Preserved GIP / GLP agonist compositions

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 provides a preserved pharmaceutical GIP / GLP1 dual agonist peptide composition for subcutaneous injection. The composition contains an antimicrobial preservative and excipients to control undesired oligomerization and provide desirable stability. The composition contains tirzepatide, NaCl, glycerin, phenol, benzyl alcohol, and a phosphate buffer. The composition provides commercially acceptable shelf-life stability, in-use stability, and pharmaceutically desirable control of peptide oligomerization. [Background technology]

[0002] Diabetes is a chronic disease characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. In type 2 diabetes mellitus ("T2D"), the combined effects of impaired insulin secretion 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 FDA approval in May 2022, tirzepatide was marketed in the United States under the trade name Mounjaro™. Tirzepatide is useful for the treatment of obesity. Pharmaceutically acceptable multi-use compositions are desirable to enable alternative device and delivery options. Compositions suitable for multi-use delivery generally require an antimicrobial agent to preserve the composition during multiple uses. Benzyl alcohol and phenol are preservatives that can be used in multi-use formulations. However, preservatives have been reported to interact with biologics. Interactions between biologics and preservatives can lead to oligomerization, cloudiness, instability, and other undesirable effects. There is a need for stable, pharmaceutically acceptable, preserved incretin formulations.

[0003] U.S. Patent No. 9,474,780 generally describes compositions containing a GIP / GLP1 agonist administered parenterally. U.S. Patent No. 9,474,780 describes and claims tirzepatide. U.S. Patent No. 11,357,820 describes and claims compositions for pharmaceutically desirable single-use presentations, such as in single-use pens. U.S. Patent No. 11,357,820 discloses preserved formulations. However, the present applicants have discovered that tirzepatide undergoes self-association or oligomerization when stored in the presence of 4 mg / mL or more of NaCl using typical pharmaceutical preservatives. Self-association or oligomerization of tirzepatide can affect the stability, shelf life, and properties of the peptide. A preserved composition of tirzepatide that provides acceptable stability, shelf life, and pharmaceutically desirable control of peptide oligomerization is desired. [Brief explanation of the drawings]

[0004] [Figure 1] 1 is static light scattering of tirzepatide in a solution containing 140 mM NaCl at pH 7.0. [Figure 2] 1 is static light scattering of tirzepatide in a solution containing 140 mM NaCl and 5 mg / mL phenol at pH 7.0, and tirzepatide in a solution containing 140 mM NaCl at pH 7.0. [Figure 3] Static light scattering of tirzepatide in 200 mM NaCl, 140 mM NaCl, 85 mM NaCl, 30 mM NaCl, phenol with 0 mM NaCl, glycerin with 0 mM NaCl, and 0 mM NaCl. [Figure 4] Static light scattering of tirzepatide in 30 mM NaCl and 8 mg / mL phenol, 30 mM NaCl and 5 mg / mL phenol, 30 mM NaCl, 8 mg / mL phenol with 0 mM NaCl, and 5 mg / mL phenol with 0 mM NaCl. [Figure 5]Static light scattering of tirzepatide in 30 mM NaCl with 15 mg / mL benzyl alcohol, 30 mM NaCl with 9 mg / mL benzyl alcohol, 30 mM NaCl, 15 mg / mL benzyl alcohol with 0 mM NaCl, and 9 mg / mL benzyl alcohol with 0 mM NaCl. [Figure 6] Static light scattering of tirzepatide with 30 mM NaCl, 9 mg / mL benzyl alcohol, and 2 mg / mL phenol, 30 mM NaCl, and 9 mg / mL benzyl alcohol with 2 mg / mL phenol and 0 mM NaCl. [Figure 7] Ligand observation NMR of preservatives. Upper left: 1.8 mg / mL benzyl alcohol, upper right: 1.8 mg / mL benzyl alcohol and 1 mg / mL tirzepatide, lower left: 1.5 mg / mL phenol, lower right: 1.5 mg / mL phenol and 1.0 mg / mL tirzepatide. [Figure 8] The 1H-13C HSQC spectrum of tirzepatide (black) is overlaid with that of tirzepatide with benzyl alcohol. No significant differences are observed between the spectra. [Figure 9] The 1H-13C HSQC spectrum of tirzepatide (black) is overlaid with that of tirzepatide with phenol. Significant differences between the spectra are observed, indicating the interaction of phenol with tirzepatide. DETAILED DESCRIPTION OF THE INVENTION

[0005] Applicants have discovered that NaCl concentration is an important aspect involved in tirzepatide self-association.

