Preserved GIP / GLP agonist composition

Abstract

A preserved composition of tirzepatide comprising about 3 mg / mL or less of NaCl, a phosphate buffer, phenol, benzyl alcohol, and glycerin.

Description

Technical Field

[0001] The present invention is a stored pharmaceutical GIP / GLP1 dual agonist peptide composition for subcutaneous injection. The composition contains an antibacterial preservative and excipients to control unwanted oligomerization and provide desirable stability. The composition contains tirzepatide, NaCl, glycerin, phenol, benzyl alcohol, and a phosphate buffer. The composition provides stability over a commercially acceptable shelf life, stability during use, and control of pharmaceutically desirable peptide oligomerization.

Background Art

[0002] Diabetes is a chronic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. In type 2 diabetes mellitus ("T2D"), the combined effects of insulin secretory deficiency and insulin resistance are associated with elevated blood glucose levels. Tirzepatide is a GIP / GLP1 dual agonist peptide useful for the treatment of diabetes. After being approved by the FDA in May 2022, tirzepatide is sold in the United States under the trade name Mounjaro™. Tirzepatide is useful for the treatment of obesity. A pharmaceutically acceptable multi-use composition is desirable to enable alternative device and delivery options. Compositions suitable for multi-use delivery generally require an antibacterial agent to preserve the composition during multi-use. Benzyl alcohol and phenol are preservatives that can be used in multi-use formulations. However, preservatives have been reported to interact with biologic agents. The interaction between a biologic agent and a preservative can result in oligomerization, turbidity, instability, and other unwanted effects. A stable pharmaceutically acceptable stored incretin formulation is needed.

[0003] U.S. Patent No. 9,474,780 generally describes compositions containing GIP / GLP1 agonists administered via parenteral routes. U.S. Patent No. 9,474,780 describes and claims tilzepatide. U.S. Patent No. 1,135,7820 describes and claims compositions for pharmaceutically desirable single-use forms, for example, in single-use pens. U.S. Patent No. 1,135,7820 discloses preserved formulations. However, the applicants have found that tilzepatide undergoes self-association or oligomerization when preserved in the presence of 4 mg / mL or more of NaCl using typical pharmaceutically acceptable preservatives. Self-association or oligomerization of tilzepatide can affect the peptide's stability, shelf life, and properties. There is a need for preserved compositions of tilzepatide that provide acceptable stability, shelf life, and control of pharmaceutically desirable peptide oligomerization. [Brief explanation of the drawing]

[0004] [Figure 1] This is static light scattering of tilzepatide in a solution containing 140 mM NaCl at pH 7.0. [Figure 2] This shows the static light scattering of tilzepatide in a solution containing 140 mM NaCl and 5 mg / mL phenol at pH 7.0, and tilzepatide in a solution containing 140 mM NaCl at pH 7.0. [Figure 3] This is static light scattering of phenol in 200 mM NaCl, 140 mM NaCl, 85 mM NaCl, 30 mM NaCl, and 0 mM NaCl, glycerin in 0 mM NaCl, and tilzepatide in 0 mM NaCl. [Figure 4] This is static light scattering of tilzepatide in 30 mM NaCl and 8 mg / mL phenol, 30 mM NaCl and 5 mg / mL phenol, 8 mg / mL phenol with 30 mM NaCl and 0 mM NaCl, and 5 mg / mL phenol with 0 mM NaCl. [Figure 5]This is static light scattering of tilzepatide in 30 mM NaCl containing 15 mg / mL benzyl alcohol, 30 mM NaCl containing 9 mg / mL benzyl alcohol, 15 mg / mL benzyl alcohol containing 30 mM NaCl and 0 mM NaCl, and 9 mg / mL benzyl alcohol containing 0 mM NaCl. [Figure 6] This is static light scattering of tilzepatide containing 30 mM NaCl, 9 mg / mL benzyl alcohol, and 2 mg / mL phenol, 30 mM NaCl, and 9 mg / mL benzyl alcohol containing 2 mg / mL phenol and 0 mM NaCl. [Figure 7] This is an NMR spectrum of ligands for preservatives. The top left shows 1.8 mg / mL benzyl alcohol, the top right shows 1.8 mg / mL benzyl alcohol and 1 mg / mL tylzepatide, the bottom left shows 1.5 mg / mL phenol, and the bottom right shows 1.5 mg / mL phenol and 1.0 mg / mL tylzepatide. [Figure 8] The 1H-13C HSQC spectrum of tirzepatide (black) is superimposed on that of tirzepatide containing benzyl alcohol. No significant difference is observed between the spectra. [Figure 9] The 1H-13C HSQC spectrum of tirzepatide (black) is superimposed on that of tirzepatide containing phenol. A significant difference between the spectra is observed, indicating an interaction between tirzepatide and phenol. [Modes for carrying out the invention]

[0005] The applicants discovered that NaCl concentration is a key factor involved in the self-association of tilzepatide.

[0006] In one embodiment, the stored formulation is such that the oligomeric state of tilzepatide is considered equivalent to that of a Mounjaro® substrate in accordance with U.S. regulatory standards. In another embodiment, the stored tilzepatide has a low risk of fibril formation.

[0007] The composition described herein is a pharmaceutically acceptable composition comprising tilzepatide or a pharmaceutically acceptable salt thereof, NaCl, glycerin, phenolbenzyl alcohol, and phosphate buffer, wherein the concentration of NaCl is approximately 3 mg / mL or less, thereby meeting these needs.

[0008] In one embodiment, the concentration of NaCl is approximately 1.5 mg / mL to approximately 3 mg / mL. In one embodiment, the concentration of NaCl is approximately 25 mM to approximately 50 mM. In one embodiment, the concentration of NaCl is approximately 30 mM. In one embodiment, the concentration of NaCl is approximately 1.75 mg / mL. In one embodiment, NaCl is an isotonic agent. In one embodiment, NaCl and glycerin act as isotonic agents. In one embodiment, the composition has a glycerin concentration of approximately 8 mg / mL to approximately 12 mg / mL. In one embodiment, the concentration of NaCl is approximately 1.75 mg / mL and the concentration of glycerin is approximately 8 mg / mL. In one embodiment, the concentration of NaCl is approximately 50 mM and the concentration of glycerin is approximately 8 mg / mL. In one embodiment, the concentration of NaCl is approximately 30 mM and the concentration of glycerin is approximately 8 mg / mL. In one embodiment, the concentration of NaCl is approximately 50 mM and the concentration of glycerin is approximately 12 mg / mL. In one embodiment, the concentration of phenol is about 2 mg / mL to about 5 mg / mL. In one embodiment, the concentration of phenol is greater than about 5.5 mg / mL. In one embodiment, the concentration of phenol is greater than about 5.5 mg / mL. In one embodiment, the preservative consists of phenol and benzyl alcohol. In one embodiment, the preservative contains phenol and benzyl alcohol. In one embodiment, the preservative contains phenol and about 9 mg / mL of benzyl alcohol. In one embodiment, the preservative is about 2 mg / mL of phenol and about 9 mg / mL of benzyl alcohol. In one embodiment, the concentration of phenol is less than about 6 mg / mL.

[0009] In one embodiment, the phosphate buffer is dibasic sodium phosphate. In one embodiment, the concentration of the phosphate buffer is approximately 0.67 mg / mL to approximately 2.0 mg / mL. In one embodiment, the concentration of the phosphate buffer is approximately 1.34 mg / mL. In one embodiment, the phosphate buffer is approximately 5 mM.

