prior embodiments, wherein NaCl is used at a concentration of 130 mM.

[0396] 153. A pharmaceutical preparation according to any one of the prior embodiments, wherein NaCl is used at a concentration of 150 mM.

[0397] 154. A pharmaceutical formulation according to any one of the prior embodiments, wherein sucrose is used at a concentration of 5%.

[0398] 155. A pharmaceutical formulation according to any one of the prior embodiments, wherein sucrose is used at a concentration of 8%.

[0399] 156. A pharmaceutical formulation according to any one of the prior embodiments, wherein sucrose is used at a concentration of 10%.

[0400] 157. A pharmaceutical formulation according to any one of the prior embodiments, wherein trehalose is used at a concentration of 5%.

[0401] 158. A pharmaceutical preparation according to any one of the prior embodiments, wherein trehalose is used at a concentration of 8%.

[0402] 159. A pharmaceutical preparation according to any one of the prior embodiments, wherein trehalose is used at a concentration of 10%.

[0403] 160. A pharmaceutical formulation according to any one of the prior embodiments, wherein arginine-HCl is used at a concentration of 50 mM.

[0404] 161. A pharmaceutical formulation according to any one of the prior embodiments, wherein arginine-HCl is used at a concentration of 100 mM.

[0405] 162. A pharmaceutical preparation according to any one of the prior embodiments, wherein methionine is used at a concentration of 5 mM.

[0406] 163. A pharmaceutical preparation according to any one of the prior embodiments, wherein methionine is used at a concentration of 10 mM.

[0407] 164. A pharmaceutical preparation according to any one of the prior embodiments, wherein methionine is used at a concentration of 15 mM.

[0408] 165. A pharmaceutical formulation according to any one of the prior embodiments, wherein proline is used at a concentration of 25 mM.

[0409] 166. A pharmaceutical formulation according to any one of the prior embodiments, wherein proline is used at a concentration of 50 mM.

[0410] 167. A pharmaceutical formulation according to any one of the prior embodiments, wherein proline is used at a concentration of 75 mM.

[0411] 168. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-20 with a concentration of 0.005% (w / v).

[0412] 169. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-20 with a concentration of 0.02% (w / v).

[0413] 170. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-20 with a concentration of 0.05% (w / v).

[0414] 171. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-60 with a concentration of 0.005% (w / v).

[0415] 172. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-60 with a concentration of 0.02% (w / v).

[0416] 173. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-60 with a concentration of 0.05% (w / v).

[0417] 174. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-80 with a concentration of 0.005% (w / v).

[0418] 175. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-80 with a concentration of 0.02% (w / v).

[0419] 176. A pharmaceutical preparation according to any one of the prior embodiments, wherein the polysorbate is polysorbate-80 with a concentration of 0.05% (w / v).

[0420] 177. A pharmaceutical preparation according to any one of the prior embodiments, wherein the pH of the preparation is 6.5.

[0421] 178. A pharmaceutical preparation according to any one of the prior embodiments, wherein the pH of the preparation is 6.6.

[0422] 179. A pharmaceutical preparation according to any one of the prior embodiments, wherein the pH of the preparation is 6.7.

[0423] 180. A pharmaceutical preparation according to any one of the prior embodiments, wherein the pH of the preparation is 6.8.

[0424] 181. A pharmaceutical preparation according to any one of the prior embodiments, wherein the pH of the preparation is 6.9.

[0425] 182. A pharmaceutical preparation according to any one of the prior embodiments, wherein the pH of the preparation is 7.0.

[0426] 183. A pharmaceutical preparation according to any one of the prior embodiments, wherein GLP-1 or its analog comprises or consists of the amino acid sequence shown in Sequence ID No. 3, and the concentration is 300 μg / ml ± 20%.

[0427] 184. A pharmaceutical preparation according to any one of the prior embodiments, wherein GLP-1 or its analog comprises or consists of the amino acid sequence shown in Sequence ID No. 3, and the concentration is 300 μg / ml ± 10%.

[0428] 185. A pharmaceutical preparation according to any one of the prior embodiments, wherein the pharmaceutical preparation is a liquid.

[0429] 186. A pharmaceutical formulation that is stable, as described in any one of the prior embodiments.

[0430] 187. A pre-filled syringe containing a pharmaceutical preparation as described in any one of the prior embodiments.

[0431] 188. A pre-filled syringe containing a pharmaceutical preparation according to any one of the prior embodiments, comprising approximately 20 μg to approximately 1 mg of GLP-1, a GLP-1 analog, or ROSE-010.

[0432] 189. A pre-filled syringe comprising a pharmaceutical formulation according to any one of the prior embodiments, comprising GLP-1 or a GLP-1 analog or ROSE-010 in a dose of at least 150 μg.

[0433] 190. A pre-filled syringe comprising a pharmaceutical preparation according to any one of the prior embodiments, wherein the concentration of GLP-1 or a GLP-1 analog or its ROSE-010 is 300 μg / ml ± 10%.

[0434] 191. A method for treating a disorder or condition for which administration of GLP-1 or a GLP-1 analog or ROSE-010 is indicated, comprising administering a pharmaceutical formulation described in any one of the preceding embodiments to an individual in need thereof.

[0435] 192. A method for treating irritable bowel syndrome (IBS), comprising administering a pharmaceutical preparation described in any one of the preceding embodiments to an individual in need thereof.

[0436] 193. A method for treating constipation-predominant irritable bowel syndrome (IBS-C), comprising administering a pharmaceutical preparation described in any one of the preceding embodiments to an individual in need thereof.

[0437] 194. A method for treating diarrhea-predominant irritable bowel syndrome (IBS-D), comprising administering a pharmaceutical preparation described in any one of the preceding embodiments to an individual in need thereof.

[0438] 195. A method for treating mixed or alternating type IBS (IBS-M), comprising administering a pharmaceutical preparation described in any one of the preceding embodiments to an individual in need thereof.

[0439] 196. A method for treating diabetes, ischemia, tissue injury due to reperfusion, dyslipidemia, diabetic cardiomyopathy, myocardial infarction, acute coronary syndrome, obesity, postoperative catabolic changes, hyperglycemia, irritable bowel syndrome, stroke, neurodegenerative disorders, memory and learning disorders, islet transplantation, functional dyspepsia, and / or regenerative therapy, comprising administering a pharmaceutical preparation described in any one of the preceding embodiments to an individual in need thereof.