[0006] In one embodiment, the oligomerization state of tirzepatide is considered equivalent to that of Mounjaro™ substrate according to US regulatory standards. In one embodiment, the preserved tirzepatide has a reduced risk of fibril formation.

[0007] The compositions herein seek to meet these needs by providing a pharmaceutically acceptable composition comprising tirzepatide or a pharmaceutically acceptable salt thereof, NaCl, glycerin, phenol benzyl alcohol, and phosphate buffer, wherein the NaCl concentration is about 3 mg / mL or less.

[0008] In one embodiment, the concentration of NaCl is about 1.5 mg / mL to about 3 mg / mL. In one embodiment, the concentration of NaCl is about 25 mM to about 50 mM. In one embodiment, the concentration of NaCl is about 30 mM. In one embodiment, the concentration of NaCl is about 1.75 mg / mL. In one embodiment, NaCl is a tonicity agent. In one embodiment, NaCl and glycerin function as tonicity agents. In one embodiment, the composition has a glycerin concentration of about 8 mg / mL to about 12 mg / mL. In one embodiment, the concentration of NaCl is about 1.75 mg / mL and the concentration of glycerin is about 8 mg / mL. In one embodiment, the concentration of NaCl is about 50 mM and the concentration of glycerin is about 8 mg / mL. In one embodiment, the concentration of NaCl is about 30 mM and the concentration of glycerin is about 8 mg / mL. In one embodiment, the concentration of NaCl is about 50 mM and the concentration of glycerin is about 12 mg / mL. In one embodiment, the concentration of phenol is from 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 includes phenol and benzyl alcohol. In one embodiment, the preservative includes phenol and about 9 mg / mL benzyl alcohol. In one embodiment, the preservative is about 2 mg / mL phenol and about 9 mg / mL 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 about 0.67 mg / mL to about 2.0 mg / mL. In one embodiment, the concentration of the phosphate buffer is about 1.34 mg / mL. In one embodiment, the phosphate buffer is about 5 mM.

[0010] In one embodiment, the concentration of tirzepatide is about 2.09 mg / mL to about 41.67 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is about 4.17 mg / mL to about 25.0 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is about 4.17 mg / mL to about 33.4 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is about 4.17 mg / mL to about 41.67 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is about 10 mg / mL to about 30 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is about 5 mg / mL to about 50.0 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is about 2.5 mg / mL to about 30 mg / mL. In one embodiment, about 0.6 mL is delivered per dose administration. In one embodiment, about 0.5 mL is delivered per dose administration.

[0011] The concentration of tirzepatide or its pharmaceutically acceptable salt may be adjusted to deliver the desired dose per injection. For example, when a volume of about 0.6 mL is administered per dose, the concentration of tirzepatide or its pharmaceutically acceptable salt will be adjusted to ensure accurate delivery of the desired dose of tirzepatide or its pharmaceutically acceptable salt. In one embodiment, the dose of tirzepatide or its pharmaceutically acceptable salt 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 tirzepatide or its pharmaceutically acceptable salt 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 tirzepatide 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 tirzepatide 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 tirzepatide or a pharmaceutically acceptable salt thereof 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 tirzepatide or a pharmaceutically acceptable salt thereof 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, the tirzepatide or pharmaceutically acceptable salt thereof composition is administered about once a week. In one embodiment, the tirzepatide or pharmaceutically acceptable salt thereof composition dose is administered once every seven days.

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

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

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

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

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

[0019] According to another aspect of the present invention, there is provided an article of manufacture comprising one of the above compositions.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 pre-filled syringe.

[0020] The Mounjaro™ drug product is formulated as a single-use, once-weekly, unpreserved subcutaneous injection. Tirzepatide formulated as Mounjaro™ is approved for use in the treatment of type 2 diabetes and is also being investigated for other indications, such as obesity. It is desirable to develop a multi-use, preserved formulation of tirzepatide or a pharmaceutically acceptable salt thereof so that treatment can reach and serve more patients. A preserved formulation would be 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 may be inadvertently introduced into the product. Such compounds typically contain aromatic rings in their chemical structure, which allow them to interact with other molecules. For example, preservatives with aromatic ring structures have been reported to induce instability in protein formulations through mechanisms including unfolding of larger proteins with tertiary structure, aggregation of polysorbates in drug product compositions, etc.

