Compositions containing incretin analogs and their use

Abstract

Compositions are provided that include an incretin analog having activity at each of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon (GCG) receptors (i.e., avian receptor agonists) and one or more additional agents, such as a tonicity agent and a preservative. Methods are also provided for treating diseases, such as type 2 diabetes, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and obesity, with the compositions.

Description

[Technical Field]

[0001] This disclosure relates to compositions having incretin analogs having activity at glucose-dependent insulinotropic polypeptide (GIP) receptors, glucagon-like peptide-1 (GLP-1) receptors, and glucagon (GCG) receptors, respectively. The compositions further include agents that provide commercially acceptable shelf-life stability, in-use stability, and acceptable patient injection site experience. Such incretin analog-containing compositions may be used to treat conditions, diseases, and disorders including diabetes (particularly type 2 diabetes mellitus (T2DM)), dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or obesity.

[0002] Over the past few decades, the prevalence of diabetes mellitus, a chronic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both, has continued to rise. T2DM is the most common form of diabetes, accounting for approximately 90% of all diabetes cases. In T2DM, a combined effect of impaired insulin secretion and insulin resistance is associated with elevated blood glucose levels.

[0003] Uncontrolled diabetes mellitus can lead to one or more conditions that affect the morbidity and mortality rates of individuals with T2DM. Obesity is one of the main risk factors for T2DM, and a large percentage (about 90%) of individuals with T2DM are overweight or obese. It has been demonstrated that reducing body fat accumulation will lead to improvements in obesity-related comorbidities, including hyperglycemia and cardiovascular events.

[0004] Current standard treatments for T2DM include dietary restrictions and exercise, as well as oral medications and injectable hypoglycemic agents, including incretin-based therapies such as GLP-1 receptor agonists and GIP / GLP-1(GG) receptor agonists. Despite the available treatment options, a significant number of individuals receiving approved therapies fail to achieve glycemic control targets (see, e.g., Casagrande et al. (2013) Diabetes Care 36:2271-2279).

[0005] International Patent Application Publications 2019 / 125929 and 2019 / 125938, and International Patent Application PCT / US2020 / 064512 describe incretin analogs that act as GCG, GLP-1, and GIP (GGG) tri-receptor agonists and can be used to treat T2DM. Therefore, a composition comprising such a GGG tri-receptor agonist with acceptable stability and acceptable injection site experience is needed for the individual receiving it, in order to be effective in glucose control and weight loss in the management of T2DM disease.

[0006] To address this need, the disclosure first describes pharmaceutically acceptable compositions comprising an incretin analog or a pharmaceutically acceptable salt thereof, an isotonic agent, and optionally a preservative.

[0007] In some cases, the incretin analog may be SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. In some cases, the incretin analog may be at concentrations of about 1 mg / mL to about 30 mg / mL. In certain cases, the incretin analog may be at concentrations of 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 8 mg / mL, 9 mg / mL, 12 mg / mL, 18 mg / mL, 24 mg / mL, or 30 mg / mL. In some cases, the pharmaceutically acceptable salt for use herein may be selected from sodium salts, trifluoroacetate salts, hydrochloride salts, and / or acetate salts. In some cases, the pharmaceutically acceptable salt may be a tetrasodium salt.

[0008] In some cases, the isotonic agent can be selected from glycerin, mannitol, and propylene glycol. When the isotonic agent is glycerin, the concentration may be about 5 mg / mL to about 50 mg / mL, particularly 20 mg / mL. When the isotonic agent is mannitol, the concentration may be about 10 mg / mL to about 100 mg / mL, particularly 46 mg / mL. When the isotonic agent is propylene glycol, the concentration may be about 5 mg / mL to about 50 mg / mL, particularly 15 mg / mL. In a particular example, the isotonic agent is 46 mg / mL of mannitol.

[0009] In some cases, the preservative can be selected from m-cresol and phenol. When the preservative is m-cresol, the concentration can be about 1 mg / mL to about 10 mg / mL, particularly 3.15 mg / mL. When the preservative is phenol, the concentration can be about 1 mg / mL to about 10 mg / mL, particularly 5 mg / mL. In a particular example, the preservative is 3.15 mg / mL of m-cresol.

[0010] In some examples, the composition may have a pH of about 7.0 to about 8.0, particularly about 7.5. In certain examples, a buffer system, particularly a TRIS buffer system, may be used at a concentration of about 10 mM to about 100 mM, particularly 10 mM, to maintain the pH.

[0011] Considering the above, in certain examples, the composition contains an incretin analog at a concentration of approximately 2 mg / mL to approximately 30 mg / mL and an isotonic agent at a concentration of 10 to 50 mg / mL in a TRIS buffer system at a pH of approximately 7.5. In some examples, the incretin analog is SEQ ID NO: 1. In some examples, the isotonic agent is mannitol at a concentration of 46 mg / mL. In some examples, the composition also contains a preservative such as m-cresol at a concentration starting from 3.15 mg / mL. In other examples, the composition also contains a preservative such as phenol at a concentration of 5.0 mg / mL.

[0012] This disclosure also describes methods for treating diabetes mellitus, such methods comprising at least the step of administering an effective amount / dose of the composition herein to an individual in need. In some examples, diabetes mellitus is T2DM. Alternatively, this disclosure describes methods for treating obesity, such methods comprising at least the step of administering an effective amount of the composition herein to an individual in need. Alternatively, this disclosure describes methods for treating dyslipidemia, such methods comprising at least the step of administering an effective amount / dose of the composition herein to an individual in need. Alternatively, this disclosure describes methods for treating fatty liver disease, such methods comprising at least the step of administering an effective amount / dose of the composition herein to an individual in need. Alternatively, this disclosure describes methods for treating metabolic syndrome, such methods comprising at least the step of administering an effective amount / dose of the composition herein to an individual in need. Alternatively, this disclosure describes a method for treating NAFLD, which includes at least the step of administering an effective dose of the composition herein to an individual in need. Alternatively, this disclosure describes a method for treating NASH, which includes at least the step of administering an effective dose of the composition herein to an individual in need. Alternatively, this disclosure describes a method for providing therapeutic weight loss, which includes at least the step of administering an effective dose of the composition herein to an individual in need. Alternatively, this disclosure describes a method for providing non-therapeutic weight loss, which includes at least the step of administering an effective dose of the composition herein to an individual in need. Alternatively, this disclosure describes a method for treating a condition mediated by GGG tri receptor agonist activity, which includes at least the step of administering an effective amount of the composition herein to an individual in need.

[0013] In some cases, the composition is administered approximately once a week. In other cases, the composition is administered once every seven days.

[0014] This disclosure further describes compositions of this specification for use as pharmaceuticals.

[0015] This disclosure further describes compositions of this specification for use in the treatment of diabetes. Alternatively, this disclosure describes compositions of this specification for use in the treatment of obesity. Alternatively, this disclosure describes compositions of this specification for use in providing therapeutic weight loss. Alternatively, this disclosure describes compositions of this specification for use in providing non-therapeutic weight loss.