[0440] 197. The method according to any one of the prior embodiments, wherein the pharmaceutical preparation is administered subcutaneously.

[0441] 198. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered in a dose of approximately 20 μg to approximately 1 mg.

[0442] 199. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered daily in a dose of approximately 30 μg to approximately 300 μg.

[0443] 200. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered in a dose of approximately 50 μg.

[0444] 201. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered in a dose of approximately 100 μg.

[0445] 202. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered in a dose of approximately 150 μg.

[0446] 203. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered in a dose of approximately 200 μg.

[0447] 204. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered in a dose of approximately 300 μg.

[0448] 205. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered in a dose of approximately 400 μg.

[0449] 206. The method according to any one of the prior embodiments, wherein GLP-1 or a GLP-1 analog or ROSE-010 is administered in a dose of approximately 500 μg.

[0450] 207. A pharmaceutical preparation administered in response to acute pain associated with IBS, according to any one of the preceding embodiments.

[0451] 208. A pharmaceutical preparation administered in response to acute pain associated with IBS-C, IBS-D, or IBS-M, according to any one of the preceding embodiments.

[0452] 209. A pharmaceutical preparation according to any one of the prior embodiments, for use in the treatment method according to any one of the prior embodiments.

[0453] The following embodiments are provided to further illustrate the aspects and embodiments of the present disclosure. These embodiments are non-limiting and should not be construed as limiting the aspects and embodiments of the present disclosure. [Examples]

[0454] Example 1: Peptide material, formulation, and method Take 200 mg of solid ROSE-010 acetate (net peptide content 88.12%; purity (HPLC) 96.1%) and store at -20°C. Re-thaw the amount to be used for the experiment at room temperature.

[0455] Prepare a stock solution of each component (buffering agent, isotonic agent, pharmaceutical additive, and / or surfactant, etc.), filter it, and use it immediately or store it at room temperature or 2-8°C.

[0456] Prepare a 1 mg / ml stock formulation by using a high-concentration peptide solution and adding it to water or to a stock solution of a buffer, pharmaceutical additive, and / or isotonic agent, then filling up with water. If necessary, add an acid such as HCl to increase the solubility of ROSE-010 (acetate). Adjust the pH of the sample as needed.

[0457] The peptide concentration is confirmed by UV spectroscopy (λ=280nm). The final peptide concentration of the test formulation is set to 300 μg / ml (Table 4). A corresponding placebo formulation (without peptide) is prepared using the same buffer, pharmaceutical excipients, and / or isotonic agents.

[0458] The sample is filtered under laminar airflow (LAF) using a 0.22 μm PVDF syringe filter unit. Then, 1.5 ml of the filtered formulation is filled into a washed and sterile 2R glass vial.

[0459] Use the following reagents (United States Pharmacopeia or European Pharmacopeia grade): [Table 1]

[0460] To confirm the effects of pH, buffers, isotonic agents, pharmaceutical additives, and surfactants on the stability of ROSE-010 peptide, several formulations were tested. Representative formulations are shown in Tables 1A-1E and 4. The pH values ​​in Tables 1A-1D and 4 in this specification are for illustrative purposes only and should be understood to be variable without affecting the stability of the formulation. For example, the pH of formulations containing histidine-HCl or sodium phosphate may be in the range of 6.5±0.5 to 7.5±0.5, e.g., pH 6.5±0.5, pH 7.0±0.5, pH 7.5±0.5, etc. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 3-1] [Table 3-2] [Table 3-3] Table 3-4 Table 3-5 Table 3-6 Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 5-1 Table 5-2 Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 6

[0461] Next, analytical methods were developed and validated to test the physicochemical properties of various formulation candidates under stress conditions. Table 2 shows an overview of the analytical methods used. [Table 7]

[0462] Table 3 shows the stress conditions applied to various formulations. Some formulations underwent accelerated storage for 4 weeks at 25°C and 40°C, while others underwent accelerated storage for at least 3 months at 5°C, 25°C, and 40°C. [Table 8]

[0463] Each of the conditions at the various time points outlined in Table 3 can be considered a stress condition (excluding the no-stress condition).

[0464] Example 2: Stability Test The formulations shown in Table 4 were prepared and tested using one or more of the following series of experiments.

[0465] Visual inspection In accordance with the European Pharmacopoeia (8th edition; monograph 2.9.20), the vial is gently and manually agitated radially for 5 seconds in front of a white background and 5 seconds in front of a black background, and then tested for the presence of visible particles.

[0466] Based on the above, at T0, a considerable amount of visible particles were formed (precipitated) in one formulation containing 10 mM sodium citrate and 10% trehalose at pH 5.0 ± 0.15, and in another formulation containing 10 mM histidine-HCl and 10% trehalose at pH 5.5 ± 0.15. For the remaining 26 test formulations, no visible particles were observed at T0, or only very small amounts of visible particles were observed.

[0467] Even after being stored at 5°C for one month, no substantial effect was observed on the visible particle content of the formulations tested under these conditions.

[0468] When stored at 25°C for one month and / or at 40°C for one month, a large amount of visible particles were observed in low pH (5.5±0.15) formulations containing sodium acetate, sodium citrate, or histidine-HCl, as well as in some formulations containing histidine-HCl and 10% trehalose or sucrose (without pharmaceutical additives or surfactants) with a pH between 6.0±0.15 and 7.0±0.15.

[0469] Other formulations containing histidine or phosphate buffers and sugars performed adequately in terms of measured visible particle content even after being stored for one month at 25°C and 40°C, despite the absence of surfactants.

[0470] When a test formulation containing histidine-HCl, an isotonic agent, and a surfactant, and with or without the presence of a pharmaceutical additive amino acid, with a pH of 7.0±0.15, or a test formulation containing sodium phosphate, an isotonic agent, and with or without the presence of a surfactant, with a pH of 6.5±0.15, was stored at 5°C, 25°C, and / or 40°C for 3 months, a very small amount of visible particles was observed.

[0471] Under freeze-thaw stress, a significant amount of visible particles were formed only in two histidine-based formulations containing arginine (each containing either 10 mM histidine-HCl, 50 mM arginine-HCl, 3% mannitol, and 0.02% (w / v) PS20, or 10 mM histidine-HCl, 150 mM arginine-HCl, and 0.02% (w / v) PS20, at a pH of 7.0 ± 0.15). Furthermore, phase separation was observed in most of the test formulations, but this disappeared upon gentle homogenization of the samples.