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

[0023] As shown in the figures, phenol, benzyl alcohol, and NaCl interact with tirzepatide to varying degrees. Although benzyl alcohol has been reported to interact with peptides, Figures 7, 8, and 9 show no significant interaction with tirzepatide. Furthermore, sufficient preservatives and agents must be included to provide stability and safety during multiple doses in a single patient. Figures 1, 2, 3, 4, 5, and 6 demonstrate the unpredictable oligomerization of tirzepatide with various excipients and conditions.

[0024] As used herein, "tirzepatide" refers to the GIP / GLP1 dual agonist peptide described in U.S. Pat. No. 9,474,780, described by CAS Registry Number 2023788-19-2, and as the active pharmaceutical ingredient in the USFDA-approved product Mounjaro™.

[0025] Tirzepatide is described in Example 1 of U.S. Pat. No. 9,474,780 and has the following sequence: YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS X1 is Aib, X2 is Aib, K at position 20 is chemically modified via 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 salts" are well known to those skilled in the art. In one embodiment, the pharmaceutically acceptable salt is tirzepatide trifluoroacetate salt. The composition is sterile when initially prepared.

[0027] The pH of the tirzepatide or pharmaceutically acceptable salt thereof compositions herein is typically about 6.5 to 7.5 and can be adjusted using physiologically appropriate acids and bases as needed to achieve the desired pH. In one embodiment, the target pH is 6.7 to 7.3. In one 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 dissolution of tirzepatide or a pharmaceutically acceptable salt thereof in a buffer solution.In one embodiment, HCl is added to adjust the pH of the composition in which tirzepatide is dissolved to a desired pH range.

[0029] The composition of the present invention is typically administered subcutaneously.The composition is typically administered using a pre-filled disposable pen, a reusable pen with a cartridge, or an automatic pen injector.The composition can also be administered using a multi-use vial or using a pump device.

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

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

[0032] As used herein, the term "about" refers to the range of variability allowed according to applicable regulatory guidelines. In one embodiment, "about" means ±10% of the stated value. In one embodiment, "about" means ±5% of the stated value. In one embodiment, "about" means ±2% of the stated value.

[0033] As used herein, low peroxide benzyl alcohol refers to 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 less than about 4 ppm peroxide. In one embodiment, the low peroxide grade benzyl alcohol is used within one week of first opening the benzyl alcohol container. In one embodiment, the low peroxide grade benzyl alcohol is used within one day of first opening the benzyl alcohol container. In one embodiment, the low peroxide grade benzyl alcohol is stored under refrigeration and used within six months of first opening the container. In one embodiment, the low peroxide grade benzyl alcohol is stored with a nitrogen overlay and used within six months of first opening. In one embodiment, the low peroxide grade benzyl alcohol is stored with a nitrogen overlay and used within one month.

[0034] Those skilled in the art will understand that the structures encompass natural isotopic forms and other stable isotopes, for example and without limitation, hydrogen may be deuterated.

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

[0036] Static light scattering and solution NMR techniques were used to study the interactions between tirzepatide and preservatives.

[0037] Assay: Light scattering of tirzepatide samples Tirzepatide formulations were prepared for light scattering measurements with the compositions detailed in Table 1.a and Table 1.b. 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. A corresponding drug product placebo was used as a scattering blank. A single 15- or 30-second acquisition was collected for each sample at a scattering angle of 90 degrees using dynamic light scattering (DLS) mode. The resulting DLS autocorrelation functions were analyzed using intensity-weighted normalized size distributions and shown to be unimodal before proceeding. The time-averaged scattering intensity values ​​of the sample, placebo, and toluene were used to calculate the excess Rayleigh ratio.