[0016] This disclosure further describes products comprising the compositions of this specification. In some examples, the product is a multi-use vial. In some examples, the product is a pre-filled syringe. In some examples, the product is an automatic injector ("automatic syringe," see, for example, U.S. Patent No. 8,734,394). In some examples, the product is a continuous perfusion pump, particularly a subcutaneous injection pump.

[0017] overview GCG is a group of 29 amino acid hormones involved in the metabolism of amino acids, lipids, and carbohydrates. GCG plays a crucial role in intermeal blood glucose regulation and overall weight loss. GLP-1 is an incretin hormone that stimulates insulin secretion and inhibits glucagon secretion. GIP is a gastric inhibitory peptide that exhibits a strong incretin effect on glucose-dependent insulin secretion and has known complementary effects with GLP-1 to improve glucose control and weight loss. The synergistic effect of GGG tri receptor agonists on these three receptors is hypothesized to result in a more potent and effective treatment than current standard therapies. The incretin analog of SEQ ID NO: 1 is a fatty acid acylated, long-acting GGG tri receptor agonist.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of incretin analogs, pharmaceutical compositions, and methods, the preferred methods and materials are described herein.

[0019] Also, references to an element by the indefinite article “a” or “an” do not exclude the possibility of there being more than one element, unless the context clearly requires that there be one and only one element. Thus, the indefinite articles “a” or “an” typically mean “at least one.”

[0020] definition As used herein, “about” means within a statistically significant range of a value (s), such as, for example, a concentration, length, molecular weight, pH, percent sequence identity, time frame, temperature, or volume as described. Such a value or range can be within the order of typically 20% of a given value or range, more typically within 10% of the given value or range, and even more typically within 5% of the given value or range. The allowable variation encompassed by “about” depends on the particular system in the study and can be readily appreciated by one of ordinary skill in the art.

[0021] As used herein, with respect to one or more of the GIP, GLP-1, or GCG receptors, “active,” “activate,” “activation,” etc. mean the ability of a compound, such as an incretin analog of the present specification, to bind to the receptor and to induce a response at the receptor, measured using assays known in the art, such as the in vitro assays described below.

[0022] As used herein, "amino acid" means, from a chemical perspective, a molecule characterized by containing one or more amine groups and one or more carboxylic acid groups, and may contain other functional groups. As is known in the art, there is a set of 20 amino acids designated as standard amino acids and used as components of most peptides / polypeptides / proteins produced by all organisms.

[0023] As used herein, "analogue" means a compound such as a synthetic peptide or polypeptide that activates a target receptor and induces at least one in vivo or in vitro effect induced by a natural receptor agonist.

[0024] As used herein, "chemical stability" means the ability of a therapeutic agent, substance, or product to resist potential changes in the composition in the product due to possible chemical reactions such as isomerization, aggregation, oxidation, polymerization, fragmentation, and hydrolysis.

[0025] As used herein, "effective amount" means the amount, concentration, or dosage of one or more of the incretin analogues herein, or a pharmaceutically acceptable salt thereof, which, by single or multiple administrations to an individual in need thereof, provides a desired effect in such an individual during diagnosis or treatment (i.e., can cause a clinically measurable difference in the condition of the individual, such as a decrease in blood glucose, a decrease in HbA1c, a decrease in body weight or body fat, and / or a change in body composition). The effective amount can be readily determined by one of ordinary skill in the art by using known techniques and observing the results obtained under similar circumstances. When determining the effective amount for an individual, a number of factors are considered, including, but not limited to, the mammalian species, its size, age, and general health, the particular disease or disorder involved, the degree, involvement, or severity of the disease or disorder, the individual's response, the particular incretin analogue administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dosage regimen selected, the use of concomitant medications, and other related circumstances.

[0026] As used herein, "half maximal effective concentration" or "EC 50 " means the concentration of a compound that brings about 50% activation / stimulation of an assay endpoint, such as a dose-response curve (e.g., cAMP).

[0027] As used herein, "incretin analog" means a compound that has structural similarity to each of GIP, GLP-1, and GCG, particularly human GIP, human GLP-1, and human GCG, but has a plurality of differences. The incretin analogs herein include amino acid sequences that result in compounds having affinity for GIP, GLP-1, and GCG receptors and activity at each of them (i.e., triple receptor agonist activity). Exemplary incretin analogs for use herein, as well as the sequences of human GIP, GLP-1, and GCG, are described in International Patent Application Publication Nos. 2019 / 125929 and 2019 / 125938, and International Patent Application No. PCT / US2020 / 064512. Particularly useful herein is Example 12 of International Patent Application Publication No. 2019 / 125938, which has the following sequence, YX2QGTFTSDYSIX 13 LDKX 17 AX 19 X 20 AFIEYLLX 28 X 29 GPSSX 34 APPPS wherein X2 is Aib, X 13 is αMeL, X 17 is K, X 19 is Q, X 20 is Aib, X 28 is E, X 29 is G, X 34 is G, X 17 where K at is (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18Chemical modification occurs via conjugation of the K side chain to the epsilon amino group at CO2H, and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1).

[0028] The following diagram shows the structure of the incretin analog of Sequence ID No. 1, using standard single-letter amino acid codes, with the exception of amino acid residues Aib2, αMeL13, K17, and Aib20, whose amino acid residue structures have been extended.

[0029] [ka]

[0030] As used herein, “individuals in need of treatment” means mammals, such as humans, that have a condition, disease, disorder, or symptom in need of treatment or therapy, including, for example, those listed herein. In particular, the preferred individual to be treated is a human.

[0031] As used herein, “long-acting” means that the binding affinity and activity of the incretin analogs herein last longer than that of reference peptides such as natural human GIP (SEQ ID NO: 2), human GLP-1 (SEQ ID NO: 3), and / or human GCG (SEQ ID NO: 4), and that they can be administered at a low frequency of at least once daily, three times a week, twice a week, once a week, or even once a month. The duration of action profiles of the incretin analogs described herein may be measured using known pharmacokinetic testing methods, such as those described in the following examples.

[0032] As used herein, “microbiological stability” means the ability of a therapeutic agent, substance, or product to maintain its sterility when exposed to environmental microorganisms or other microorganisms.

[0033] As used herein, “non-standard amino acids” refer to amino acids that may occur spontaneously within cells but do not participate in peptide synthesis. Non-standard amino acids can be components of peptides and can be produced by modifying standard amino acids within peptides (i.e., via post-translational modification). Non-standard amino acids may include D-amino acids that have absolute chirality opposite to that of the standard L-amino acids described above.

[0034] As used herein, “pharmaceutically acceptable salts” are well known to those skilled in the art. pharmaceutically acceptable salts and general techniques for preparing them are well known in the art (see, for example, Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011)). pharmaceutically acceptable salts for use herein include sodium salts, trifluoroacetates, hydrochlorides, and / or acetates.