[0472] When mechanical stress was applied, the visible particle content increased significantly in some test formulations that did not contain polysorbate.

[0473] pH pH was measured using a calibrated pH meter.

[0474] The pH of various formulations was measured at room temperature (e.g., roughly between 20 and 25°C, more specifically between 22 and 24°C). The pH values ​​of the test formulations remained relatively constant throughout the stability tests. Generally, histidine-based formulations showed greater variability than phosphate-based formulations.

[0475] Osmolality At T0, the gravimetric osmolality (GMO) values ​​of formulations containing the target peptide, buffer, and isotonic agent ranged from 299 to 369 mOsmol / kg. For formulations containing pharmaceutical additives and / or surfactants, the values ​​were between 276 and 313. One formulation containing proline measured a lower GMO of 235 mOsmol / kg. It was also possible to increase the GMO of such formulations by increasing the sugar content, if necessary.

[0476] UV spectroscopy UV measurements will be performed using a 96-well plate. Absorbance (A) will be measured at 280 nm (A280 nm) and 320 nm (A320 nm).

[0477] The peptide concentrations at T0 and / or after one month at 25°C were within the target range (0.3 ± 0.05 mg / ml) for all formulations except for some citrate-based formulations that showed visible precipitates and / or formulations with a pH of 5.5 ± 0.01 or less. Storage at 40°C for one month did not affect the peptide content, and the peptide concentrations remained unchanged or well within the target range, except for one formulation in which precipitates formed.

[0478] Some of the test formulations that did not contain polysorbate showed adverse effects due to mechanical stress.

[0479] Freeze-thaw stress and storage at 5°C for one month did not affect the peptide content of the test formulation. The peptide content remained stable even in formulations stored at 5°C and 25°C for three months.

[0480] When stored at 40°C for three months, a slight decrease in the peptide concentration of the test formulation was observed. However, all of these levels remained well within the target range.

[0481] Turbidity The optical density (OD) value measured at 350 nm (OD350 nm), 550 nm (OD550 nm), or 580 nm (OD580 nm) is used to evaluate the turbidity of the sample.

[0482] The turbidity at T0 (OD350nm and OD550nm) was very low for all formulations except for one formulation in which precipitation was observed during preparation.

[0483] The turbidity values ​​remained very low after subjecting the test formulations to freeze-thaw stress and mechanical stress, as well as after storage for one month (at all temperatures). However, the turbidity of the polysorbate-free test formulations became very high after mechanical stress (OD350nm ± 0.10). The turbidity values ​​remained low even after storage at 25°C for one month. After storage at 40°C for one month, the turbidity (OD350nm) increased slightly in some formulations, including those that showed precipitation at T0. The OD550nm value remained substantially unchanged after storage at both 25°C and 40°C.

[0484] After three months of storage, a slight increase in turbidity was observed in some of the formulations stored at 40°C. However, the OD350nm values ​​were 0.03 and 0.02, indicating that the turbidity of these samples remained generally low.

[0485] Microflow Imaging (MFI) By using a flow imaging microscope, subvisible particles present in a sample can be visualized in an organized manner.

[0486] This technique involves capturing bright-field images in a series of frames as a continuous flow of sample passes through a flow cell placed within the field of view of a microscope system. Digital images of particles present in the sample are processed using image morphology analysis software to quantify their size and number (Zoells, S et al., The AAPS Journal. Vol 15(4), p.1200, 2013).

[0487] Microflow imaging measurements are performed using a 5200-particle analysis system.

[0488] When performing measurements, use MFI View System Software (MVSS) version 2-R2-6.1.20.1915, and for sample analysis, use MFI View Analysis Suite (MVAS) software version 1.3.0.1007.

[0489] At T0, MFI revealed that all formulations except those in which precipitation was observed (i.e., high concentrations of subvisible particles were measured) contained low concentrations of subvisible particles.

[0490] Even after storage at 5°C for one month, no effect was observed on the subvisible particle concentration of any of the test formulations.

[0491] When stored at 25°C or 40°C for one month, most formulations showed a very slight increase in the number of subvisible particles, but the concentration of subvisible particles remained low, indicating good stability.

[0492] Furthermore, at T-1m_25℃ and / or T-1m_40℃, high concentrations of subvisible particles were observed in one formulation that did not contain polysorbate.

[0493] At T-1m_25℃ and / or T-1m_40℃, high concentrations of subvisible particles were also observed in other formulations, such as those that showed precipitates at T0 and those with a pH of 5.5±0.01 or lower. In one formulation containing 10 mM histidine-HCl and 10% trehalose at pH 6.0±0.01, the subvisible particle content changed considerably.

[0494] After storage at 5°C, 25°C, and 40°C for 3 months, the subvisible particle concentration of the test formulation was low, indicating excellent stability.

[0495] Freeze-thaw stress did not affect the particle count of most formulations tested under these conditions. Only two histidine-based formulations containing arginine showed a significant increase in subvisible particles under these conditions, consistent with visual inspection.

[0496] Most formulations showed very good stability against mechanical stress. Only the two polysorbate-free formulations showed a significant increase in subvisible particles, consistent with visual inspection.

[0497] Generally, citrate preparations and / or preparations with a pH of 5.0–5.5 appear to have the highest number of subvisible particles, while preparations containing histidine or phosphates appear to have fewer subvisible particles.

[0498] High-speed size exclusion chromatography (HP-SEC) In the unstressed ROSE-010 sample, in addition to a clear monomer peak, peaks corresponding to high molecular weight species (HMWS) and low molecular weight species (LMWS) were also observed at 280 nm. The ability of the HP-SEC method to detect changes in monomer, HMWS, and LMWS content was investigated using stressed samples. This method was capable of detecting degradation products, as indicated by a slight increase in HMWS content after storage at 40°C for one week. Multiple freeze-thaw cycles did not affect the SEC profile. Mechanical stress substantially reduced the overall signal intensity.

[0499] Relative monomer content At T0, the monomer content of several test formulations was approximately 96%.