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

[0040] [Table 1]

[0041] [Table 2]

[0042] Thioflavin T (ThT) fluorescence assay of tirzepatide 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 solution was added to each of three wells in a black, clear-bottom 96-well plate, followed by 10 mL of 20 mM ThT stock solution. The plate was sealed, and kinetic fluorescence measurements were performed for 24 hours at an excitation wavelength of 450 nm and an emission wavelength of 480 nm. The temperature was set to 37°C, and measurements were taken 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] Effect of preservatives and NaCl on the self-association of tirzepatide. The conformation of tirzepatide was characterized using far-ultraviolet circular dichroism (CD) spectroscopy and Fourier-transform infrared spectroscopy (FTIR). In Mounjaro™ matrix (5 mM phosphate buffer, 140 mM NaCl, pH 7.0), tirzepatide has a predominantly α-helical structure. Light scattering indicates that the self-association of tirzepatide exists as a monomer-trimer-hexamer equilibrium between the 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 effect of preservatives, m-cresol, phenol, or benzyl alcohol were added to the standard Mounjaro™ composition at selected concentrations. These concentrations of preservatives were chosen so that the formulations would meet the pass 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 previously.

[0046] In the presence of both 140 mM NaCl and preservatives, the WAMW of tirzepatide was determined to be greater than 70 kDa, consistent with 14-mer to 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] Fibrillation tendency of tirzepatide in the presence of preservatives Fibrils are large macromolecular self-assemblies of proteins or peptides with specific characteristics. Most notably, individual peptide backbones are converted into a beta-sheet-rich conformation. Undesirable physical, chemical, and therapeutic risks can result. Experimentally, fibril formation can be observed visually as increased turbidity, precipitation, or gelation, and can also be studied using a number of techniques ranging from size-exclusion chromatography, analytical ultracentrifugation, light scattering, and microscopic imaging. These methods can be complemented by spectroscopic techniques, which can confirm the conformational change to beta-sheets and the formation of larger aggregates at the molecular level.

[0049] In this study, we used fluorescence spectroscopy to evaluate the risk of fibrillation of tirzepatide in the presence of preservatives using thioflavin T as a binding dye. ThT is a strong fluorescent marker of fibrils. Upon selective binding to fibril deposits, a dramatic increase in the fluorescent signal indicates the presence or increase of fibrils. This method has been applied to various peptides to study their fibrillation propensity. Tirzepatide was formulated in matrices with different concentrations, tonicity agents, and preservatives (Table 2). A positive control (oxyntomodulin, 2 mg / mL, pH 6.5), which is known to fibrillate, was included in the measurements. The increase in ThT fluorescent signal was clearly visible in the positive control. However, none of the tirzepatide samples showed a statistically significant increase in signal, indicating a very low risk of fibrillation.

[0050] Size Exclusion Chromatography (SEC) Shelf Life and In-Use Stability Testing The procedure is an isocratic 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 x 300 mm, or equivalent. The mobile phase is 50 / 50 / 0.05% acetonitrile / water / TFA, with a flow rate of 0.5 mL / min. The column temperature is 25°C. High molecular weight species are reported as peak area percent of total area. The procedure demonstrates stability as measured by its ability to resolve known impurities from tirzepatide. This study compares alternative compositions to composition embodiments herein.

[0051] RP-HPLC shelf life and in-use stability testing The procedure is a gradient reverse-phase HPLC method employing a C18 reverse-phase column of 2.6 μm, 4.6 × 250 mm, or equivalent dimensions, 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), with the gradient profile shown in Table 4.

[0052] [Table 5]

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

[0054] Stability testing The primary stability study included six batches of multi-dose tirzepatide injection drug product in a prefilled pen (PFP) configuration. The drug product from each of these batches was filled into 3 mL clear glass cartridges, sealed on one side with an elastomeric plunger and on the other side with a disk seal consisting of a two-layer elastomeric disk and an aluminum shell.

[0055] Samples from each batch were stable for at least 24 months at long-term storage conditions of 5°C (2°C to 8°C) and for 6 months at accelerated conditions of 25°C / 60% relative humidity (RH). In addition, samples were stored at stress-stabilizing conditions of 30°C / 65% RH. The stability protocol for the drug product 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, an in-use stability study was conducted to demonstrate acceptable stability over the period that the multi-dose drug product was available to patients unrefrigerated. For this study, two primary stability batches were selected according to a concentration bracketing approach, one at the low end (2.5 mg / 0.6 mL) and one at the high end (15 mg / 0.6 mL) of the intended drug product concentration range. Testing was performed on prefilled pen batches with concentrations of 2.5 mg / 0.6 mL and 15 mg / 0.6 mL after approximately 2-3 months of storage at 2-8°C. 1 For the point-of-use study, both batches were stored at in-use conditions of 30°C and tested over a 30-day period, as shown in Table 6 below. At four time points within the point-of-use study (days 0, 14, 22, and 30), samples were removed from 30°C storage and the needle was secured to the prefilled pen. After priming, the drug product solution was expelled from the prefilled pen, after which the needle was removed and the sample was either tested or returned to 30°C for expulsion and testing at a later time point. In this way, samples that reached the end of the point-of-use study were exposed to conditions (e.g., 30°C) and manipulations (e.g., securing the needle, expelling the drug product solution, removing the needle) that simulated intended use by patients. The protocol for multi-dose product stability is shown in Table 6.