[0010] In one embodiment, the concentration of tilzepatide is approximately 2.09 mg / mL to approximately 41.67 mg / mL. In one embodiment, the concentration of tilzepatide or its pharmaceutically acceptable salt is approximately 4.17 mg / mL to approximately 25.0 mg / mL. In one embodiment, the concentration of tilzepatide or its pharmaceutically acceptable salt is approximately 4.17 mg / mL to approximately 33.4 mg / mL. In one embodiment, the concentration of tilzepatide or its pharmaceutically acceptable salt is approximately 4.17 mg / mL to approximately 41.67 mg / mL. In one embodiment, the concentration of tilzepatide or its pharmaceutically acceptable salt is approximately 10 mg / mL to approximately 30 mg / mL. In one embodiment, the concentration of tilzepatide or its pharmaceutically acceptable salt is approximately 5 mg / mL to approximately 50.0 mg / mL. In one embodiment, the concentration of tilzepatide or its pharmaceutically acceptable salt is approximately 2.5 mg / mL to approximately 30 mg / mL. In one embodiment, approximately 0.6 mL is delivered per dose. In another embodiment, approximately 0.5 mL is delivered per dose.

[0011] The concentration of tilzepatide or a pharmaceutically acceptable salt thereof may be adjusted to deliver a desired dose per injection. For example, when approximately 0.6 mL per dose is administered, the concentration of tilzepatide or a pharmaceutically acceptable salt thereof will be adjusted to ensure accurate delivery of the desired dose for tilzepatide or a pharmaceutically acceptable salt thereof. In one embodiment, the dose of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg. In one embodiment, the dose of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, and 25 mg. In one embodiment, the dose of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, and 25 mg. In one embodiment, the dose of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of 10 mg and 15 mg. In one embodiment, the dose is selected from the group consisting of 10 mg, 12.5 mg, 15 mg, 20 mg, and 25 mg. In one embodiment, the dose is selected from about 1.25 mg, 2.5 mg, and 5 mg.

[0012] In one embodiment, the concentration of tilzepatide or its pharmaceutically acceptable salt is about 4.17 to about 25 mg / mL, and the concentration of NaCl is about 1.75 mg / mL. In another embodiment, the concentration of tilzepatide or its pharmaceutically acceptable salt is about 2.09 mg / mL to about 25 mg / mL, and the concentration of NaCl is about 1.75 mg / mL.

[0013] In one embodiment, a composition of tilzepatide or a pharmaceutically acceptable salt thereof is administered approximately once a week. In another embodiment, the dose of a composition of tilzepatide or a pharmaceutically acceptable salt thereof is administered once every seven days.

[0014] In one embodiment, a method for treating diabetes is provided, which includes administering to a human subject in need thereof, an effective dose of one of the above compositions.

[0015] In one embodiment, a method for treating obesity is provided, which includes administering to a human subject in need thereof, an effective dose of one of the above compositions. In one embodiment, a method for providing therapeutic weight loss is provided, which includes administering to a human subject in need thereof, an effective dose of one of the above compositions. In one embodiment, a method for improving long-term weight management is provided, which includes administering to a human subject in need thereof, an effective dose of one of the above compositions. In one embodiment, a method for treating a condition mediated by GIP / GLP1 coagonist activity is provided, which includes administering to a human subject in need thereof, an effective dose of one of the above compositions.

[0016] In one embodiment, one of the above compositions for use as a medicament is provided.

[0017] In one embodiment, one of the above compositions for use in the treatment of diabetes is provided. In one embodiment, one of the above compositions for use in the treatment of obesity is provided.

[0018] In one embodiment, one of the above compositions for use in providing therapeutic weight loss is provided. In one embodiment, one of the above compositions for use in providing non-therapeutic weight loss is provided. In one embodiment, one of the above compositions for use in improving long-term weight management is provided.

[0019] According to another aspect of the present invention, an article of manufacture comprising one of the above compositions is provided. In certain embodiments, the article of manufacture is a multi-use vial. In certain embodiments, the article of manufacture is a multi-use cartridge. In certain embodiments, the article of manufacture is a multi-use pen. In certain embodiments, the article of manufacture is a prefilled syringe.

[0020] The Mounjaro (trademark) pharmaceutical product is formulated as a once-weekly non-preserved single-use subcutaneous injection. Tirzepatide formulated as Mounjaro (trademark) is approved for use in the treatment of type 2 diabetes and is also being investigated for other indications such as obesity. It is desired to develop a formulation of multi-use preserved tirzepatide or a pharmaceutically acceptable salt thereof so that the treatment can reach and benefit more patients. The preserved formulation is desirable for use in prefilled cartridges, pens, or vials intended for multiple uses.

[0021] Antimicrobial preservatives are added to formulations to prevent or kill microorganisms that can inadvertently be introduced into the product. Such compounds typically contain an aromatic ring in their chemical structure that enables interaction with other molecules. For example, preservatives with an aromatic ring structure have been reported to induce instability in protein formulations via mechanisms including the unfolding of larger proteins with a tertiary structure and the aggregation of polysorbates in pharmaceutical product compositions.

[0022] In the case of Mounjaro (trademark), a single-use pharmaceutical product, the composition is 5 mg / mL to 30 mg / mL of tirzepatide in 5 mM phosphate buffer at pH 7.0 and 140 mM NaCl. Under these conditions, the peptide reversibly self-associates and exhibits a monomer-trimer-hexamer equilibrium. The equilibrium provided by the single-use pharmaceutical product Mounjaro (trademark) composition may be related to product stability and peptide properties. It is desired to maintain a substantially similar monomer-trimer-hexamer peptide self-association equilibrium between the non-preserved and the preserved formulations to ensure a consistent patient experience.

[0023] As shown in the figures, phenol, benzyl alcohol, and NaCl interact with tilzepatide to varying degrees. While benzyl alcohol has been reported to interact with peptides, Figures 7, 8, and 9 do not show significant interaction with tilzepatide. Furthermore, sufficient preservatives and drugs are necessary to provide stability and safety during multiple use in a single patient. Figures 1, 2, 3, 4, 5, and 6 show the unpredictable oligomerization of tilzepatide under various excipients and conditions.

[0024] As used herein, “Tilzepatide” means the GIP / GLP1 dual agonist peptide as the active pharmaceutical ingredient in the USFDA-approved product Mounjaro®, as described in U.S. Patent No. 9,474,780, CAS Registry No. 2023788-19-2.

[0025] Chilzepatide is described in Example 1 of U.S. Patent No. 9474,780 and has the following sequence: YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS X1 is Aib, X2 is Aib, the K at position 20 is chemically modified via the conjugation of (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2)18-CO2H to the epsilon-amino group of the K side chain, and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1).

[0026] As used herein, “pharmaceutically acceptable salt” is well known to those skilled in the art. In one embodiment, the pharmaceutically acceptable salt is trifluoroacetate tylzepatide salt. The composition is sterile when first prepared.

[0027] The pH of compositions of tilzepatide or its pharmaceutically acceptable salts as herein is typically about 6.5 to 7.5 and can be adjusted using physiologically appropriate acids and bases as may be necessary to achieve a desired pH. In one embodiment, the target pH is 6.7 to 7.3. In another embodiment, the target pH is about 7.