[0500] However, at T0, the monomer content of the citrate preparation was lower, at approximately 80%. The monomer content of the preparation containing NaCl as an isotonic agent was also low (ranging from 67.6% to 81.9%). The monomer content of the two histidine-based preparations containing arginine was also very low at T0 (64.9%). In these preparations, the monomer content decreased further after storage at 25°C for one month (monomer content ranged from 63.2% to 70.7% for the citrate-based preparation and from 44.4% to 59.6% for the NaCl-based preparation). Generally, the monomer content decreased further when the preparations were stored at 40°C for one month (especially the preparations containing NaCl). The monomer content of the test preparations containing NaCl also decreased compared to T0 when stored at 5°C for one month.

[0501] The monomer content of the remaining test formulations remained relatively unchanged after storage at 5°C for one month or at 25°C for one month, with the exception of two histidine-based formulations containing arginine (66.5% at 5°C and 78.3% at 25°C). The monomer content of these formulations decreased slightly after storage at 40°C for one month.

[0502] The measured monomer content for most stable formulations was over 96% at T-1m_5℃, over 95.8% at T-1m_25℃, and over 94.3% at T-1m_40℃.

[0503] Even after storage at 5°C for 3 months, the monomer content of the test formulations remained unaffected under these conditions (monomer content ≥ 95.9%). After storage at 25°C for 3 months, the monomer content of two of these formulations decreased slightly (a decrease of 0.7% and 1.6% compared to T0, i.e., monomer content ≥ 95.1% and 95.3%, respectively). After storage at 40°C for 3 months, the monomer content of all three test formulations decreased slightly, with two showing a moderate decrease (7.2% and 8.2% compared to T0). The monomer content of all three formulations at T-3m_40°C remained ≥ 93.0%.

[0504] When mechanical stress was applied, the monomer content in two of the polysorbate-free test formulations decreased significantly (by approximately 54-60%) compared to the unstressed T0 sample. All other formulations remained relatively stable under mechanical stress.

[0505] Freeze-thaw stress had virtually no effect on the monomer content of any of the formulations tested under these conditions.

[0506] Relative content of HMWS At T0, most histidine-based formulations had a relative aggregate content of approximately 1%. Citrate-based formulations had a higher aggregate content, approximately 15–17.7% (at 280 nm). The aggregate content of citrate-based formulations increased further under both thermal stress conditions (ranging from approximately 27–33.7% at T-1m_25°C and approximately 21.7–38.6% at T-1m_40°C, at 280 nm).

[0507] The relative aggregate content of most histidine-based formulations remained very low at T-1m_5℃ and / or T-1m_25℃ (ranging from 0.8% to 1.6%) and slightly increased at T-1m_40℃ (ranging from 1.2% to 3.0%). The relative aggregate content of two histidine-based formulations containing arginine was between 10.2% and 19.7% at 5℃, 10.3% and 20.0% at 25℃, and 13.1% and 20.3% at 40℃. One formulation containing histidine-HCl and NaCl at pH 7.0±0.15 showed a considerable increase in aggregate content after storage at 40℃ for one month (approximately 30% at T-1m_40℃, 280nm). Small increases were observed in other formulations (ranging from approximately 1.2% to 3.0% at T-1m_40℃, 280nm).

[0508] After applying mechanical stress, a clear increase in the relative HMWS content was observed in one of the polysorbate-free formulations (reaching 11.1%).

[0509] Freeze-thaw stress did not substantially affect the relative HMWS content of the formulations tested under these conditions.

[0510] In some formulations, particularly those containing sodium phosphate as a buffer, a different peak shape was already present at T0, which was interpreted as a high molecular weight species. However, two of these formulations (one containing glycerol and polysorbate, and the other containing sucrose and polysorbate) had very low aggregate content (less than 1.6%) measured at T0, T-1m_5°C, and T-1m_25°C, and increased slightly at T-1m_40°C (reaching 4.9% and 2.6%, respectively).

[0511] After storage at 5°C for 3 months, no effect was observed on the relative HMWS content of any of the test formulations. Storage at 25°C for 3 months resulted in a slight increase in HMWS content in all three formulations (reaching 1.7%, 1.9%, and 2.2%). Storage at 40°C for 3 months resulted in a significant increase in HMWS content in all test formulations (2.2–8.2%), with the highest levels observed in these two formulations (5.7% and 8.2%). The HMWS content of all formulations remained below 10%.

[0512] Relative content of LMWS At T0, the relative amount of LMWS for all test formulations was approximately 2-3.3% at 280 nm.

[0513] Upon application of mechanical stress, the relative LMWS content increased considerably, particularly in the two polysorbate-free formulations (49.5–50.1%), as well as in one of the two histidine-based formulations containing arginine (15.0%) and several formulations containing NaCl as an isotonic agent (ranging from 16.5–22.8%). These formulations also showed increased LMWS content after being stored for one month at 5°C, 25°C, and 40°C. For example, the LMWS content of the two histidine-based formulations containing arginine ranged from 13.7% to 34.8% after being stored for one month at 5°C.

[0514] When freeze-thaw stress was applied, the relative LMWS content of formulations containing NaCl as an isotonic agent clearly increased (8.9-18.1%), while the LMWS content of all other test formulations remained unchanged.

[0515] The remaining formulations showed no substantial effect on their relative LMWS content after being stored for one month at 5°C, 25°C, and 40°C (reaching 1.6-5.5%).

[0516] After storage at 5°C or 25°C for 3 months, no effect was observed on the relative LMWS content of any of the test formulations. After storage at 40°C for 3 months, the relative LMWS content of all test formulations increased slightly, reaching 4.6–5.1% in two of these formulations.

[0517] The entire peak remained stable at all time points and for all samples. The only exception was the polysorbate-free formulation after mechanical stress was applied, in which case the signal almost completely disappeared.

[0518] Reverse-phase ultrahigh-performance liquid chromatography (RP-UPLC) The potential of using RP-UPLC as a stability-indicating method was investigated using stressed samples. RP-UPLC can detect decomposition products, as indicated by new peaks that appear after storage at 40°C for one week. Precipitates observed in the samples after mechanical stress reduced the total peak area of ​​the RP-UPLC chromatogram.

[0519] RP-UPLC has high sensitivity for detecting impurities and can be used for the analysis of pharmaceutical formulations.

[0520] Main peak content At T0, the relative principal peak area of ​​the test formulation was in the range of 94.7% to 97.1%.

[0521] No effect was observed on the relative principal peak area in any of the test formulations after storage at 5°C for one month.

[0522] After storage at 25°C for one month, the relative principal peak area was slightly reduced in formulations that showed precipitation during preparation (91.6% and 93.1%), but overall remained within the same range for the other formulations (93.1–96.3%).