[0059] [Table 8] a TO is the date the samples were removed from long-term storage conditions at 5°C and tested, ie, 30 days prior to the end of the point-of-use study.

[0060] These tests include drug product attributes that are susceptible to change during storage and may affect quality, safety, and / or efficacy. Color, clarity, and pH were tested to ensure that, similar to single-dose products, no significant changes were observed to stability and that they are not shelf-life limiting attributes. Antimicrobial effectiveness testing (AET) was performed on samples exposed to in-use conditions. AET testing in combination with preservative content testing indicates the microbial safety of the drug product during its in-use period.

[0061] RP-HPLC purity Purity was evaluated at long-term (5°C), accelerated (25°C / 60% RH), and stress stability (30°C / 65% RH) storage conditions. At accelerated conditions, batches show a slight decrease in purity. Based on available data, all batches met end-of-shelf-life acceptance criteria at long-term and accelerated storage conditions.

[0062] Total Impurities Total impurities were evaluated at long-term (5°C), accelerated (25°C / 60% RH), and stress stability (30°C / 65% RH) storage conditions. At accelerated conditions, batches show a slight increase in total impurities. Based on available data, all batches met end-of-shelf-life acceptance criteria at long-term and accelerated storage conditions.

[0063] High molecular weight species High molecular weight species (HMWS) were evaluated at long-term (5°C), accelerated (25°C / 60% RH), and stress stability (30°C / 65% RH) storage conditions. At accelerated conditions, batches show a slight increase in HMWS. Based on available data, all batches met end-of-shelf acceptance criteria for HMWS at long-term and accelerated storage conditions.

[0064] benzyl alcohol Benzyl alcohol content was evaluated at long-term (5°C) and accelerated (25°C / 60% RH) storage conditions. At accelerated conditions, the data show no clear trends for benzyl alcohol stability. Based on the available data, all batches met end-of-shelf acceptance criteria for benzyl alcohol at long-term and accelerated storage conditions.

[0065] phenol Phenol content was evaluated at long-term (5°C) and accelerated (25°C / 60% RH) storage conditions. At accelerated conditions, the data show no clear trends for phenol stability. Based on the available data, all batches met the end-of-shelf-life acceptance criteria for phenol at long-term and accelerated storage conditions.

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

[0067] transparency An instrumental (turbidimetric) method was used to assess clarity at long-term (5°C) and accelerated (25°C / 60%RH) storage conditions. No trends or significant variability beyond method variability was observed.

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

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

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

[0071] Injection (glide) force A compression test was used to evaluate injection (glide) force at long-term (5°C) and accelerated (25°C / 60% RH) storage conditions. No trends or significant variability other than method variability was observed at either condition. All batches in the study met the acceptance criteria for injection force at both long-term and accelerated conditions. Glide force is not considered to be a shelf-life limiting parameter.

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

[0073] Antimicrobial Efficacy Testing (AET) A signature study, Antimicrobial Effectiveness Testing (AET), was performed on samples from point-of-use samples from the 22-day and 30-day time points. A time-of-use study to verify the effectiveness of the antimicrobial preservative. Testing was performed according to USP on point-of-use samples from the 22-day and 30-day time points. These results confirm that the multi-dose product meets the official AET criteria after storage at in-use conditions throughout the in-use period and at the end of the in-use period after storage at accelerated stability conditions for 6 months. The results confirm that the multi-dose tirzepatide injection drug product has a shelf life of 24 months when stored at long-term storage conditions of approximately 5°C (2°C to 8°C) with a 30-day use period up to approximately 30°C. The in-use stability results 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. Average values ​​are reported for reference only.

[0076] The storage stability results for 0 and 3 months at storage temperatures of 2-8C are shown in Table 8.