[0035] As used herein, “physical stability” means the ability of a therapeutic agent, substance, or product to maintain its physical dimensions and properties when exposed to conditions that it would ordinarily encounter in its environment of use, such as agitation and shearing.

[0036] As used herein, "propylene glycol" is well known to those skilled in the art and is represented by the formula C3H8O2.

[0037] As used herein, "saturated" means that the fatty acid portion does not contain carbon-carbon double or triple bonds.

[0038] As used herein, “shelf life stability” means the time required for a therapeutic agent, such as an incretin analog as herein, to degrade to about 90% of its original concentration. Shelf life stability also means the time a therapeutic agent remains stable when stored under recommended storage conditions, for example, measured under controlled conditions of about 5°C.

[0039] As used herein, “therapeutic stability” means the extent to which a therapeutic agent, substance, or product retains, within certain limits, the same properties and characteristics it had at the time of manufacture throughout its storage and use period. Exemplary properties of therapeutic stability that can be evaluated include, but are not limited to, its chemical, physical, microbiological, therapeutic, and / or toxicological properties. Factors that may affect therapeutic stability include, but are not limited to, concentration, dosage form, light, moisture, oxygen, pH, and temperature.

[0040] As used herein, “to treat,” “to cure,” and “to treat” mean to suppress, delay, halt, or reverse the progression or severity of an existing condition, disease, disorder, or symptom.

[0041] As used herein, with reference to incretin analogs, “triple receptor agonist activity” means an incretin analog having activity at each of the GIP, GLP-1, and GCG receptors, in particular an analog having balanced and sufficient activity at each receptor to provide the benefits of receptor agonism while avoiding the undesirable side effects associated with excessive activity of that receptor. Furthermore, incretin analogs having triple receptor agonist activity have long-lasting effects at each of the GIP, GLP-1, and GCG receptors, which advantageously allows for administration at low frequencies of once daily, three times a week, twice a week, or once a week.

[0042] A certain abbreviation is defined as follows: "Aib (α-aminoisobutyric acid)" refers to α-aminoisobutyric acid, "αMeL" refers to α-methylleucine, "αMeK" refers to α-methyllysine, "αMeF" refers to α-methylphenylalanine, "αMeF(2F)" refers to α-methyl2-fluorophenylalanine, "αMeY" refers to α-methyltyrosine, "EDTA (ethylenediaminetetraacetic acid)" refers to ethylenediaminetetraacetic acid, "HIAC (high accuracy liquid particle counting)" refers to high-precision liquid particle counting using light shielding technology, "hr" refers to time, "IV (intravenous)" refers to intravenous, "Iva (isovaline)" refers to isovaline, "kDa (kilodalton)" refers to kilodalton, "LC-MS (liquid chromatography-mass spectrometry)" refers to liquid chromatography-mass spectrometry, "MFI (microflow) "imaging)" refers to microflow imaging, "min" refers to minutes, "MS (mass spectrometry)" refers to mass spectrometry, "Orn (ornithine)" or "O (ornithine)" refers to ornithine, "RP-HPLC (reversed-phase high performance liquid chromatography)" refers to reversed-phase high performance liquid chromatography, "sec" refers to seconds, "SEM (standard error of the mean)" refers to the standard error of the mean, "SPA (scintillation proximity assay)" refers to scintillation proximity assay, "SQ (subcutaneous)" refers to the subcutaneous tissue, "TFA (trifluoroacetic acid)" refers to trifluoroacetic acid, "tBu (tert-butyl)" refers to tert-butyl, "TRIS" refers to tris(hydroxymethyl)aminomethane, and "Trt (trityl)" refers to trityl.

[0043] composition The compositions of this specification, for example, contain an incretin analog of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof at a concentration of about 1 mg / mL to about 30 mg / mL. In some examples, the concentration of the incretin analog may be about 2 mg / mL to about 29 mg / mL, about 3 mg / mL to about 28 mg / mL, about 4 mg / mL to about 27 mg / mL, about 5 mg / mL to about 26 mg / mL, about 6 mg / mL to about 25 mg / mL, about 7 mg / mL to about 24 mg / mL, about 8 mg / mL to about 23 mg / mL, about 9 mg / mL to about 22 mg / mL, about 10 mg / mL to about 21 mg / mL, about 11 mg / mL to about 20 mg / mL, about 12 mg / mL to about 19 mg / mL, about 13 mg / mL to about 18 mg / mL, about 14 mg / mL to about 17 mg / mL, or about 15 mg / mL to about 16 mg / mL. In other cases, the concentration of the incretin analog may be approximately 1 mg / mL, approximately 2 mg / mL, approximately 3 mg / mL, approximately 4 mg / mL, approximately 5 mg / mL, approximately 6 mg / mL, approximately 7 mg / mL, approximately 8 mg / mL, approximately 9 mg / mL, approximately 10 mg / mL, approximately 11 mg / mL, approximately 12 mg / mL, approximately 13 mg / mL, approximately 14 mg / mL, approximately 15 mg / mL, approximately 16 mg / mL, approximately 17 mg / mL, approximately 18 mg / mL, approximately 19 mg / mL, approximately 20 mg / mL, approximately 21 mg / mL, approximately 22 mg / mL, approximately 23 mg / mL, approximately 24 mg / mL, approximately 25 mg / mL, approximately 26 mg / mL, approximately 27 mg / mL, approximately 28 mg / mL, approximately 29 mg / mL, or approximately 30 mg / mL. In certain cases, the concentration of the incretin analog may be 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 12 mg / mL, 18 mg / mL, 24 mg / mL, or 30 mg / mL.

[0044] In some cases, the dose range may be approximately 0.5 mg to 15 mg. In other cases, the dose range may be approximately 6 mg to 24 mg.

[0045] Incretin analogs can be produced recombinantly or synthetically (see, for example, International Patent Application Publications 2019 / 125929, 2019 / 125938, and International Patent Application PCT / US2020 / 064512).

[0046] In addition to the foregoing, the compositions herein also include isotonic agents for making isotonic formulations suitable for subcutaneous administration. Examples of isotonic agents include, but are not limited to, glycerin, mannitol, and propylene glycol, or combinations thereof. In some embodiments, the isotonic agent is mannitol.

[0047] When the isotonic agent is glycerin, the concentration of the isotonic agent can be approximately 5 mg / mL to approximately 50 mg / mL, and particularly 20 mg / mL.

[0048] When the isotonic agent is mannitol, the concentration of the isotonic agent can be approximately 10 mg / mL to approximately 100 mg / mL, particularly 46 mg / mL.

[0049] When the isotonic agent is propylene glycol, the concentration of the isotonic agent can be approximately 5 mg / mL to approximately 50 mg / mL, particularly 15 mg / mL.