[0523] When stored at 40°C for one month, some formulations showed a further decrease in primary peak content (83.3% to 89.2%). For example, a pH 5.0 formulation containing sodium citrate and trehalose showed a primary peak content of 83.3%, one pH 6.0 formulation containing sodium citrate and trehalose showed a primary peak content of 89.2%, and one pH 7.0 formulation containing histidine-HCl and sucrose, and one pH 7.5 formulation containing sodium phosphate and sucrose (neither containing pharmaceutical additives or surfactants) showed primary peak content of 89.0% and 87.6%, respectively. Overall, the primary peak content for the other test formulations remained in the range of 90.0% to 94.5%.

[0524] No effect was observed on the relative principal peak area in any of the test formulations after storage at 5°C for 3 months. After storage at 25°C for 3 months, the relative principal peak area decreased slightly (varying in the range of 94.2-94.9%), while after storage at 40°C for 3 months, it decreased considerably, with the minimum observed relative principal peak area being 82.0-83.0%.

[0525] Freeze-thaw stress did not affect the relative principal peak area of ​​any formulation tested under these conditions.

[0526] Mechanical stress had virtually no effect on most of the test formulations, except for the polysorbate-free formulations (relative principal peak areas of 72.0% and 89.8%).

[0527] Total impurity content The opposite trend was observed regarding the total impurity content. At T0, the total impurity content of most formulations varied within the range of 2.9-3.9%. The highest amount of impurities measured at T0 was in one formulation where precipitation was observed during preparation (5.3%).

[0528] In polysorbate-free formulations, an increase in total impurities was observed after applying mechanical stress (total impurities of 10.3% and 28.0%). Freezing and thawing did not significantly affect the total impurity content of the formulations.

[0529] Except for the formulations in which precipitation was observed during preparation (6.9% and 8.4%), the amount of impurities increased slightly after one month at 25°C, generally ranging from 4.2% to 5.5%.

[0530] After storage at 40°C for one month, the amount of impurities increased further in all formulations. In the four formulations where the main peak decreased (83.3% to 89.2%), the amount of impurities also increased (10.8% to 16.7%). However, most of the histidine-based or sodium phosphate-based test formulations remained below 10% impurity levels.

[0531] At 5°C, no effect was observed on the test formulations even after storage for 3 or 6 months. A gradual increase was observed in formulations stored for 3 months at 25 and 40°C. The total impurity content at T3m-5°C was between 3.5% and 4.0%, at T3m-25°C it was between 5.1% and 5.8%, and at T3m-40°C it was between 11.7% and 18.0%.

[0532] The total peak area of ​​the test formulation remained constant for most time points. The peak area was slightly higher in the T-mech and T-1m_40°C samples. In the polysorbate-free formulation, the signal almost completely disappeared after mechanical stress was applied (data not shown).

[0533] Pharmaceutical formulations appear to be more stable at higher pH levels (e.g., pH 6.0±0.15 to 7.5±0.15), while such formulations containing low pH buffers appear to be less stable. A pH between 6.5±0.15 and 7.0±0.15 appears to be favorable for peptide stability. Surfactants and amino acid stabilizers can help maintain the stability of formulations, particularly under stressful conditions.

[0534] Formulations containing GLP-1 or other GLP-1 analogs are also expected to be stable under the same conditions as described herein, more specifically, under the same conditions as described in the experimental section. [Table 9-1] [Table 9-2]

[0535] The embodiments, examples, and models described herein are illustrative and not limiting. Variations of the embodiments described above, including substitutes, modifications, and equivalents, are intended to be incorporated herein by the inventors. The referenced documents described herein are incorporated by reference as forming part of this specification.

[0536] Sequence ID: 1 X1X2EGTFTSDVSSYLX3GQAAKX4FIAWLVKGRX5 (In the formula, X1 may be L-histidine, D-histidine, desaminohistidine, 2-aminohistidine, β-hydroxyhistidine, homohistidine, α-fluoromethylhistidine, or α-methylhistidine.) X2 can be V, A, G, T, I, or α-methyl-Ala. X3 can be E, Q, A, T, S, or G. X4 can be E, Q, A, T, S, or G. X5 is either absent or can be Gly-NH2 or Gly-OH. Sequence ID: 2(GLP-1(7-37) H-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-OH Sequence ID: 3 (ROSE-010) H-HVEGTFTSDVSSYLEGQAAKEFIAWLVKGRG-OH Sequence ID: 4 (Sequence ID: 2 without terminal glycine residue) H-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 Sequence ID: 5 (ROSE-010 without terminal glycine residues) H-HVEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

[0537] Statement of the invention 1. A liquid pharmaceutical formulation comprising glucagon-like peptide 1 (GLP-1) as defined in Sequence ID No. 1 or its GLP-1 analog, a buffer, an isotonic agent, and an optional pharmaceutical excipient and / or surfactant.

[0538] 2. The pharmaceutical preparation described in Statement 1, wherein the pH of the pharmaceutical preparation is between 6.5±0.5 and 7.5±0.5.

[0539] 3. The pharmaceutical preparation described in Statement 1, wherein the pH of the pharmaceutical preparation is between 6.0±0.15 and 7.5±0.15.

[0540] 4. The pharmaceutical preparation according to Statement 1 or 2, wherein GLP-1 or its analog is GLP-1(7-37) and comprises the amino acid sequence shown in Sequence ID No. 2.

[0541] 5. A pharmaceutical preparation according to any one of statements 1 to 4, wherein GLP-1 or its analog is ROSE-010 and contains the amino acid sequence shown in Sequence ID No. 3.

[0542] 6. A pharmaceutical preparation as described in any one of statements 1 to 5, wherein the concentration of GLP-1 or its analog is between 10 μg / ml and 2 mg / ml.

[0543] 7. A pharmaceutical preparation as described in any one of statements 1 to 5, wherein the concentration of GLP-1 or its analog is between 50 μg / ml and 2 mg / ml.

[0544] 8. A pharmaceutical preparation as described in any one of statements 1 to 5, wherein the concentration of GLP-1 or its analog is between 100 μg / ml and 1 mg / ml.

[0545] 9. A pharmaceutical preparation as described in any one of statements 1 to 5, wherein the concentration of GLP-1 or its analog is between 10 μg / ml and 1 mg / ml.