[0028] In one embodiment, the pH is adjusted using a base to promote dissolution in a buffer solution. Adding an acid to the composition may be necessary to adjust the pH to a desired pH range. In one embodiment, NaOH is used to promote the dissolution of tilzepatide or a pharmaceutically acceptable salt thereof in the buffer solution. In one embodiment, HCl is added to adjust the pH of the composition in which tilzepatide is dissolved to a desired pH range.

[0029] The compositions of the present invention are typically administered subcutaneously. These compositions are typically administered using pre-filled disposable pens, reusable pens with cartridges, or automatic pen injectors. They may also be administered using multi-use vials or pump devices.

[0030] As used herein, “shelf life stability” is measured under controlled conditions at approximately 5 degrees Celsius. As used herein, the term “stability in use” refers to the stability of the composition measured under controlled conditions at approximately 25 degrees Celsius or approximately 40 degrees Celsius.

[0031] In one embodiment, the term "phenol" means liquefied and distilled phenol, where phenol is about 90% phenol and about 10% water.

[0032] As used herein, the term “approximately” refers to the range of variability permitted in accordance with applicable regulatory guidelines. In one embodiment, “approximately” means ±10% of the stated value. In one embodiment, “approximately” means ±5% of the stated value. In one embodiment, “approximately” means ±2% of the stated value.

[0033] As used herein, low peroxide benzyl alcohol means benzyl alcohol having a peroxide value of about 5 or less, and / or a Japanese Pharmacopoeia (JP) value of less than about 1, and / or a peroxide content of less than about 4 ppm. In one embodiment, low peroxide grade benzyl alcohol is used within one week of the first opening of the benzyl alcohol container. In one embodiment, low peroxide grade benzyl alcohol is used within one day of the first opening of the benzyl alcohol container. In one embodiment, low peroxide grade benzyl alcohol is stored under refrigeration and used within six months of the first opening of the container. In one embodiment, low peroxide grade benzyl alcohol is stored using a nitrogen overlay and used within six months of the first opening. In one embodiment, low peroxide grade benzyl alcohol is stored using a nitrogen overlay and used within one month.

[0034] Those skilled in the art will understand that the structure encompasses natural isotopic forms and other stable isotopes. For example, but not limited to, hydrogen may be deuterated.

[0035] Antimicrobial preservatives have been reported to induce instability in formulations through various hypotheses regarding the interaction between peptides and preservatives. A combination of mechanisms may simultaneously contribute to the interaction between peptides and preservatives.

[0036] The interaction between tilzepatide and preservatives was studied using static light scattering and solution NMR techniques.

[0037] Assay: Light scattering of tilzepatide samples For light scattering measurements, tilzepatide formulations with the compositions detailed in Tables 1.a and 1.b were prepared. Light scattering data were collected using an ALV-CGS3 goniometer-based light scattering instrument (ALV-GmbH, Langen, Germany), a self-contained system with a 22 mW 633 nm HeNe laser.

[0038] Samples were filtered into disposable glass tubes using appropriate filters. The corresponding drug product, a placebo, was used as a scattering blank. Using dynamic light scattering (DLS) mode, single acquisitions of 15 or 30 seconds in length were collected for each sample at a scattering angle of 90 degrees. The obtained DLS autocorrelation functions were analyzed using intensity-weighted normalized size distributions and were shown to be unimodal before proceeding. The excess Rayleigh ratio was calculated using the time-averaged scattering intensity values ​​for the sample, placebo, and toluene.

[0039] The apparent weight-average molecular weight (WAMW) value was calculated using equation (1). WAMW=[(K·c) / R] -1 (1) In the formula, K is the optical constant, c is the peptide mass concentration, and R is the excess Rayleigh ratio. A refractive index increment of 0.185 mL / g (dn / dc) was assumed.

[0040] [Table 1]

[0041] [Table 2]

[0042] Thioflavin T (ThT) fluorescence assay of tilzepatide samples ThT fluorescence was collected using a SpectraMax Gemini EM microplate reader (Molecular Devices, San Jose, California). For each sample or placebo (Table 2), 40 mL of the solution was added to each of three wells in a black, clear-bottomed 96-well plate, followed by 10 mL of 20 mM ThT stock solution. The plate was sealed, and dynamic fluorescence measurements were performed for 24 hours at excitation wavelength 450 nm and emission wavelength 480 nm. The temperature was set to 37°C, and measurements were performed every 10 minutes with 3 seconds of shaking before each measurement. A positive control sample (oxyntomodulin, 2 mg / mL, pH=6.5) was included in the measurements.

[0043] [Table 3]

[0044] Effects of preservatives and NaCl on the self-association of tilzepatide The higher-order structure of tilzepatide was characterized using far-ultraviolet circular dichroism (CD) spectroscopy and Fourier-transform infrared spectroscopy (FTIR). In Mounjaro™ substrate (5 mM phosphate buffer, 140 mM NaCl, pH=7.0), tilzepatide mainly possesses an α-helix structure. Using light scattering, it is shown that self-association of tilzepatide exists in monomer-trimer-hexamer equilibrium between dose and concentration ranges of 2.5 mg / 0.5 mL (5 mg / mL) and 15 mg / 0.5 mL (30 mg / mL).

[0045] To study the effects of preservatives, m-cresol, phenol, or benzyl alcohol were added to standard Mounjaro® compositions at selected concentrations. These concentrations of preservatives were chosen so that the formulations met the acceptance criteria for antimicrobial efficacy testing. The results of the light scattering experiments are summarized in Table 3. The Mounjaro® composition ("Sample 5") exhibits a WAMW of 23.6 kDa. This value is consistent with the monomer-trimer-hexamer equilibrium described earlier.

[0046] In the presence of both 140 mM NaCl and the preservative, the WAMW of tilzepatide was determined to be greater than 70 kDa, corresponding to 14-16 mer oligomers (Table 3, "Samples 6-8"). Correspondingly, the solution appeared milky white, in contrast to the "clear" appearance of the Mounjaro® solution.

[0047] [Table 4]

[0048] The tendency of tilzepatide to fibrillate in the presence of preservatives. Fibrils are large, macromolecular self-assemblies of proteins or peptides possessing specific characteristics. Most notably, individual peptide backbones are transformed into β-sheet-rich three-dimensional structures. As a result, undesirable physical, chemical, and therapeutic risks may arise. Experimentally, fibril formation can be observed visually as an increase in turbidity, precipitation, or gelation, and can also be studied using a number of techniques ranging from size exclusion chromatography, analytical ultracentrifugation, light scattering, and microscopy imaging. These methods can be complemented by spectroscopy, thereby allowing confirmation at the molecular level of the conformational change to β-sheets and the formation of larger assemblies.

[0049] In this study, fluorescence spectroscopy was used with thioflavin T as the binding dye to evaluate the risk of fibrillation of tilzepatide in the presence of a preservative. ThT is a potent fluorescent marker for fibrils. When selectively bound to fibril deposits, the fluorescence signal shows a dramatic increase, indicating the presence or increase of fibrils. This method has been applied to various peptides to study their fibrillation tendencies. Tilzepatide was formulated in substrates with different concentrations, isotonic agents, and preservatives (Table 2). A positive control known to fibrillate (oxyntomodulin, 2 mg / mL, pH=6.5) was included in the measurements. The increase in the ThT fluorescence signal was clearly visible in the positive control. On the other hand, none of the tilzepatide samples showed a statistically significant increase in signal, indicating a very low risk of fibrillation.