[0050] buffer system In addition to the above, the composition may also include a buffer system to maintain an appropriate pH. Examples of buffer systems include, but are not limited to, phosphate (PO4) buffer and TRIS buffer, particularly TRIS.

[0051] If the buffer system is TRIS, the buffer system concentration can be approximately 10 mM to 100 mM, particularly 10 mM.

[0052] Regardless of the buffer system, the pH of the composition may be approximately 7.0 to approximately 8.0, particularly 7.5. In some examples, the pH is approximately 7.1 to approximately 7.9, approximately 7.2 to approximately 7.8, approximately 7.3 to approximately 7.7, approximately 7.4 to approximately 7.6, or approximately 7.5. In other examples, the pH of the composition is approximately 7.0, approximately 7.1, approximately 7.2, approximately 7.3, approximately 7.4, approximately 7.5, approximately 7.6, approximately 7.7, approximately 7.8, approximately 7.9, or approximately 8.0.

[0053] Preservatives The compositions described herein are sterile when first prepared. Therefore, the compositions may optionally contain preservatives that are compatible with the other components of the composition and can be added in sufficient strength to meet applicable regulatory antimicrobial preservative requirements. Pharmaceutically acceptable preservatives are known to those skilled in the art (e.g., Remington: The Science and Practice of Pharmacy (Troy, Ed., 21)). st (See Edition, Lippincott, Williams & Wilkins, 2006).

[0054] Considering the above, the composition may also contain preservatives to maintain sterility. Examples of preservatives include, but are not limited to, m-cresol and phenol, particularly m-cresol.

[0055] When the preservative is m-cresol, the concentration of the preservative can be approximately 1 mg / mL to approximately 10 mg / mL, particularly 3.15 mg / mL.

[0056] When the preservative is phenol, the concentration of the preservative can be approximately 1 mg / mL to approximately 10 mg / mL, particularly 5.0 mg / mL.

[0057] Packaging / Delivery Devices The compositions described herein may be administered intravenously (IV), intramuscularly (IM), or subcutaneously (SQ). The compositions are typically administered using pre-filled disposable pens, reusable pens, or auto-pen injectors. Alternatively, the compositions may be administered using multi-use vials or pump devices. In some examples, the device is an auto-injector, such as that described in U.S. Patent No. 8,734,394.

[0058] Therefore, the compositions herein may be provided in pre-filled syringes / multi-use vials. Such pre-filled syringes / multi-use vials may be useful for administering about 0.5 mL to about 1 mL of the composition per patient per dose. The dose of the composition may be administered using a dosing schedule determined by a clinician, physician, or other trained healthcare professional.

[0059] Alternatively, the composition may be prepared for use in cartridges and would therefore differ from the above composition by containing a preservative.

[0060] Alternatively, the composition may be prepared as part of a product containing the composition, which may be a reusable vial, a reusable pen-type syringe, a pre-filled disposable pen, an auto-injector, or a pump.

[0061] Considering the above, the compositions herein relate to acceptable shelf-life stability, stability in use, and acceptable injection site experience.

[0062] method The incretin analogs described herein may be used to treat a variety of conditions, disorders, diseases, or symptoms. For example, the incretin analogs described herein may be used to treat diabetes mellitus (particularly T2DM), dyslipidemia, metabolic syndrome, NAFLD, NASH, and / or obesity. In particular, a method for treating T2DM in an individual is provided, such a method comprising at least the step of administering an effective amount of the incretin analog described herein, or a pharmaceutically acceptable salt thereof, to an individual in need of such treatment.

[0063] In addition, methods for treating obesity in individuals are provided, such methods comprising at least the step of administering to an individual in need of such treatment an effective amount of an incretin analog described herein, or a pharmaceutically acceptable salt thereof.

[0064] In addition, methods are provided for inducing non-therapeutic weight loss in an individual, such methods comprising at least the step of administering to an individual in need of such treatment an effective amount of an incretin analog described herein, or a pharmaceutically acceptable salt thereof.

[0065] In addition, methods for treating metabolic syndrome in an individual are provided, such methods comprising at least the step of administering to an individual in need of such treatment an effective amount of an incretin analog described herein, or a pharmaceutically acceptable salt thereof.

[0066] In addition, methods for treating NASH in an individual are provided, such methods comprising at least the step of administering to an individual in need of such treatment an effective amount of an incretin analog described herein, or a pharmaceutically acceptable salt thereof.

[0067] In addition, methods for treating NAFLD in an individual are provided, such methods comprising at least the step of administering to an individual in need of such treatment an effective amount of an incretin analog described herein, or a pharmaceutically acceptable salt thereof.

[0068] In these methods, the effectiveness of the composition can be evaluated, for example, by observing a significant decrease in blood glucose, a significant increase in insulin, a significant decrease in HbA1c, and / or a significant decrease in body weight. [Examples]

[0069] The following non-limiting embodiments are provided for illustrative purposes only, not limiting purposes.

[0070] formulation Example 1: A composition containing an incretin analog, an isotonic agent, and an optional preservative. The compositions are prepared essentially as described herein. Such compositions comprise 2, 6, or 10 mg / mL of the incretin analog of SEQ ID NO: 1 and the additional components listed in Table 1. The effects of preservatives and isotonic agents are studied by varying each type at fixed concentrations. The preservative concentrations are fixed at 3.15 mg / mL and 5 mg / mL for m-cresol and phenol, respectively. The isotonic agent concentrations are selected so that the isotonic formulation is suitable for subcutaneous administration.

[0071] The solution is prepared by adding the incretin analog of SEQ ID NO: 1 to a suitable matrix, mixing until dissolution in the solution is achieved, and then bringing the solution to its final volume using a volumetric flask of appropriate size. Each formulation solution is aseptically filtered through a 0.22 μm PVDF filter and packed into 5 mL glass vials with a filling volume of 3 mL.

[0072] [Table 1]

[0073] The samples are stored at 5°C, 30°C, or 40°C for further study, as described in the subsequent examples.

[0074] In vitro data (chemical and physical stability) Example 2: Study on stability during use Stability indicator analysis and characterization techniques selected to measure the chemical and physical stability of a formulation include size exclusion chromatography (SEC), reversed-phase high-performance liquid chromatography (RP-HPLC), and visual inspection.

[0075] The sampling schedule is outlined in Table 2. The model is used to estimate the trend over 24 months at a nominal storage temperature of 5°C and an additional month at 30°C during use. Zero-order Arrhenius modeling is used for SEC (monomers, aggregates) and RP-HPLC (purity).

[0076] [Table 2] X = sample time

[0077] SEC: A non-gradient size exclusion HPLC method with UV detection at 214 nm is used to determine the relative amounts of incretin analog monomers and total aggregates. Monomers and aggregates are reported as peak area percentages relative to total area. The procedure demonstrates stability, as measured by its ability to decompose known impurities from incretin analogs. The results of the stability study are shown in Table 3, which shows the monomer value percentages for selected formulations in Table 1 under storage conditions of 5°C, 30°C, and 40°C. Stability data are available for storage up to 8 weeks.