[0546] 10. A pharmaceutical preparation as described in any one of statements 1 to 5, wherein the concentration of GLP-1 or its analog is between 50 μg / ml and 750 μg / ml.

[0547] 11. A pharmaceutical preparation as described in any one of statements 1 to 5, wherein the concentration of GLP-1 or its analog is between 100 μg / ml and 500 μg / ml.

[0548] 12. A pharmaceutical preparation as described in any one of statements 1 to 5, wherein the concentration of GLP-1 or its analog is between 200 μg / ml and 500 μg / ml.

[0549] 13. A pharmaceutical preparation whose pH is between 6.5±0.15 and 7.0±0.15, as described in any one of statements 1 to 12.

[0550] 14. A pharmaceutical preparation containing a surfactant, as described in any one of statements 1 to 13.

[0551] 15. The surfactant is a nonionic surfactant, as described in Statement 14.

[0552] 16. The pharmaceutical formulation described in Statement 14, wherein the surfactant is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, Triton X-100, poloxamer, Pluronic® F-68, or a combination thereof.

[0553] 17. The pharmaceutical preparation is a pharmaceutical preparation containing polysorbate, as described in any one of statements 1 to 13.

[0554] 18. The buffering agent is an acetate, carbonate, citrate, histidine, maleate, phosphate, succinate, tartrate, or tromethamine, as described in any one of statements 1 to 17.

[0555] 19. The isotonic agent is a sugar, as described in any one of statements 1 to 18.

[0556] 20. The isotonic agent is selected from the group consisting of dextrose, glucose, glycerin, glycerol, mannitol, potassium chloride, sodium chloride, sodium sulfate, sorbitol, sucrose, trehalose, or a combination thereof, as described in any one of statements 1 to 18.

[0557] 21. A pharmaceutical preparation is a pharmaceutical preparation containing pharmaceutical additives, as described in any one of statements 1 to 20.

[0558] 22. The pharmaceutical additive is a pharmaceutical preparation as described in Statement 21, which contains an amino acid that is a pharmaceutical additive.

[0559] 23. The pharmaceutical preparation described in Statement 22, wherein the amino acids that are pharmaceutical additives are alanine, arginine, isoleucine, glutamic acid, glycine, leucine, methionine, proline, and the same, as well as combinations thereof.

[0560] 24. A pharmaceutical preparation whose pH is 6.5 ± 0.5, as described in any one of statements 1 to 23.

[0561] 25. A pharmaceutical preparation whose pH is 7.0 ± 0.5, as described in any one of statements 1 to 23.

[0562] 26. A pharmaceutical preparation whose pH is 7.5 ± 0.5, as described in any one of statements 1 to 23.

[0563] 27. A pharmaceutical preparation having a pH of 7.0 ± 0.15, as described in any one of statements 1 to 23.

[0564] 28. A pharmaceutical preparation having a pH of 6.5 ± 0.15, as described in any one of statements 1 to 23.

[0565] 29. The GLP-1 analog is as shown in Sequence ID No. 3, and the concentration is approximately 50 μg / ml to approximately 2 mg / ml, as described in Statement 1 or 28.

[0566] 30. The GLP-1 analog is as shown in Sequence ID No. 3, and the concentration is approximately 100 μg / ml to approximately 1 mg / ml, as described in Statement 1 or 28.

[0567] 31. The GLP-1 analog is as shown in Sequence ID No. 3, and the concentration is approximately 100 μg / ml to approximately 500 μg / ml, as described in Statement 1 or 28.

[0568] 32. The pharmaceutical preparation described in Statement 1 or 31, wherein the GLP-1 analog is as shown in Sequence ID No. 3, and the concentration is 300 μg / ml ± 20%.

[0569] 33. Pharmaceutical preparations described herein.

[0570] 34. Pharmaceutical preparations listed in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, or Table 4.

[0571] 35. A pharmaceutical preparation described in any one of statements 1 to 34, contained in a single-dose vial, multi-dose vial, cartridge, or pre-filled syringe.

[0572] 36. The preparation is a encapsulated pharmaceutical preparation as described in any one of statements 1 to 34.

[0573] 37. A single-dose or multi-dose container containing a pharmaceutical preparation described in any one of statements 1 to 34.

[0574] 38. A pre-filled syringe containing a pharmaceutical preparation described in any one of statements 1 to 34.

[0575] 39. A method for treating a disorder or condition for which administration of GLP-1 or a GLP-1 analog is indicated, comprising administering a pharmaceutical preparation described in any one of statements 1 to 36 to an individual in need thereof.

[0576] 40. The method according to Statement 39, wherein the disorder is irritable bowel syndrome (IBS), constipation-predominant irritable bowel syndrome (IBS-C), diarrhea-predominant irritable bowel syndrome (IBS-D), or diarrhea-predominant irritable bowel syndrome (IBS-D).

[0577] 41. A pharmaceutical preparation administered subcutaneously, as described in Statement 39 or 40.

[0578] 42. A pharmaceutical preparation administered in the event of acute pain associated with IBS, IBS-C, IBS-D, or IBS-M, according to any one of the methods described in Statements 39 to 41.

[0579] 43. The disorder is diabetes mellitus, ischemia, tissue injury due to reperfusion, dyslipidemia, diabetic cardiomyopathy, myocardial infarction, acute coronary syndrome, obesity, postoperative catabolic changes, hyperglycemia, stroke, neurodegenerative disorders, memory and learning disorders, islet transplantation, functional dyspepsia, and / or a disorder requiring regenerative therapy, as described in Statement 42.

[0580] 44. The GLP-1 analog is administered in a dose of 50 μg to 150 μg, according to any one of the methods described in statements 39 to 43.