[0050] Size exclusion chromatography (SEC) storage life and stability testing during use. This procedure is a non-gradient size exclusion HPLC method with UV detection at 214 nm and is designed to determine the relative amounts of high molecular weight species. The SEC column is a 125 A SEC column, 3.5 μm particle size, 7.8 mm × 300 mm, or equivalent. The mobile phase is 50 / 50 / 0.05% acetonitrile / water / TFA at a flow rate of 0.5 mL / min. The column temperature is 25°C. High molecular weight species are reported as peak area percentage relative to the total area. The procedure demonstrates stability, as measured by its ability to decompose known impurities from tilzepatide. In this study, alternative compositions are compared with the composition embodiments herein.

[0051] RP-HPLC shelf life and stability testing during use This procedure is a gradient reversed-phase HPLC method employing a 2.6 μm, 4.6 × 250 mm, or equivalent C18 reversed-phase column with UV detection at 214 nm. Mobile phase A is 0.1% trifluoroacetic acid in water, and mobile phase B is 0.1% trifluoroacetic acid in acetonitrile (ACN). The gradient profile is shown in Table 4.

[0052] [Table 5]

[0053] The column temperature is controlled at 60°C, and this method is designed to assay, determine identity, and determine purity of tilzepatide in a drug product. Identity is determined by matching the retention time of the main peak with that of the main peak in an external reference standard. Amount is determined by comparing the main peak area with the corresponding peak in the external reference standard. Impurities and related substances are reported as a peak area percentage of the total area. This procedure demonstrates stability, as judged by its ability to decompose known impurities from tilzepatide. Compositions containing 30 mM–50 mM NaCl, 8 mg / mL glycerin, 5 mM phosphate buffer, and phenol as a preservative can provide acceptable stability during use.

[0054] Stability testing The primary stability test included six batches of multi-dose tylzepatide injection drug products in a prefilled pen (PFP) configuration. The drug product from each of these batches was filled into a 3 mL clear glass cartridge, sealed on one end with an elastomer plunger, and sealed on the other end with a disc seal consisting of a double-layer elastomer disc and an aluminum shell.

[0055] Samples from each batch were stabilized for at least 24 months under long-term storage conditions of 5°C (2°C–8°C) and for 6 months under accelerated conditions of 25°C / 60% relative humidity (RH). In addition, samples were stored under stress-stable conditions of 30°C / 65%RH. The stability protocol for the drug products is outlined in Table 5.

[0056] [Table 6]

[0057] [Table 7]

[0058] In addition to the long-term (5°C), accelerated (25°C / 60%RH), and stress (30°C / 65%RH) conditions studied, as summarized in Table 5, a use-in stability study was conducted to demonstrate acceptable stability over the period during which patients could use the multi-dose drug product without refrigeration. For this study, two primary stability batches were selected according to a concentration bracketing approach, one at the lower end of the intended drug product concentration range (2.5 mg / 0.6 mL) and the other at the upper end (15 mg / 0.6 mL). The tests were performed on pre-filled pen batches with concentrations of 2.5 mg / 0.6 mL and 15 mg / 0.6 mL after storage at 2°C–8°C for approximately 2–3 months. 1 In the use-in-use test, both batches were stored at use-in-use conditions of 30°C and tested over a period of 30 days, as shown in Table 6 below. At four time points within the use-in-use test (days 0, 14, 22, and 30), the samples were removed from 30°C storage and the needles were fixed to the pre-filled pens. After priming, the drug product solution was discharged from the pre-filled pens, the needles were then removed, and the samples were tested, or returned to 30°C for discharge and testing at later time points. In this way, the samples reaching the end of the use-in-use test were exposed to conditions (e.g., 30°C) and procedures (e.g., fixing the needles, discharging the drug product solution, and removing the needles) that simulate intended use by a patient. The protocol for multi-dose product stability is shown in Table 6.

[0059] [Table 8] a T0 is the date the sample was removed from long-term storage conditions at 5°C and tested, i.e., 30 days before the end of the use-by-use study.

[0060] These tests include attributes of drug products that are susceptible to change during storage and may affect quality, safety, and / or potency. Color, clarity, and pH were tested to confirm that, as with single-dose products, no significant changes were observed in terms of stability and that these were not attributes that limited shelf life. Antimicrobial effectiveness testing (AET) was performed on samples exposed to conditions of use. AET testing, combined with preservative content testing, demonstrates the microbial safety of drug products during their shelf life.

[0061] RP-HPLC purity Purity was evaluated under long-term (5°C), accelerated (25°C / 60%RH), and stress-stable (30°C / 65%RH) storage conditions. Under accelerated conditions, batches showed a slight decrease in purity. Based on the available data, all batches met the acceptable criteria for the end of their shelf life under both long-term and accelerated storage conditions.

[0062] Total impurities Total impurities were evaluated under long-term (5°C), accelerated (25°C / 60%RH), and stress-stable (30°C / 65%RH) storage conditions. Under accelerated conditions, batches showed a slight increase in total impurities. Based on the available data, all batches met the acceptable criteria for the end of their storage life under both long-term and accelerated storage conditions.

[0063] High molecular weight species High molecular weight species (HMWS) were evaluated under long-term (5°C), accelerated (25°C / 60%RH), and stress-stable (30°C / 65%RH) storage conditions. Under accelerated conditions, batches showed a slight increase in HMWS. Based on the available data, all batches met the acceptable end-of-life criteria for HMWS under long-term and accelerated storage conditions.

[0064] benzyl alcohol Benzyl alcohol content was evaluated under long-term (5°C) and accelerated (25°C / 60%RH) storage conditions. Under accelerated conditions, the data did not show a clear trend regarding the stability of benzyl alcohol. Based on the available data, all batches met the acceptable end-of-storage criteria for benzyl alcohol under both long-term and accelerated storage conditions.

[0065] phenol Phenol content was evaluated under long-term (5°C) and accelerated (25°C / 60%RH) storage conditions. Under accelerated conditions, the data did not show a clear trend regarding phenol stability. Based on the available data, all batches met the acceptable end-of-storage criteria for phenol under both long-term and accelerated storage conditions.

[0066] color The color was evaluated using a series of reference solutions under long-term (5°C) and accelerated (25°C / 60%RH) storage conditions. Based on the available data, all batches met the acceptable color criteria under both long-term and accelerated conditions. Color is not a parameter that limits the shelf life of this composition.

[0067] transparency Transparency was evaluated using the instrumental (turbidimetric) method under long-term (5°C) and accelerated (25°C / 60%RH) storage conditions. No trends or significant variability other than method variability were observed.

[0068] sterility All primary stability batches met sterilization requirements. Container closure integrity (CCI) may be used in place of sterilization testing. All available CCI results obtained from primary stability testing were "pass".

[0069] pH pH was evaluated under long-term (5°C), accelerated (25°C / 60%RH), and stress-stable conditions. Based on available data, all batches met the acceptable end-of-life criteria for pH under both long-term and accelerated storage conditions. No trends were observed in the results, demonstrating that pH remained well-controlled throughout storage.