[0078] [Table 3]

[0079] As the temperature increases, monomer purity decreases after 8 weeks. As shown in Table 4, there is no essential change in monomer purity after 8 weeks at 5°C, and monomer purity decreases as a function of temperature. At 8 weeks, the SEC results from formulation 1 (m-cresol / mannitol) at 30°C are approximately 1% lower than the SEC results at 40°C at 8 weeks. These data suggest anomalies, and therefore, the 8-week, 30°C condition data for formulation 1 is excluded from the model predictions. Data from all other conditions are used for stability modeling, and Arrhenius dynamics are assumed.

[0080] [Table 4]

[0081] The trends in formulation factors of aggregates across the studied design domain closely follow the trends in monomer purity. Table 5 shows the increasing total aggregates as a function of temperature. Table 6 shows the predicted change in total aggregates % over 24 months at 5°C and 1 month at 30°C, and the effect of input variables on the predicted values. The input variables do not significantly affect aggregates due to SEC.

[0082] [Table 5]

[0083] [Table 6]

[0084] RP-HPLC: The RP-HPLC method utilizes a nonpolar stationary phase and an aqueous, moderately polar mobile phase. HPLC is equipped with UV detection at 214 nm.

[0085] As shown in Table 7, the RP-HPLC main peak purity percentage decreases significantly as a function of temperature. However, formulation factors do not significantly affect the stability profile. Furthermore, the predicted purity value approaches 95% after 2 years of storage at 5°C, demonstrating robustness across the formulation space under nominal conditions.

[0086] [Table 7]

[0087] Table 8 shows the effect of formulation factors on the predicted RP-HPLC values ​​after 24 months at 5°C and 1 month at 30°C, indicating that none of the study variables had a significant impact on the main peak purity.

[0088] [Table 8]

[0089] Table 9 shows that total impurities measured by RP-HPLC increase at higher temperatures, resulting in a more rapid degradation rate.

[0090] [Table 9]

[0091] Table 10 shows the effect of formulation factors on the predicted total impurities measured by RP-HPLC after 24 months of storage at 5°C and 1 month at 30°C, indicating that the overall influence of the study variables is not significant.

[0092] [Table 10]

[0093] Physical Stability and LCMS: Physical appearance and visible particulate matter data were determined by visual inspection. No visible particulate matter was reported at any time point / storage condition. In addition, the solution remained clear and colorless up to 8 weeks at 40°C. Formulations 3, 8, 9, 15, 16, and 17 appeared slightly amber compared to the control (WFI) vial. Formulations 9 and 17 underwent LCMS analysis, and formulation 19, being clear and colorless, underwent further analysis for comparison. A matrix of formulations that experienced color change is shown in Table 11.

[0094] [Table 11]

[0095] Formulations 9 and 19 share the same pH, buffer, and isotonic adjuster, and are therefore comparable; however, formulation 9 contains m-cresol, while formulation 19 does not contain preservatives. After storage at 40°C for 8 weeks, there were no significant differences in the total ion chromatogram (TIC) species identified between the formulations. LCMS analysis showed clipping at S8, isomerization and / or clipping at S32, clipping at Aib2, and Y1 modification. The degradation pathways appear similar between the two formulations, although formulation 9 shows relatively higher levels of these modifications. Given that the difference between these formulations is the presence of m-cresol in formulation 9, the color change in formulation 9 may result from the degradation of the preservative.

[0096] Conclusion: All formulations exhibit similar stability profiles. Statistical analysis does not show a significant impact on chemical stability arising from the study variables. Therefore, there is no interaction between excipients, preservatives, and incretin analog concentrations. In fact, incretin analog concentrations of 2 mg / mL to 10 mg / mL do not affect stability. These data indicate that m-cresol and phenol are preservatives for the incretin analogs. The stability profile of formulation 19 (without preservatives) is similar to all others. The predicted shelf life of the primary study group and the non-preserved group shows chemical stability of up to 24 months at 5°C and 1 month at 30°C. Differences in physical stability observed for some of the preserved formulations appear to be related to the stability of preservatives, as opposed to specific degradation pathways of the incretin analogs. The data herein indicate that non-preserved or preserved solution formulations with incretin analogs of 2 to 10 mg / mL are feasible using either propylene glycol, glycerol, or mannitol. Furthermore, the data does not demonstrate a significant advantage in terms of shelf life of isotonic agents or preservatives.

[0097] Example 3: In-use stability study of the optimized prototype formulation Optimization: The optimization study determines the time-dependent chemical and physical stability under nominal, accelerated, and stressed conditions. Here, the buffer and pH are optimized based on the above examples, with 10 mM TRIS buffer and a pH of 7.5 selected. As in the above examples, the optimization here involves three isotonic modifiers: propylene glycol, glycerin, and mannitol. Vial presentations are selected for optimization, and syringe presentations are included to study the compatibility of the incretin analog with pre-filled syringes. Table 12 lists the optimization parameters for prototype formulations using the incretin analog of SEQ ID NO: 1 or its pharmaceutically acceptable salts.

[0098] [Table 12] Note: All samples are prepared in 10 mM TRIS buffer at pH 7.5 at 25°C.

[0099] Stability testing of prototype formulations: Samples are stabilized for up to 6 months and tested according to Table 13. The main analytical assays are RP-HPLC and SEC. The AEX method is also used for orthogonal characterization testing.

[0100] [Table 13] * MFI will only be tested for syringe presentation.

[0101] CSD, ISTA 3A, and photolysis tests: Determined using a solution matrix based on the above examples. Exemplary drug product unit formulations used herein are summarized in Table 14.

[0102] [Table 14]

[0103] The incretin analog (SEQ ID NO: 1) tetrasodium salt is tested for shear and vibration susceptibility using a capillary shear device and the ISTA 3A test method. To support manufacturing and packaging operations, photostability is also tested at this stage. The capillary shear device is designed to model shear similar to that which may be caused by manufacturing unit operations (mixing, pumping, filling, etc.). The ISTA 3A test is a simulated transport study designed to mimic vibration stress during transport. Both methods represent worst-case scenarios for either type of physical stress they are designed to model. Both study methods follow standard test protocols. Photostability testing is performed as follows: the sample is loaded into a photostability chamber and exposed to one of three levels of intensity and type (both UV and visible) according to ICH guidelines: 0%, 20%, and 100% of the ICH recommended intensity. Table 15 outlines the design and test plan for these studies.

[0104] [Table 15]

[0105] In these studies, bioassay analyses (data not shown) were performed on prototypes P1 and P2 at time 0, and only on P2 at 6 months. The bioassay results did not show significant differences between the tested samples. Overall, these studies demonstrated robust chemical and physical stability profiles, with temperature playing the most significant role in degradation.