[0581] References All patents, patent applications, and publications referenced throughout this application are incorporated herein by reference as constituting a part of this specification. Hellstroem PM, et al., Clinical trial: the GLP-1 analogue ROSE-101 for management of acute pain in patients with irritable bowel syndrome: a randomized, placebo-controlled, double-blind study. Aliment Pharmacol Ther 29: 198 - 206, 2009 Michael Camilleri, et al., Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 303: G120-G128, 2012 Mojsov, S., Int. J. Peptide Protein Research, 40:333-343 (1992) Doyle, BD et al, Biophysical Signatures of Noncovalent Aggregates Formed by a Glucagonlike Peptide-1 Analog: A Prototypical Example of Biopharmaceutical Aggregation, Journal of Pharmaceutical Sciences, vol. 94(12), p. 2749, 2005 U.S. Patent No. 8,642,548 by Peter Richardson et al., registered on February 4, 2014. U.S. Patent No. 6583111 International Publication No. 2007 / 028394 International Publication No. 91 / 11457 Zoells, S et al., The AAPS Journal. Vol 15(4), p.1200, 2013 (MFI bibliography, page 78) Some aspects of the present invention are described below. 1. A liquid pharmaceutical preparation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the pH of the liquid pharmaceutical preparation is between 6.5±0.5 and 7.5±0.5, and the liquid pharmaceutical preparation comprises a) histidine HCl at a concentration of approximately 10 mM ± 10%, b) a sugar-based isotonic agent at a concentration of 100 mM to 450 mM, c) polysorbate 20 at a concentration of 0.005 to 0.05%, and d) an amino acid that is a pharmaceutical additive at a concentration of 5 mM to 75 mM. 2. The liquid pharmaceutical preparation described in item 1, wherein the sugar-based isotonic agent is mannitol at a concentration of 150 mM to 350 mM. 3. The liquid pharmaceutical preparation described in item 1, wherein the sugar-based isotonic agent is sucrose at a concentration of 145 mM to 440 mM. 4. The liquid pharmaceutical preparation described in item 1, wherein the amino acid used as a pharmaceutical additive is methionine at a concentration of 5 mM to 25 mM. 5. The liquid pharmaceutical preparation described in item 1, wherein the amino acid used as a pharmaceutical additive is proline at a concentration of 25 mM to 75 mM. 6. The liquid pharmaceutical preparation described in item 1, wherein the concentration of the GLP-1 analog is 50 μg / ml to 2 mg / ml. 7. The liquid pharmaceutical preparation described in item 1, wherein the concentration of the GLP-1 analog is 100 μg / ml to 1 mg / ml. 8. The liquid pharmaceutical preparation described in item 1, wherein the concentration of the GLP-1 analog is 100 μg / ml to 500 μg / ml. 9. The liquid pharmaceutical preparation described in item 1, wherein the concentration of the GLP-1 analog is 300 μg / ml ± 20%. 10. The liquid pharmaceutical preparation according to item 1, wherein the surfactant is polysorbate 20. 11. The liquid pharmaceutical preparation described in item 1, wherein the pH of the liquid pharmaceutical preparation is 7.0 ± 0.5. 12. The liquid pharmaceutical preparation according to item 1, wherein the GLP-1 analog comprises the amino acid sequence shown in Sequence ID No. 3 and has a concentration of 50 μg / ml to 2 mg / ml, and the liquid pharmaceutical preparation comprises histidine-HCl at a concentration of about 10 mM, mannitol at a concentration of about 275 mM, methionine at a concentration of about 10 mM, and polysorbate 20 at a concentration of about 0.02%. 13. The liquid pharmaceutical preparation according to item 1, wherein the GLP-1 analog comprises the amino acid sequence shown in Sequence ID No. 3 and has a concentration of 50 μg / ml to 2 mg / ml, and the liquid pharmaceutical preparation comprises histidine-HCl at a concentration of about 10 mM, sucrose at a concentration of about 235 mM, methionine at a concentration of about 10 mM, and polysorbate 20 at a concentration of about 0.02%. 14. The liquid pharmaceutical preparation is: a. A liquid pharmaceutical preparation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the concentration of the GLP-1 analog is 100 μg / ml to 1 mg / ml, and the liquid pharmaceutical preparation comprises 10 mM histidine-HCl, 275 mM mannitol, 10 mM methionine, and 0.02% polysorbate 20; and b. A liquid pharmaceutical preparation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the concentration of the GLP-1 analog is 100 μg / ml to 1 mg / ml, and the liquid pharmaceutical preparation comprises 10 mM histidine-HCl, 233 mM (8%) sucrose, 10 mM methionine, and 0.02% polysorbate 20; A liquid pharmaceutical preparation as described in item 1, selected from the group consisting of the following. 15. The liquid pharmaceutical preparation described in item 14, wherein the pH of the liquid pharmaceutical preparation is 7.0 ± 0.5. 16. Single-dose or multi-dose containers containing liquid pharmaceutical preparations as described in item 14. 17. A method for treating a disorder or condition for which administration of GLP-1 or a GLP-1 analog is indicated, comprising administering a liquid pharmaceutical preparation as described in item 14. 18. The method according to item 17, wherein the disorder is irritable bowel syndrome (IBS), constipation-predominant irritable bowel syndrome (IBS-C), diarrhea-predominant irritable bowel syndrome (IBS-D), or diarrhea-predominant irritable bowel syndrome (IBS-D). 19. The pharmaceutical preparation is administered subcutaneously according to the method described in item 17. 20. The pharmaceutical preparation described above is administered in the event of acute pain associated with IBS, IBS-C, IBS-D, or IBS-M, as described in item 18. 21. The method according to item 17, wherein the disorder is diabetes mellitus, ischemia, tissue injury due to reperfusion, dyslipidemia, diabetic cardiomyopathy, myocardial infarction, acute coronary syndrome, obesity, postoperative catabolic changes, hyperglycemia, stroke, neurodegenerative disorders, memory and learning disorders, islet transplantation, functional dyspepsia, and / or disorders requiring regenerative therapy. 22. The method described in item 17, wherein the GLP-1 analog is administered in a dose of 50 μg to 150 μg. 23. A method for treating a disorder or condition for which administration of GLP-1 or a GLP-1 analog is indicated, comprising administering the liquid pharmaceutical preparation described in item 1. 24. The method according to item 23, wherein the disorder is irritable bowel syndrome (IBS), constipation-predominant irritable bowel syndrome (IBS-C), diarrhea-predominant irritable bowel syndrome (IBS-D), or diarrhea-predominant irritable bowel syndrome (IBS-D). 25. The pharmaceutical preparation is administered subcutaneously according to the method described in item 23. 26. The pharmaceutical preparation described above is administered in the event of acute pain associated with IBS, IBS-C, IBS-D, or IBS-M, as described in item 24. 27. The method according to item 23, wherein the disorder is diabetes mellitus, ischemia, tissue injury due to reperfusion, dyslipidemia, diabetic cardiomyopathy, myocardial infarction, acute coronary syndrome, obesity, postoperative catabolic changes, hyperglycemia, stroke, neurodegenerative disorders, memory and learning impairments, islet transplantation, functional dyspepsia, and / or disorders requiring regenerative therapy. 28. The method described in item 23, wherein the GLP-1 analog is administered in a dose of 50 μg to 150 μg. 29. A liquid pharmaceutical preparation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the concentration of the GLP-1 analog is 50 μg / ml to 2 mg / ml, and the pH of the liquid pharmaceutical preparation is between 6.5 ± 0.5 and 7.5 ± 0.5: a. Histidine-HCl at a concentration of approximately 10 mM ± 10%, mannitol at a concentration of 100 mM to 350 mM, and polysorbate 20 at a concentration of 0.01 to 0.03% (w / v); b. Histidine-HCl at a concentration of approximately 10 mM ± 10%, mannitol at a concentration of 165 mM ± 10%, and polysorbate 20 at a concentration of 0.01-0.03% (w / v); c. Histidine-HCl at a concentration of 10 mM ± 10%, mannitol at a concentration of 275 mM ± 10%, and polysorbate 20 at a concentration of 0.01-0.03% (w / v); d. Histidine-HCl at a concentration of 10 mM ± 10%, mannitol at a concentration of 275 mM ± 10%, polysorbate 20 at a concentration of 0.01-0.03% (w / v), and methionine at a concentration of 5 mM-25 mM; e. Histidine-HCl at a concentration of 10 mM ± 10%, mannitol at a concentration of 165 mM ± 10%, polysorbate 20 at a concentration of 0.01-0.03% (w / v), and methionine at a concentration of 5 mM-25 mM; f. Histidine-HCl at a concentration of 10 mM ± 10%, mannitol at a concentration of 275 mM ± 10%, polysorbate 20 at a concentration of 0.01-0.03% (w / v), and proline at a concentration of 25 mM-75 mM; g. Histidine-HCl at a concentration of 10 mM ± 10%, mannitol at a concentration of 165 mM ± 10%, polysorbate 20 at a concentration of 0.01-0.03% (w / v), and proline at a concentration of 25 mM-75 mM; h. Histidine-HCl at a concentration of 10 mM ± 10%, sucrose at a concentration of 145 mM to 450 mM, and polysorbate 20 at a concentration of 0.01 to 0.03% (w / v); i. Histidine-HCl at a concentration of approximately 10 mM ± 10%, sucrose at a concentration of approximately 235 mM ± 10%, and polysorbate 20 at a concentration of 0.01-0.03% (w / v); j. Histidine-HCl at a concentration of approximately 10 mM ± 10%, sucrose at a concentration of approximately 290 mM ± 10%, and polysorbate 20 at a concentration of 0.01-0.03% (w / v); k. Histidine-HCl at a concentration of approximately 10 mM ± 10%, sucrose at a concentration of approximately 235 mM ± 10%, polysorbate 20 at a concentration of 0.01-0.03% (w / v), and methionine at a concentration of 5 mM-25 mM; l. Histidine-HCl at a concentration of approximately 10 mM ± 10%, sucrose at a concentration of approximately 290 mM ± 10%, polysorbate 20 at a concentration of 0.01-0.03% (w / v), and methionine at a concentration of 5 mM-25 mM; m. Histidine-HCl at a concentration of approximately 10 mM ± 10%, sucrose at a concentration of approximately 235 mM ± 10%, polysorbate 20 at a concentration of 0.01-0.03% (w / v), and proline at a concentration of 25 mM-75 mM; or n. Histidine-HCl at a concentration of approximately 10 mM ± 10%, sucrose at a concentration of approximately 290 mM ± 10%, polysorbate 20 at a concentration of 0.01-0.03% (w / v), and proline at a concentration of 25 mM-75 mM; A liquid pharmaceutical formulation containing [a specific ingredient / method]. 30. A liquid pharmaceutical preparation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the pH of the liquid pharmaceutical preparation is between 6.5±0.5 and 7.5±0.5, and the liquid pharmaceutical preparation comprises histidine-HCl as a buffer, sucrose or mannitol as an isotonic agent, methionine or proline as a pharmaceutical additive and surfactant.