[0070] particulate matter Particulate matter was evaluated under long-term (5°C), accelerated (25°C / 60%RH), and stress-stable (30°C / 65%RH) storage conditions. All batches in the study met the requirements under both long-term and accelerated conditions.

[0071] Injection (glide) power The injection (glide) force was evaluated using compression tests under long-term (5°C) and accelerated (25°C / 60%RH) storage conditions. No trends or significant variability other than method variability were observed under either condition. All batches in the study met the acceptable criteria for injection force under both long-term and accelerated conditions. Injection force is not considered a parameter limiting shelf life.

[0072] Dose accuracy Dose accuracy was evaluated using gravimetric volume under long-term (5°C) and accelerated (25°C / 60%RH) storage conditions. No trends or significant variability other than method variability were observed under either condition. All batches in the study met acceptable criteria for dose accuracy under both long-term and accelerated conditions. Dose accuracy is not expected to be a parameter limiting shelf life.

[0073] Antimicrobial efficacy test (AET) A characteristic antimicrobial efficacy test (AET) was conducted on samples from use-time samples starting at 22 and 30 days. This was a use-time study to verify the efficacy of the antimicrobial preservative. The test was performed on use-time samples starting at 22 and 30 days, in accordance with the USP. These results confirm that this multi-dose product meets the official AET criteria at the end of the use period after storage under use-time conditions and after storage under 6 months of accelerated stability conditions throughout the entire use period. The results confirm that the shelf life of this multi-dose tilzepatide injection drug product is 24 months when stored under long-term storage conditions of approximately 5°C (2°C to 8°C) for a 30-day use period at a maximum of approximately 30°C. The results of the use-time stability are summarized in Table 7.

[0074] [Table 9]

[0075] [Table 10] a Testing is completed on representative samples according to an acceptable sampling plan defined by internal quality standards. Mean values ​​are reported for reference only.

[0076] Table 8 shows the storage stability results for 0 and 3 months at storage temperatures of 2-8°C.

[0077] [Table 11] * Passing grade = A transparent, colorless solution with no visible particles. *** A CCI test will be performed on cartridge batch D589770.

[0078] NMR research and self-assembly For light scattering measurements and NMR, tilzepatide formulations having the compositions detailed in Tables 9, 10, and 11 were prepared.

[0079] [Table 12]

[0080] [Table 13]

[0081] [Table 14] [Examples]

[0082] Exemplary formulations for preserved tilzepatide Table 12 shows examples of stored formulations. In addition to 50 mM NaCl, an appropriate amount of glycerin is added as a second isotonic agent. The formulations are tested to verify their antimicrobial efficacy and the desired physical and chemical stability of the drug product.

[0083] [Table 15]

[0084] The concentration of NaCl plays a crucial role in determining the association state of tilzepatide, i.e., the higher WAMW with increasing NaCl concentration. Peptide self-association is amplified when preservatives are added. In 50 mM NaCl in the formulations of Examples 1 and 2, the oligomerization state of tilzepatide is considered equivalent to that in the Mounjaro® substrate. These results support the low risk of tilzepatide forming fibrils in preserved formulations with 50 mM NaCl.

[0085] The synergistic effect was observed in the formulations of Examples 1 and 2 with 50 mM NaCl. In Examples 1 and 2, the oligomerization state of tilzepatide was considered equivalent to that of 30 mg / mL tilzepatide in the Mounjaro® substrate.

[0086] Examples 3 and 4 The formulations of Examples 3 and 4 are prepared substantially as described herein, as shown in Table 13.

[0087] [Table 16] a The concentration of tilzepatide in the stored preparation is adjusted based on a 0.6 mL injection volume. The dose range of 2.5 mg to 15 mg remains unchanged. The concentration depends on the injection volume, as shown below.

[0088] Table 14 shows examples of tilzepatide concentrations using the formulations described herein.

[0089] [Table 17]