[0106] RP-HPLC results: There is no intrinsic change at 5°C, and the main peak purity decreases as a function of temperature. Differences between formulations under stress and accelerated conditions are within the range of method variability.

[0107] [Table 16]

[0108] [Table 17]

[0109] SEC Results: The SEC results under 5°C conditions show no significant differences or discernible trends. Monomer purity results under accelerated and stressed conditions decrease at 2 and 3 months, respectively. Similarly, total aggregates increase dramatically under accelerated and stressed conditions. Monomer purity results for all conditions under accelerated and stressed conditions are within 1% of each other, which is close to method variability.

[0110] [Table 18]

[0111] [Table 19]

[0112] AEX results: Under 5°C conditions, AEX results show an increase of approximately 2% in acidic mutants after 6 months, although there is some inherent variability in the data. Acidic mutants appear to increase overall as a function of temperature, leveling off at around 7%.

[0113] [Table 20]

[0114] [Table 21]

[0115] Results for invisible particulate matter: Particulate matter data across the entire study did not show significant differences as a function of isotonic modifiers. Particulate matter ≥10 μm and ≤25 μm were well below the specification limits. Table 22 shows particulate matter ≥2 μm as measured by HIAC. Cumulative counts per 1 mL were low across all conditions but spontaneously increased in syringe presentation due to the presence of silicone oil not present during vial presentation. Particulate matter data by MFI collected during syringe presentation (data not shown) were highly variable and did not show a clear trend. However, the counts as a whole did not show an interaction with the increase in silicone oil present during syringe presentation.

[0116] [Table 22]

[0117] Appearance, pH, and Visible Particulate Matter Results: Appearance results under all conditions (data not shown) were clear and colorless. No visible particulate matter was reported throughout the study. pH results are summarized in Table 23, showing variability and no clear trend. All pH values ​​were within the target 0.2 pH units.

[0118] [Table 23]

[0119] Break-loose and glide-force (BLGF) results: Prototype formulation P4 was tested for BLGF. Data were collected only under 25°C conditions. Table 24 shows that the BLGF data remained well below their respective functional limits, suggesting good compatibility with this system. The functional limits are the established maximum operating limits for the break-loose and glide-force for the Irma auto-injector, which are 13.6 N and 9.5 N, respectively.

[0120] [Table 24]

[0121] Chemical stability results: RP-HPLC and SEC results show slight differences between the 100% photostressed sample and the control sample. The change in purity is approximately 0.8%. Other conditions are within the range of variability for this method. Table 26 shows that the SEC results show a higher level of aggregates for the 100% photostressed sample, while the results for other aggregates are generally lower. The AEX results do not show significant changes due to stress conditions.

[0122] [Table 25]

[0123] Physical stability results: The results for particulate matter by HIAC are summarized in Tables 27 and 28. These data do not show significant differences between control and stress samples. Visible particulate matter (data not shown) has been reported for transport and photostability stress samples; however, these results have been shown to be false positives.

[0124] [Table 26]

[0125] The studies described herein demonstrate the acceptable physical and chemical stability of incretin analog formulations up to 6 months under nominal, accelerated, and stressed conditions. Incretin analog degradation is primarily a function of temperature. There are no significant differences among the three prototypes (Note: P3 and P4 are identical compositions except that P4 is filled in a syringe instead of a vial). Syringe presentation also demonstrates acceptable BLGF results and compatibility with the third-generation platform syringe system. Considering this, P2 is the primary formulation for clinical research.

[0126] Following exposure to shear and vibrational stresses in CSD and transport studies, P2 levels did not show a significant difference between stressed and non-stressed (control) samples. Furthermore, photostability studies under 20% ICH conditions did not show significant differences compared to the dark-controlled samples. However, small differences were observed after exposure to 100% ICH conditions compared to the dark-controlled samples.

[0127] Based on these data, a pH 7.5 solution composition containing 4.8% mannitol and 10 mM Tris buffer is selected. The incretin analog concentration is fixed at 6 mg / mL in a 2 mL filled volume to cover the proposed dose range (e.g., approximately 0.5 mg to approximately 12 mg). The container / closure size for clinical studies is a 2 mL Schott vial with corresponding serum stoppers and seals (BT5973 / VS5558 / AZ5450). P2 statistical analysis predicts robust stability after 2 years of storage, including a 30-day shelf life at 30°C.

[0128] Example 4: Stability study of prototype formulation P2 under various levels of incretin analog peptide concentration and pH. The objective of this Design of Experiment (DOE) study is to define and confirm the robustness of the prototype P2 formulation under various levels of incretin analog peptide concentration and pH conditions.

[0129] The solution matrix components are as follows: 10 mM Tris, 4.8% mannitol. The peptide concentration is tested at three concentration levels: 1, 18, and 30 mg / mL of SEQ ID NO: 1 (tetrasodium salt). The pH effect is studied at three pH levels: 7, 7.5, and 8. To prepare the solution, the peptide is dissolved in a known amount of buffer matrix, the concentration is measured using a UV / Vis spectrophotometer with a variable path length extension, the target weight is calculated based on the assay results and the density of the target formulation, and the required amount of buffer is added to achieve the final target weight. The primary packaging material used is a commercial-shaped (second-generation) pre-filled syringe barrel coupled with a non-layered (second-generation) stopper. The syringe is filled to a nominal capacity of 0.5 mL. The formulations are shown in Table 28 below.

[0130] [Table 27]

[0131] Stability indicator analysis and characterization techniques selected to measure the chemical and physical stability of the formulation include size exclusion chromatography (SEC), reverse-phase high-performance liquid chromatography (RP-HPLC), anion exchange chromatography (AEX), HIAC, microflow imaging technique (MFI), and visual inspection. Samples are stored under two temperature conditions (5°C and 30°C). The sampling schedule is outlined in Table 29, and the data are shown in Tables 30-32. To predict the degradation level at the end of the shelf life, a prediction plot is created based on statistical analysis, covering 23 months at 5°C and 30 days at 30°C.

[0132] [Table 28]

[0133] [Table 29-1]

[0134] [Table 29-2]

[0135] [Table 30-1]

[0136] [Table 30-2]

[0137] [Table 30-3]

[0138] [Table 31-1]

[0139] [Table 31-2]

[0140] [Table 31-3]

[0141] [Table 31-4]

[0142] physical stability Physical appearance data and visible particulate matter are consistent across all formulations, conditions, and time points. No visible particulate matter has been reported. The solution remains clear and colorless. The data is shown in Table 30.

[0143] Size exclusion chromatography (SEC) Table 31 shows the SEC monomer percentage and total aggregate percentage for all research formulations under 5°C and 30°C storage conditions. Stability data is available for storage up to 6 months. The data indicates that monomer loss is primarily due to fragmentation. Table 31 shows the SEC total fragmentation values ​​for all research formulations under 5°C and 30°C storage conditions.