[0077] [Table 11] * Pass = clear, colorless solution, no visible particles. *** Cartridge batch D589770 will undergo CCI testing.

[0078] NMR studies and self-association Tirzepatide formulations with the compositions detailed in Tables 9, 10, and 11 were prepared for light scattering measurements and NMR.

[0079] [Table 12]

[0080] [Table 13]

[0081] [Table 14] [Example]

[0082] Exemplary Formulations for Preserved Tirzepatide An example of a preserved formulation is shown in Table 12. In addition to 50 mM NaCl, an appropriate amount of glycerin is added as a secondary tonicity agent. The formulation is tested to verify the antimicrobial efficacy of the formulation, as well as the desired physical and chemical stability of the drug product.

[0083] [Table 15]

[0084] The concentration of NaCl plays an important role in determining the association state of tirzepatide, i.e., a higher WAMW with increasing NaCl concentration. The self-association of the peptide is amplified when a preservative is added. At 50 mM NaCl in the formulations of Examples 1 and 2, the oligomerization state of tirzepatide is considered to be equivalent to that in the Mounjaro™ matrix. These results confirm that there is a low risk of tirzepatide forming fibrils in the stored formulations of 50 mM NaCl.

[0085] A synergistic effect was found at 50 mM NaCl in the formulations of Examples 1 and 2. At 50 mM NaCl, Examples 1 and 2, the oligomerization state of tirzepatide is considered to be equivalent to that in the Mounjaro™ matrix at 30 mg / mL tirzepatide.

[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 tirzepatide in the stored formulation is adjusted based on a 0.6 mL injection volume. The dose range of 2.5 mg to 15 mg remains unchanged. The concentration is dependent on the injection volume, as shown below.

[0088] Examples of tirzepatide concentrations using the formulations herein are shown in Table 14.

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

[0091] array Sequence number 1: Tirzepatide YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS (X1 is Aib, X2 is Aib, and K at position 20 is an amino group linked to 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 a -CO2H bond, The C-terminal amino acid is amidated as a C-terminal primary amide).

[0092] SEQ ID NO: 2 YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS X1 is Aib, X2 is Aib, K at position 20 is chemically modified by conjugation of a C16-C20 fatty acid or derivative thereof 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] SEQ ID NO: 3 YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO: 3) (X1 is Aib, X2 is Aib, and K at position 20 is chemically modified by conjugation to the epsilon-amino group of the K side chain of a fatty acid selected from the group consisting of:

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

[0095] SEQ ID NO:4

[0096] [ka]

Claims

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

2. 2. The pharmaceutical composition according to claim 1, wherein the concentration of the tirzepatide or a pharmaceutically acceptable salt thereof is about 2 to about 50 mg / mL.

3. 3. The pharmaceutical composition according to claim 1, wherein the concentration of tirzepatide 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 claims 1 to 3, wherein the concentration of the tirzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of about 10, about 20, and about 30 mg / mL.

5. 3. The pharmaceutical composition according to claim 2, wherein the concentration of the tirzepatide or a pharmaceutically acceptable salt thereof is about 4.2 to about 41.8 mg / mL.

6. 6. The pharmaceutical composition of claim 5, wherein the concentration of tirzepatide 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. 7. The pharmaceutical composition according to claim 5 or 6, wherein the concentration of tirzepatide 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. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the unit dose of tirzepatide or a pharmaceutically acceptable salt thereof is in a unit dose format selected from the group consisting of about 5, about 7.5, about 10, about 12.5, about 15, about 20, and about 25 mg.

9. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the unit dose of tirzepatide and its pharmaceutically acceptable salts is in a unit dose format selected from the group consisting of 5, 7.5, 10, 12.5, and 15 mg.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the administered dose volume is about 0.5 mL.

11. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the administered dose volume is about 0.6 mL.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the concentration of the phosphate buffer is about 5 mM.

13. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the concentration of the phosphate buffer is about 1.34 mg / mL.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the concentration of NaCl is from about 30 mM to about 50 mM.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the concentration of NaCl is about 30 mM.

16. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein the concentration of NaCl is about 1.75 mg / mL.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein the concentration of glycerin is from about 8 mg / mL to about 12 mg / mL.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein the concentration of glycerin is about 8 mg / mL.