[0090] Embodiments: Embodiment 1. A pharmaceutical composition comprising SEQ ID NO: 2 or a pharmaceutically acceptable salt thereof, NaCl, glycerin, phenol, and phosphate buffer, wherein the concentration of NaCl is approximately 3 mg / mL or less. 2. The pharmaceutical composition according to Embodiment 1, wherein the concentration of the phosphate buffer is approximately 5 mM. 3. The pharmaceutical composition according to Embodiment 1 or 2, wherein the concentration of the phosphate buffer is approximately 1.34 mg / mL. 4. A pharmaceutical composition according to any one of Embodiments 1 to 3, wherein the concentration of NaCl is approximately 30 mM to approximately 50 mM. 5. A pharmaceutical composition according to any one of Embodiments 1 to 4, wherein the concentration of NaCl is approximately 30 mM. 6. A pharmaceutical composition according to any one of Embodiments 1 to 5, wherein the concentration of NaCl is approximately 1.75 mg / mL. 7. A pharmaceutical composition according to any one of Embodiments 1 to 6, wherein the concentration of glycerin is approximately 8 mg / mL to 12 mg / mL. 8. A pharmaceutical composition according to any one of Embodiments 1 to 7, wherein the concentration of glycerin is approximately 8 mg / mL. 9. A pharmaceutical composition according to any one of Embodiments 1 to 8, wherein the concentration of phenol is approximately 1.5 mg / mL to approximately 6 mg / mL. 10. A pharmaceutical composition according to any one of Embodiments 1 to 9, wherein the concentration of phenol is approximately 2 mg / mL to approximately 5.5 mg / mL. 11. A pharmaceutical composition according to any one of Embodiments 1 to 10, wherein the concentration of phenol is approximately 5.5 mg / mL. 12. A pharmaceutical composition according to any one of Embodiments 1 to 11, wherein the composition further comprises benzyl alcohol. 13. A pharmaceutical composition according to any one of Embodiments 1 to 12, wherein the preservative comprises phenol and benzyl alcohol. 14. A pharmaceutical composition according to any one of Embodiments 1 to 12, wherein the preservative comprises approximately 9 mg / mL of benzyl alcohol. 15. The pharmaceutical composition according to Embodiment 14, wherein the preservative comprises approximately 2 mg / mL of phenol and approximately 9 mg / mL of benzyl alcohol. 16. The preservative is a pharmaceutical composition according to any one of Embodiments 1 to 15, comprising benzyl alcohol with low peroxide content. 17. The preservative is a pharmaceutical composition according to any one of Embodiments 1 to 16, comprising benzyl alcohol having a peroxide content of less than approximately 4 ppm. 18. A pharmaceutical composition according to any one of Embodiments 1 to 17, wherein the pH of the composition is approximately 6.5 to approximately 7.5. 19. A pharmaceutical composition according to any one of Embodiments 1 to 18, wherein the pH of the composition is approximately 6.7 to approximately 7.3. 20. A pharmaceutical composition according to any one of Embodiments 1 to 19, wherein the composition has a pH of approximately 7. twenty one. The pharmaceutical composition according to Embodiment 1, wherein the concentration of the phosphate buffer is approximately 5 mM, the concentration of NaCl is approximately 2.93 mg / mL, the concentration of phenol is approximately 2 mg / mL, the concentration of glycerin is approximately 8 mg / mL, and the concentration of benzyl alcohol is approximately 9 mg / mL. 22. The phosphate buffer solution has a concentration of approximately 5 mM, the NaCl concentration is approximately 30 mM, and the phosphate buffer solution contains glycerin and phenol, as described in Embodiment 1. 23. The pharmaceutical composition according to Embodiment 22, wherein the glycerin content is approximately 8 mg / mL. 24. The pharmaceutical composition according to Embodiment 22 or 23, wherein the phenol concentration is approximately 2 mg / mL to approximately 5.5 mg / mL. 25. A pharmaceutical composition according to any one of embodiments 22 to 24, wherein the phenol content is approximately 5.5 mg / mL. 26. A pharmaceutical composition according to any one of embodiments 22 to 24, wherein the phenol content is approximately 2 mg / mL. 27. A pharmaceutical composition according to any one of Embodiments 1 to 26, wherein the composition is provided in a multi-use injection device. 28. A pharmaceutical composition according to any one of Embodiments 1 to 26, wherein the composition is administered using a multi-use injection device. Embodiment 29. A pharmaceutical composition comprising SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof, NaCl, glycerin, phenol, and phosphate buffer, wherein the concentration of NaCl is approximately 3 mg / mL or less. 30. The pharmaceutical composition according to Embodiment 29, wherein the concentration of the phosphate buffer is approximately 5 mM. 31. The pharmaceutical composition according to Embodiment 29 or 30, wherein the concentration of the phosphate buffer is approximately 1.34 mg / mL. 32. A pharmaceutical composition according to any one of embodiments 29 to 31, wherein the concentration of NaCl is approximately 30 mM to approximately 50 mM. 33. A pharmaceutical composition according to any one of embodiments 29 to 32, wherein the concentration of NaCl is approximately 30 mM. 34. A pharmaceutical composition according to any one of embodiments 29 to 33, wherein the concentration of NaCl is approximately 1.75 mg / mL. 35. A pharmaceutical composition according to any one of embodiments 29 to 34, wherein the concentration of glycerin is approximately 8 mg / mL to 12 mg / mL. 36. A pharmaceutical composition according to any one of embodiments 29 to 35, wherein the concentration of glycerin is approximately 8 mg / mL. 37. A pharmaceutical composition according to any one of embodiments 29 to 36, wherein the concentration of phenol is approximately 1.5 mg / mL to approximately 6 mg / mL. 38. A pharmaceutical composition according to any one of Embodiments 29 to 37, wherein the concentration of phenol is approximately 2 mg / mL to approximately 5.5 mg / mL. 39. A pharmaceutical composition according to any one of embodiments 29 to 38, wherein the concentration of phenol is approximately 5.5 mg / mL. 40. A pharmaceutical composition according to any one of embodiments 29 to 39, wherein the composition further comprises benzyl alcohol. 41. A pharmaceutical composition according to any one of Embodiments 29 to 40, wherein the preservative comprises phenol and benzyl alcohol. 42. A pharmaceutical composition according to any one of Embodiments 29 to 41, wherein the preservative comprises approximately 9 mg / mL of benzyl alcohol. 43. The pharmaceutical composition according to Embodiment 42, wherein the preservative comprises approximately 2 mg / mL of phenol and approximately 9 mg / mL of benzyl alcohol. 44. The preservative is a pharmaceutical composition according to any one of embodiments 29 to 43, comprising benzyl alcohol with low peroxide content. 45. The preservative is a pharmaceutical composition according to any one of Embodiments 29 to 44, comprising benzyl alcohol with a peroxide content of less than approximately 4 ppm. 46. ​​A pharmaceutical composition according to any one of embodiments 29 to 45, wherein the pH of the composition is approximately 6.5 to approximately 7.5. 47. A pharmaceutical composition according to any one of embodiments 29 to 46, wherein the pH of the composition is approximately 6.7 to approximately 7.3. 48. A pharmaceutical composition according to any one of embodiments 29 to 47, wherein the composition has a pH of approximately 7. 49. The pharmaceutical composition according to Embodiment 29, wherein the concentration of the phosphate buffer is approximately 5 mM, the concentration of NaCl is approximately 2.93 mg / mL, the concentration of phenol is approximately 2 mg / mL, the concentration of glycerin is approximately 8 mg / mL, and the concentration of benzyl alcohol is approximately 9 mg / mL. 50. The phosphate buffer has a concentration of approximately 5 mM, the NaCl has a concentration of approximately 30 mM, and the glycerin and phenol are present in the pharmaceutical composition according to Embodiment 29. 51. The pharmaceutical composition according to Embodiment 50, wherein the glycerin content is approximately 8 mg / mL. 52. The pharmaceutical composition according to Embodiment 50 or 51, wherein the phenol concentration is approximately 2 mg / mL to approximately 5.5 mg / mL. 53. A pharmaceutical composition according to any one of embodiments 50 to 52, wherein the phenol content is approximately 5.5 mg / mL. 54. A pharmaceutical composition according to any one of embodiments 50 to 52, wherein the phenol content is approximately 2 mg / mL. 55. A pharmaceutical composition according to any one of embodiments 29 to 54, wherein the composition is provided in a multi-use injection device. 56. A pharmaceutical composition according to any one of embodiments 29 to 54, wherein the composition is administered using a multi-use injection device. Embodiment 57. A pharmaceutical composition comprising SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof, NaCl, glycerin, phenol, and phosphate buffer, wherein the concentration of NaCl is approximately 3 mg / mL or less. 58. The pharmaceutical composition according to Embodiment 57, wherein the concentration of the phosphate buffer is approximately 5 mM. 59. The pharmaceutical composition according to Embodiment 57 or 58, wherein the concentration of the phosphate buffer is approximately 1.34 mg / mL. 60. A pharmaceutical composition according to any one of embodiments 57 to 59, wherein the concentration of NaCl is approximately 30 mM to approximately 50 mM. 61. A pharmaceutical composition according to any one of embodiments 57 to 60, wherein the concentration of NaCl is approximately 30 mM. 62. A pharmaceutical composition according to any one of embodiments 57 to 61, wherein the concentration of NaCl is approximately 1.75 mg / mL. 63. A pharmaceutical composition according to any one of embodiments 57 to 62, wherein the concentration of glycerin is approximately 8 mg / mL to 12 mg / mL. 64. A pharmaceutical composition according to any one of embodiments 57 to 63, wherein the concentration of glycerin is approximately 8 mg / mL. 65. A pharmaceutical composition according to any one of embodiments 57 to 64, wherein the concentration of phenol is approximately 1.5 mg / mL to approximately 6 mg / mL. 66. A pharmaceutical composition according to any one of embodiments 57 to 65, wherein the concentration of phenol is approximately 2 mg / mL to approximately 5.5 mg / mL. 67. A pharmaceutical composition according to any one of embodiments 57 to 66, wherein the concentration of phenol is approximately 5.5 mg / mL. 68. A pharmaceutical composition according to any one of embodiments 57 to 67, wherein the composition further comprises benzyl alcohol. 69. A pharmaceutical composition according to any one of embodiments 57 to 68, wherein the preservative comprises phenol and benzyl alcohol. 70. A pharmaceutical composition according to any one of embodiments 57 to 69, wherein the preservative comprises approximately 9 mg / mL of benzyl alcohol. 71. The pharmaceutical composition according to Embodiment 70, wherein the preservative comprises approximately 2 mg / mL of phenol and approximately 9 mg / mL of benzyl alcohol. 72. The preservative is a pharmaceutical composition according to any one of embodiments 57 to 71, comprising benzyl alcohol with low peroxide content. 73. A pharmaceutical composition according to any one of Embodiments 57 to 72, wherein the preservative comprises benzyl alcohol having a peroxide content of less than approximately 4 ppm. 74. A pharmaceutical composition according to any one of embodiments 57 to 73, wherein the pH of the composition is approximately 6.5 to approximately 7.5. 75. A pharmaceutical composition according to any one of embodiments 57 to 74, wherein the pH of the composition is approximately 6.7 to approximately 7.3. 76. A pharmaceutical composition according to any one of embodiments 57 to 75, wherein the composition has a pH of approximately 7. 77. The pharmaceutical composition according to Embodiment 57, wherein the concentration of the phosphate buffer is approximately 5 mM, the concentration of NaCl is approximately 2.93 mg / mL, the concentration of phenol is approximately 2 mg / mL, the concentration of glycerin is approximately 8 mg / mL, and the concentration of benzyl alcohol is approximately 9 mg / mL. 78. A phosphate buffer solution with a concentration of approximately 5 mM, a NaCl concentration of approximately 30 mM, glycerin, and phenol, as described in Embodiment 57. 79. The pharmaceutical composition according to Embodiment 78, wherein the glycerin content is approximately 8 mg / mL. 80. The pharmaceutical composition according to Embodiment 78 or 79, wherein the phenol concentration is approximately 2 mg / mL to approximately 5.5 mg / mL. 81. A pharmaceutical composition according to any one of embodiments 78 to 80, wherein the phenol content is approximately 5.5 mg / mL. 82. A pharmaceutical composition according to any one of embodiments 78 to 80, wherein the phenol content is approximately 2 mg / mL. 83. A pharmaceutical composition according to any one of embodiments 57 to 82, wherein the composition is provided in a multi-use injection device. 84. A pharmaceutical composition according to any one of embodiments 57 to 82, wherein the composition is administered using a multi-use injection device.