[0144] Anion exchange chromatography (AEX) Table 31 shows the AEX main peak value, TAV value, and TBV value for all research formulations under storage conditions of 5°C and 30°C.

[0145] RP-HPLC The RP-HPLC results showed that pH had the greatest impact on stability, with higher pH leading to higher levels of degradation. Table 31 shows the RP-HPLC main peak values ​​and total impurities for all study formulations under 5°C and 30°C storage conditions.

[0146] fine particles Table 32 shows particulate matter data measured by HIAC light shielding and MFI for all formulations at each time point and under each condition, illustrating differences related to method variability. No specific trends were observed with respect to formulation factors. MFI was used to further characterize the particulate matter in each formulation and determine the particle morphology. Table 32 shows a comparison between the mean particle sizes of all formulations for particulate matter ≥ 5 μm, compared to particulate matter data ≥ 5 μm with an aspect ratio (AR) < 0.85. Particulate matter with an AR < 0.85 is considered non-spherical and more likely to be protein-associated aggregates. The results show a significant difference between the raw particulate matter data ≥ 5 μm and the particulate matter data ≥ 5 μm considering AR. These data suggest that many of the particulate matter in solution are spherical and likely attributable to silicone oil droplets, a common phenomenon in pre-filled syringe systems. The results for the round particle fraction support this conclusion, considering that the round particle fraction accounted for over 90% of all formulations.

[0147] Conclusion: Data from all formulations studied showed similar stability profiles throughout the study. This study indicates that the formulations are stable in the pH range of 7–8 and concentrations in the range of 1–30 mg / mL.

[0148] array The following amino acid sequences are referenced in this disclosure and are shown below for reference.

[0149] SEQ ID NO: 1 - Incretin analog / GGG tri receptor agonist Y-Aib-QGTFTSDYSI-αMeL-LDKK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γGlu)-CO-(CH2) 18 -CO2H)AQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2

[0150] Sequence ID 2 - Human GIP YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ

[0151] Sequence ID 3 - Human GLP-1 7-36 Amido HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

[0152] Sequence ID 4 - Human GCG HSQGTFTSDYSKYLDSRRAQDFVQWLMNT Furthermore, it should be noted that the present invention includes the following embodiments. [Aspect 1] Incretin analogs or pharmaceutically acceptable salts thereof, At least one isotonic agent selected from the group consisting of glycerin, mannitol, and propylene glycol, A pharmaceutical composition comprising an optional preservative selected from the group consisting of m-cresol and phenol. [Aspect 2] The pharmaceutical composition according to Embodiment 1, wherein the incretin analog or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg / mL to about 30 mg / mL. [Aspect 3] The pharmaceutical composition according to embodiment 1 or 2, wherein the isotonic agent is glycerin, and its concentration is about 5 mg / mL to about 50 mg / mL. [Aspect 4] The pharmaceutical composition according to embodiment 3, wherein the glycerin is present at a concentration of 20 mg / mL. [Aspect 5] The pharmaceutical composition according to embodiment 1 or 2, wherein the isotonic agent is mannitol, and the concentration is approximately 10 mg / mL to approximately 100 mg / mL. [Aspect 6] The pharmaceutical composition according to embodiment 5, wherein the mannitol is present at a concentration of 48 mg / mL. [Aspect 7] The pharmaceutical composition according to embodiment 1 or 2, wherein the isotonic agent is propylene glycol at a concentration of about 5 mg / mL to about 50 mg / mL. [Aspect 8] The pharmaceutical composition according to embodiment 7, wherein the propylene glycol is present at a concentration of 15 mg / mL. [Aspect 9] The pharmaceutical composition according to any one of embodiments 1 to 8, wherein the optional preservative is m-cresol at a concentration of about 1 mg / mL to about 10 mg / mL. [Aspect 10] The pharmaceutical composition according to embodiment 9, wherein the m-cresol is present at a concentration of 3.15 mg / mL. [Aspect 11] The pharmaceutical composition according to any one of embodiments 1 to 8, wherein the optional preservative is phenol, at a concentration of about 1 mg / mL to about 10 mg / mL. [Aspect 12] The pharmaceutical composition according to embodiment 11, wherein the phenol is present at a concentration of 5 mg / mL. [Aspect 13] The pharmaceutical composition according to any one of embodiments 1 to 12, wherein the incretin analog comprises SEQ ID NO: 1. [Aspect 14] The pharmaceutical composition according to embodiment 13, wherein the incretin analog is present in a concentration selected from the group consisting of 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 8 mg / mL, 9 mg / mL, 12 mg / mL, 18 mg / mL, 24 mg / mL, and 30 mg / mL. [Aspect 15] A pharmaceutical composition according to any one of embodiments 1 to 14, further comprising a buffer selected from the group consisting of phosphate (PO4) buffer and tris(hydroxymethyl)aminomethane (TRIS) buffer. [Aspect 16] The pharmaceutical composition according to embodiment 15, wherein the buffer solution is the TRIS buffer solution and has a concentration of 10 mM. [Aspect 17] A pharmaceutical composition according to any one of embodiments 1 to 15, further comprising ethylenediaminetetraacetic acid (EDTA) at a concentration of 0.3 mg / mL. [Aspect 18] An incretin analog containing SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof, wherein the incretin analog or pharmaceutically acceptable salt is at a concentration of about 1 mg / mL to about 30 mg / mL, Mannitol at concentrations of approximately 10 mg / mL to approximately 100 mg / mL, The pharmaceutical composition according to Embodiment 1, comprising a tris(hydroxymethyl)aminomethane (TRIS) buffer solution at a concentration of approximately 10 mM to approximately 100 mM. [Aspect 19] The pharmaceutical composition according to embodiment 18, wherein the pharmaceutical composition has a pH of about 6.5 to about 7.5. [Aspect 20] The pharmaceutical composition according to embodiment 18 or 19, wherein the mannitol is present at a concentration of 48 mg / mL. [Aspect 21] The pharmaceutical composition according to any one of embodiments 18 to 20, wherein the incretin analog or a pharmaceutically acceptable salt thereof is at a concentration selected from the group consisting of 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 8 mg / mL, 9 mg / mL, 12 mg / mL, 18 mg / mL, 24 mg / mL, and 30 mg / mL. [Aspect 22] A pharmaceutical composition according to any one of embodiments 18 to 21, further comprising a preservative selected from the group consisting of m-cresol and phenol, wherein the preservative is concentrated at a concentration of about 1 mg / mL to about 10 mg / mL. [Aspect 23] A pharmaceutical composition according to any one of embodiments 1 to 22, further comprising a pharmaceutically acceptable carrier, diluent, or excipient. [Aspect 24] The pharmaceutical composition according to any one of embodiments 1 to 23, wherein the dose of the composition is approximately 0.5 mL. [Pattern 25] The pharmaceutical composition according to embodiment 24, wherein the pharmaceutical composition is suitable for administration using an automated injection device. [Aspect 26] The pharmaceutical composition according to any one of embodiments 1 to 25, wherein the pharmaceutically acceptable salt is selected from sodium salt, trifluoroacetate salt, hydrochloride salt, and acetate salt. [Aspect 27] The pharmaceutical composition according to any one of embodiments 1 to 26, wherein the pharmaceutically acceptable salt is a tetrasodium salt. [Aspect 28] A method of treating diabetes, A method comprising the step of administering to an individual requiring treatment for diabetes a pharmaceutical composition according to any one of embodiments 1 to 27 of an effective dose. [Aspect 29] The method according to embodiment 28, wherein the effective dose is administered using an automated injection device. [Aspect 30] The method according to embodiment 28 or 29, wherein the effective dose is administered once a week. [Aspect 31] A method for treating obesity, A method comprising the step of administering to an individual requiring treatment for obesity a pharmaceutical composition according to any one of embodiments 1 to 27 of an effective dose. [Aspect 32] The method according to embodiment 31, wherein the effective dose is administered using an automated injection device. [Aspect 33] The method according to embodiment 31 or 32, wherein the effective dose is administered once a week. [Aspect 34] A pharmaceutical composition according to any one of embodiments 1 to 27, for use in treating a disease selected from the group consisting of diabetes mellitus, dyslipidemia, fatty liver disease, metabolic syndrome, non-alcoholic steatohepatitis, and obesity. [Aspect 35] A pharmaceutical composition according to any one of embodiments 1 to 27, for use in treating type 2 diabetes. [Aspect 36] A pharmaceutical composition according to any one of embodiments 1 to 27, for use in treating obesity. [Aspect 37] Use of a pharmaceutical composition according to any one of embodiments 1 to 27 in the manufacture of a drug for treating a disease selected from the group consisting of diabetes mellitus, dyslipidemia, fatty liver disease, metabolic syndrome, non-alcoholic steatohepatitis, and obesity. [Aspect 38] Use of a pharmaceutical composition according to any one of embodiments 1 to 27 in the manufacture of a drug for treating type 2 diabetes. [Aspect 39] Use of a pharmaceutical composition according to any one of embodiments 1 to 27 in the manufacture of a drug for treating obesity. [Aspect 40] A product comprising a pharmaceutical composition according to any one of embodiments 1 to 27, wherein the product is selected from a multi-use vial, a reusable pen-type syringe, a pre-filled disposable pen, an auto-injector, and a pump.