19. 19. The pharmaceutical composition of any one of claims 1 to 18, wherein the concentration of the phenol is from about 1.5 mg / mL to about 6 mg / mL.

20. 20. The pharmaceutical composition of any one of claims 1 to 19, wherein the concentration of the phenol is from about 2 mg / mL to about 5.5 mg / mL.

21. 21. The pharmaceutical composition of any one of claims 1 to 20, wherein the concentration of the phenol is about 5.5 mg / mL.

22. 22. The pharmaceutical composition of any one of claims 1 to 21, wherein the composition further comprises benzyl alcohol.

23. 21. The pharmaceutical composition of any one of claims 1 to 20, wherein the composition further comprises about 9 mg / mL of benzyl alcohol.

24. 24. The pharmaceutical composition of any one of claims 1 to 23, wherein the composition further comprises benzyl alcohol with a low peroxide rating.

25. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein the composition further comprises benzyl alcohol having less than about 4 ppm peroxide.

26. 26. The pharmaceutical composition of any one of claims 1 to 25, wherein the pH of the composition is from about 6.5 to about 7.

5.

27. 27. The pharmaceutical composition of any one of claims 1 to 26, wherein the pH of the composition is from about 6.7 to about 7.

3.

28. 28. The pharmaceutical composition of any one of claims 1 to 27, wherein the composition has a pH of about 7.

29. 2. The pharmaceutical composition according to claim 1, wherein the concentration of tirzepatide 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.

30. 2. The pharmaceutical composition of claim 1, wherein the concentration of tirzepatide 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, and glycerin is about 8 mg / mL, and the composition further comprises about 9 mg / mL of benzyl alcohol.

31. 2. The pharmaceutical composition according to claim 1, wherein the concentration of tirzepatide 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, glycerin, and phenol.

32. 32. The pharmaceutical composition of claim 31, wherein the concentration of glycerin is about 8 mg / mL.

33. 33. The pharmaceutical composition of claim 31 or 32, wherein the concentration of the phenol is from about 2 mg / mL to about 5.5 mg / mL.

34. 34. The pharmaceutical composition of any one of claims 31 to 33, wherein the concentration of the phenol is about 5.5 mg / mL.

35. 34. The pharmaceutical composition of any one of claims 31 to 33, wherein the concentration of the phenol is about 2 mg / mL.

36. 36. The pharmaceutical composition of any one of claims 31 to 35, wherein the composition further comprises benzyl alcohol.

37. 37. The pharmaceutical composition of any one of claims 31-36, wherein the composition further comprises about 9 mg / mL of benzyl alcohol.

38. 38. The pharmaceutical composition of any one of claims 1 to 37, wherein the composition is stable at a temperature between 2 and 8 degrees Celsius for at least 3 months.

39. 39. The pharmaceutical composition of any one of claims 1 to 38, wherein the composition is stable at a temperature between 2 and 8 degrees Celsius for at least 6 months.

40. 40. The pharmaceutical composition of any one of claims 1 to 39, wherein the composition is stable at a temperature between 2 and 8 degrees Celsius for at least 24 months.

41. 41. The pharmaceutical composition of any one of claims 1 to 40, wherein the composition is stable upon use for at least 30 days at 30 degrees Celsius.

42. 42. The pharmaceutical composition of any one of claims 1 to 41, wherein the composition is stable as measured using high molecular weight species.

43. The pharmaceutical composition of any one of claims 1 to 42, wherein the composition is provided in a multi-use injection device.

44. 43. The pharmaceutical composition of any one of claims 1 to 42, wherein the composition is administered using a multi-use injection device.

45. 45. A method for treating type 2 diabetes in a human in need thereof, comprising administering an effective amount of a composition according to any one of claims 1 to 44.

46. 46. ​​The method for treating type 2 diabetes of claim 45, wherein the dose is administered once a week.

47. 45. A method for improving long term weight control in a human in need thereof, comprising administering an effective amount of a composition according to any one of claims 1 to 44.

48. 48. The method of claim 47, wherein the human in need of improved long-term weight management is obese.

49. A pharmaceutical composition according to any one of claims 1 to 44 for use in the treatment of type 2 diabetes.

50. A pharmaceutical composition according to any one of claims 1 to 44 for use in improving long-term weight management.

51. A pharmaceutical composition according to any one of claims 1 to 44 for use in the treatment of obesity.

Images