[0091] array Sequence ID 1: Tilzepatide YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS (X1 is Aib, X2 is Aib, and the K at position 20 is the epsilon-amino group of the K side chain) (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 It is chemically modified by the bond of -CO2H, The C-terminal amino acid is amidated as a primary C-terminal amide.

[0092] Sequence ID 2 YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS X1 is Aib, X2 is Aib, the K at position 20 is chemically modified by conjugation of a C16-C20 fatty acid or its derivative to the epsilon-amino group of the K side chain, and the C-terminal amino acid is optionally amidated as a C-terminal primary amide.

[0093] Sequence ID 3 YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO: 3) (X1 is Aib, X2 is Aib, and the K at position 20 is chemically modified by the conjugation of a fatty acid selected from the group consisting of the following to the epsilon-amino group of the K side chain,

[0094] [ka] The C-terminal amino acid is optionally amidated as a primary C-terminal amide, or a pharmaceutically acceptable salt thereof.

[0095] Sequence ID 4

[0096] [ka] Various embodiments of the present invention are shown below. 1. A pharmaceutical composition comprising tilzepatide or a pharmaceutically acceptable salt thereof, NaCl, glycerin, phenol, and phosphate buffer, wherein the concentration of NaCl is approximately 3 mg / mL or less. 2. The pharmaceutical composition according to item 1, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is about 2 to about 50 mg / mL. 3. The pharmaceutical composition according to 1 or 2 above, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 5, about 10, about 15, about 20, about 25, about 30, about 40, and about 50 mg / mL. 4. The pharmaceutical composition according to any one of 1 to 3 above, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 10, about 20, and about 30 mg / mL. 5. The pharmaceutical composition according to item 2 above, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is approximately 4.2 to approximately 41.8 mg / mL. 6. The pharmaceutical composition according to item 5 above, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 4.17, about 8.33, about 12.5, about 16.67, about 20.83, about 25, about 33.33, and about 41.8 mg / mL. 7. The pharmaceutical composition according to 5 or 6 above, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 4.17, about 8.33, about 12.50, about 16.67, about 20.83, and about 25 mg / mL. 8. A pharmaceutical composition according to any one of items 1 to 7 above, wherein the unit dose of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 5, about 7.5, about 10, about 12.5, about 15, about 20, and about 25 mg, and is in the form of a unit dose. 9. A pharmaceutical composition according to any one of items 1 to 7 above, wherein the unit dose of tilzepatide and a pharmaceutically acceptable salt thereof is selected from the group consisting of 5, 7.5, 10, 12.5, and 15 mg, and is in the form of a unit dose. 10. A pharmaceutical composition according to any one of items 1 to 9 above, wherein the administered dose volume is approximately 0.5 mL. 11. The pharmaceutical composition according to any one of items 1 to 9 above, wherein the dose volume administered is approximately 0.6 mL. 12. The pharmaceutical composition according to any one of 1 to 11 above, wherein the concentration of the phosphate buffer is approximately 5 mM. 13. The pharmaceutical composition according to any one of 1 to 11 above, wherein the concentration of the phosphate buffer is approximately 1.34 mg / mL. 14. The pharmaceutical composition according to any one of 1 to 13 above, wherein the concentration of NaCl is approximately 30 mM to approximately 50 mM. 15. The pharmaceutical composition according to any one of 1 to 14 above, wherein the concentration of NaCl is approximately 30 mM. 16. The pharmaceutical composition according to any one of 1 to 15 above, wherein the concentration of NaCl is approximately 1.75 mg / mL. 17. The pharmaceutical composition according to any one of 1 to 16 above, wherein the concentration of glycerin is approximately 8 mg / mL to approximately 12 mg / mL. 18. The pharmaceutical composition according to any one of items 1 to 17 above, wherein the concentration of glycerin is approximately 8 mg / mL. 19. A pharmaceutical composition according to any one of 1 to 18 above, wherein the concentration of the phenol is approximately 1.5 mg / mL to approximately 6 mg / mL. 20. A pharmaceutical composition according to any one of 1 to 19 above, wherein the concentration of the phenol is approximately 2 mg / mL to approximately 5.5 mg / mL. 21. The pharmaceutical composition according to any one of 1 to 20 above, wherein the concentration of the phenol is approximately 5.5 mg / mL. 22. The pharmaceutical composition according to any one of 1 to 21 above, wherein the composition further comprises benzyl alcohol. 23. The pharmaceutical composition according to any one of items 1 to 20 above, wherein the composition further comprises about 9 mg / mL of benzyl alcohol. 24. The pharmaceutical composition according to any one of 1 to 23 above, further comprising benzyl alcohol of a low peroxide grade. 25. The pharmaceutical composition according to any one of 1 to 24 above, further comprising benzyl alcohol having a peroxide content of less than about 4 ppm. 26. The pharmaceutical composition according to any one of the above 1 to 25, wherein the pH of the composition is approximately 6.5 to approximately 7.5. 27. The pharmaceutical composition according to any one of 1 to 26 above, wherein the pH of the composition is approximately 6.7 to approximately 7.3. 28. The pharmaceutical composition according to any one of 1 to 27 above, wherein the composition has a pH of approximately 7. 29. The pharmaceutical composition according to item 1 above, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is about 5 to about 30 mg / mL, the concentration of the phosphate buffer is about 5 mM, NaCl is about 2.93 mg / mL, phenol is about 5.5 mg / mL, and glycerin is about 12 mg / mL. 30. The pharmaceutical composition according to item 1 above, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is about 5 to about 30 mg / mL, the concentration of phosphate buffer is about 5 mM, NaCl is about 2.93 mg / mL, phenol is about 2 mg / mL, glycerin is about 8 mg / mL, and the composition further comprises about 9 mg / mL of benzyl alcohol. 31. The pharmaceutically acceptable composition described in item 1 above, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is about 4.17 mg / mL to about 25 mg / mL, the concentration of phosphate buffer is about 5 mM, the concentration of NaCl is about 30 mM, and the composition contains glycerin and phenol. 32. The pharmaceutical composition according to 31, wherein the concentration of glycerin is approximately 8 mg / mL. 33. The pharmaceutical composition according to 31 or 32 above, wherein the concentration of the phenol is approximately 2 mg / mL to approximately 5.5 mg / mL. 34. A pharmaceutical composition according to any one of the above 31 to 33, wherein the concentration of the phenol is approximately 5.5 mg / mL. 35. A pharmaceutical composition according to any one of the above 31 to 33, wherein the concentration of the phenol is approximately 2 mg / mL. 36. The pharmaceutical composition according to any one of the above 31 to 35, wherein the composition further comprises benzyl alcohol. 37. The pharmaceutical composition according to any one of 31 to 36 above, wherein the composition further comprises about 9 mg / mL of benzyl alcohol. 38. The pharmaceutical composition according to any one of claims 1 to 37 above, wherein the composition is stable for at least 3 months at a temperature of 2 to 8 degrees Celsius. 39. The pharmaceutical composition according to any one of claims 1 to 38 above, wherein the composition is stable for at least 6 months at a temperature of 2 to 8 degrees Celsius. 40. The pharmaceutical composition according to any one of claims 1 to 39 above, wherein the composition is stable for at least 24 months at a temperature of 2 to 8 degrees Celsius. 41. The pharmaceutical composition according to any one of claims 1 to 40 above, wherein the composition is stable at use for at least 30 days at 30 degrees Celsius. 42. The pharmaceutical composition according to any one of items 1 to 41 above, wherein the composition is stable as measured using high molecular weight species. 43. The pharmaceutical composition according to any one of items 1 to 42 above, wherein the composition is provided in a multi-use injection device. 44. The pharmaceutical composition according to any one of items 1 to 42 above, wherein the composition is administered using a multi-use injection device. 45. A method for treating type 2 diabetes in a person requiring treatment for type 2 diabetes, comprising administering an effective amount of any of the compositions described in 1 to 44 above. 46. ​​The method for treating type 2 diabetes as described in 45 above, wherein the dose is administered once a week. 47. A method for improving long-term weight management in a person requiring improvement in long-term weight management, comprising administering an effective amount of any of the compositions described in 1 to 44 above. 48. The method according to 47 above, wherein the person requiring improvement in long-term weight management is obese. 49. A pharmaceutical composition according to any one of items 1 to 44 above, for use in the treatment of type 2 diabetes. 50. A pharmaceutical composition according to any one of items 1 to 44 above, for use in improving long-term weight management. 51. A pharmaceutical composition according to any one of items 1 to 44 above, for use in the treatment of obesity.