Claims

1. Incretin analogs or pharmaceutically acceptable salts thereof, Mannitol is an isotonic agent, A selective preservative chosen from the group consisting of m-cresol and phenol, and Includes, The incretin analog comprises SEQ ID NO: 1, The incretin analog or a pharmaceutically acceptable salt thereof is at a concentration of approximately 2 mg / mL to approximately 24 mg / mL. A pharmaceutical composition wherein the isotonic agent has a concentration of approximately 10 mg / mL to approximately 100 mg / mL.

2. The pharmaceutical composition according to claim 1, wherein the isotonic agent has a concentration of 48 mg / mL.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition contains the preservative, which is m-cresol, at a concentration of about 1 mg / mL to about 10 mg / mL.

4. The pharmaceutical composition according to claim 3, wherein the m-cresol is present at a concentration of 3.15 mg / mL.

5. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition contains the preservative, which is phenol, at a concentration of about 1 mg / mL to about 10 mg / mL.

6. The pharmaceutical composition according to claim 5, wherein the phenol is present at a concentration of 5 mg / mL.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the incretin analog is at a concentration selected from the group consisting of 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 8 mg / mL, 9 mg / mL, 12 mg / mL, 18 mg / mL, and 24 mg / mL.

8. Phosphate (PO ４ The pharmaceutical composition according to any one of claims 1 to 7, further comprising a buffer selected from the group consisting of a buffer and tris(hydroxymethyl)aminomethane (TRIS) buffer.

9. The pharmaceutical composition according to claim 8, wherein the buffer solution is the TRIS buffer solution and has a concentration of 10 mM.

10. The pharmaceutical composition according to any one of claims 1 to 9, further comprising ethylenediaminetetraacetic acid (EDTA) at a concentration of 0.3 mg / mL.

11. The pharmaceutical composition according to claim 1, further comprising a tris(hydroxymethyl)aminomethane (TRIS) buffer solution at a concentration of about 10 mM to about 100 mM.

12. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition has a pH of about 6.5 to about 7.

5.

13. The pharmaceutical composition according to claim 11 or 12, wherein the mannitol is present at a concentration of 48 mg / mL.

14. The pharmaceutical composition according to any one of claims 11 to 13, wherein the incretin analog or a pharmaceutically acceptable salt thereof is at a concentration selected from the group consisting of 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 8 mg / mL, 9 mg / mL, 12 mg / mL, 18 mg / mL, and 24 mg / mL.

15. The pharmaceutical composition according to any one of claims 11 to 14, comprising a preservative selected from the group consisting of m-cresol and phenol, wherein the preservative is concentrated at a concentration of about 1 mg / mL to about 10 mg / mL.

16. A pharmaceutical composition according to any one of claims 1 to 15, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the dose of the pharmaceutical composition is about 0.5 mL.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is suitable for administration using an automated injection device.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the pharmaceutically acceptable salt is selected from sodium salt, trifluoroacetate salt, hydrochloride salt, and acetate salt.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutically acceptable salt is a tetrasodium salt.

21. A pharmaceutical composition according to any one of claims 1 to 20, for use in treating a disease selected from the group consisting of diabetes mellitus, dyslipidemia, fatty liver disease, metabolic syndrome, non-alcoholic steatohepatitis, and obesity.

22. A pharmaceutical composition according to any one of claims 1 to 20, for use in treating type II diabetes.

23. A pharmaceutical composition according to any one of claims 1 to 20, for use in treating obesity.

24. Use of the pharmaceutical composition according to any one of claims 1 to 20 in the manufacture of a drug for treating a disease selected from the group consisting of diabetes mellitus, dyslipidemia, fatty liver disease, metabolic syndrome, non-alcoholic steatohepatitis, and obesity.

25. Use of the pharmaceutical composition according to any one of claims 1 to 20 in the manufacture of a drug for treating type II diabetes.

26. Use of the pharmaceutical composition according to any one of claims 1 to 20 in the manufacture of a drug for treating obesity.

27. A product comprising a pharmaceutical composition according to any one of claims 1 to 20, wherein the product is selected from a multi-use vial, a reusable pen-type syringe, a pre-filled disposable pen, an auto-injector, and a pump.

28. The pharmaceutical composition according to any one of claims 1 to 23, wherein the incretin analog or a pharmaceutically acceptable salt thereof is present in a concentration of about 2 mg / mL to about 10 mg / mL.

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