Claims

1. A liquid pharmaceutical preparation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the concentration of the GLP-1 analog is 300 μg / ml ± 10%, the pH of the liquid pharmaceutical preparation is between 6.5 ± 0.5 and 7.5 ± 0.5, and further comprising a) histidine HCl at a concentration of approximately 10 mM ± 10%, b) mannitol at a concentration of 150 mM to 350 mM, c) polysorbate 20 at a concentration of 0.005 to 0.05%, and d) arginine at a concentration of 50 mM ± 10%, proline at a concentration of 50 mM ± 10%, or methionine at a concentration of 10 mM ± 10%.

2. A liquid pharmaceutical preparation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the concentration of the GLP-1 analog is 300 μg / ml ± 10%, the pH of the liquid pharmaceutical preparation is between 6.5 ± 0.5 and 7.5 ± 0.5, and the liquid pharmaceutical preparation comprises a) histidine HCl at a concentration of approximately 10 mM ± 10%, b) sucrose at 8% ± 10%, c) polysorbate 20 at a concentration of 0.005 to 0.05%, and d) methionine at a concentration of 10 mM ± 10%.

3. A liquid pharmaceutical preparation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the concentration of the GLP-1 analog is 300 μg / ml ± 20%, the pH of the liquid pharmaceutical preparation is between 6.5 ± 0.5 and 7.5 ± 0.5, and further comprising: a) histidine HCl at a concentration of approximately 10 mM ± 10%, b) mannitol at a concentration of 150 mM to 350 mM, c) polysorbate 20 at a concentration of 0.005 to 0.05%, and d) arginine at a concentration of 50 mM ± 10%, proline at a concentration of 50 mM ± 10%, or methionine at a concentration of 10 mM ± 10%.

4. A liquid pharmaceutical formulation comprising a GLP-1 analog having the amino acid sequence shown in Sequence ID No. 3, wherein the concentration of the GLP-1 analog is 300 μg / ml ± 20%, the pH of the liquid pharmaceutical formulation is between 6.5 ± 0.5 and 7.5 ± 0.5, and the liquid pharmaceutical formulation comprises a) histidine HCl at a concentration of approximately 10 mM ± 10%, b) sucrose at 8% ± 10%, c) polysorbate 20 at a concentration of 0.005 to 0.05%, and d) methionine at a concentration of 10 mM ± 10%.

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