Claims

1. A pharmaceutical composition comprising tilzepatide or a pharmaceutically acceptable salt thereof, NaCl, glycerin, phenol, and phosphate buffer, wherein the concentration of NaCl is approximately 3 mg / mL or less.

2. The concentration of the aforementioned tilzepatide or a pharmaceutically acceptable salt thereof is (a) Approximately 2 to approximately 50 mg / mL, (b) Selected from the group consisting of approximately 5, approximately 10, approximately 15, approximately 20, approximately 25, approximately 30, approximately 40, and approximately 50 mg / mL, (c) Selected from the group consisting of approximately 10, approximately 20, and approximately 30 mg / mL, (d) Approximately 4.2 to approximately 41.8 mg / mL, (e) Selected from the group consisting of approximately 4.17, approximately 8.33, approximately 12.5, approximately 16.67, approximately 20.83, approximately 25, approximately 33.33, and approximately 41.8 mg / mL, or (f) The pharmaceutical composition according to claim 1, selected from the group consisting of approximately 4.17, approximately 8.33, approximately 12.50, approximately 16.67, approximately 20.83, and approximately 25 mg / mL.

3. The pharmaceutical composition according to claim 1, wherein the unit dose of tilzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 5, about 7.5, about 10, about 12.5, about 15, about 20, and about 25 mg, and is in the form of a unit dose.

4. The pharmaceutical composition according to claim 1, wherein the administered dose volume is approximately 0.5 mL or approximately 0.6 mL.

5. The pharmaceutical composition according to claim 1, wherein the concentration of the phosphate buffer is about 5 mM or about 1.34 mg / mL.

6. The concentration of NaCl is (a) about 30mM to about 50mM, (b) Approximately 30 mM, (c) The pharmaceutical composition according to claim 1, wherein the concentration is approximately 1.75 mg / mL.

7. The pharmaceutical composition according to claim 1, wherein the concentration of glycerin is about 8 mg / mL to about 12 mg / mL or about 8 mg / mL.

8. The concentration of the aforementioned phenol is (a) about 1.5 mg / mL to about 6 mg / mL, (b) Approximately 2 mg / mL to approximately 5.5 mg / mL, (c) The pharmaceutical composition according to claim 1, wherein the concentration is approximately 5.5 mg / mL.

9. The pharmaceutical composition according to claim 1, wherein the composition further comprises benzyl alcohol.

10. The pharmaceutical composition according to claim 9, wherein the composition further comprises about 9 mg / mL of benzyl alcohol, benzyl alcohol of a lower peroxide grade, and / or the benzyl alcohol has less than 4 ppm of peroxide.

11. The pharmaceutical composition according to claim 1, wherein the pH of the composition is about 6.5 to about 7.5, about 6.7 to about 7.3, or about 7.

12. The pharmaceutical composition according to claim 1, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is about 5 to about 30 mg / mL, the concentration of the phosphate buffer is about 5 mM, the concentration of NaCl is about 2.93 mg / mL, the concentration of phenol is about 5.5 mg / mL, and the concentration of glycerin is about 12 mg / mL.

13. The pharmaceutical composition according to claim 1, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is about 5 to about 30 mg / mL, the concentration of phosphate buffer is about 5 mM, NaCl is about 2.93 mg / mL, phenol is about 2 mg / mL, glycerin is about 8 mg / mL, and the composition further comprises about 9 mg / mL of benzyl alcohol.

14. The pharmaceutical composition according to claim 1, wherein the concentration of tilzepatide or a pharmaceutically acceptable salt thereof is about 4.17 mg / mL to about 25 mg / mL, the concentration of phosphate buffer is about 5 mM, and the concentration of NaCl is about 30 mM.

15. The pharmaceutical composition according to claim 1, wherein the composition is provided or administered by a multi-use injection device.

16. A pharmaceutical composition according to any one of claims 1 to 15 for treating type 2 diabetes in a person requiring treatment for type 2 diabetes.

17. The pharmaceutical composition according to claim 16, wherein the dose is administered once a week.

18. A pharmaceutical composition according to any one of claims 1 to 15 for improving long-term weight management in humans who require improvement in long-term weight management.

19. The pharmaceutical composition according to claim 18, wherein the person requiring improvement in long-term weight management is obese.

20. A pharmaceutical composition according to any one of claims 1 to 15 for use in the treatment of obesity.

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