Preservative-containing GIP / GLP agonist compositions

Abstract

A preservative-containing composition of tilpotide comprising less than or equal to about 3 mg / mL NaCl; a phosphate buffer solution, phenol, benzyl alcohol and glycerol.

Description

[0001] The present invention relates to a preserved GIP / GLP1 dual agonist peptide pharmaceutical composition for subcutaneous injection. The composition comprises an antibacterial preservative and an excipient to control unwanted oligomerization and provide desired stability. The composition comprises tirzepatide, NaCl, glycerol, phenol, benzyl alcohol, and a phosphate buffer. The composition provides commercially acceptable shelf-life stability, in-use stability, and pharmaceutically desired peptide oligomerization control.

[0002] Diabetes is a chronic disease characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both. In type 2 diabetes (“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 for the treatment of diabetes. After obtaining FDA approval in May 2022, tirzepatide is sold in the United States under the brand name Mounjaro TM and is available for the treatment of obesity. There is a need for pharmaceutically acceptable multi-use compositions to enable alternative devices and delivery options. Compositions suitable for multi-use delivery typically require antibacterial agents to preserve the composition during multiple uses. Benzyl alcohol and phenol are preservatives that can be used in multi-use formulations; however, it has been reported that preservatives can interact with biologic agents. The interaction between biologic agents and preservatives can lead to oligomerization, cloudiness of the solution, instability, and other adverse reactions. Therefore, there is a need for a stable, pharmaceutically acceptable preservative-containing incretin formulation.

[0003] US9474780 generally describes compositions containing GIP / GLP1 agonists, administered by a parenteral route. US9474780 describes and claims tirzepatide. US11357820 describes and claims pharmaceutical compositions for pharmaceutically desired single-use presentations (e.g., single-use pens). US11357820 discloses a preservative-containing formulation; however, the applicant has found that when using typical pharmaceutical preservatives and storing in the presence of 4 mg / mL or higher concentration of NaCl, tirzepatide undergoes self-association or oligomerization. The self-association or oligomerization of tirzepatide can affect the stability, shelf-life, and properties of the peptide. Therefore, there is a desire for a preservative-containing tirzepatide composition that can provide acceptable stability, shelf-life, and pharmaceutically desired peptide oligomerization control. Brief Description of the Drawings

[0005] Figure 1. Static light scattering of tirzepatide in a solution containing 140 mM NaCl, pH 7.0.

[0006] Figure 2 . Static light scattering of tirzepatide in a solution containing 140 mM NaCl and 5 mg / mL phenol, pH 7.0, and static light scattering of tirzepatide in a solution containing 140 mM NaCl, pH 7.0.

[0007] Figure 3 . Static light scattering of tirzepatide in 200 mM NaCl; 140 mM NaCl; 85 mM NaCl; 30 mM NaCl; phenol containing 0 mM NaCl; glycerol containing 0 mM NaCl and 0 mM NaCl.

[0008] 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 containing 0 mM NaCl and 5 mg / mL phenol containing 0 mM NaCl.

[0009] Figure 5 . Static light scattering of tirzepatide in 30 mM NaCl containing 15 mg / mL benzyl alcohol; 30 mM NaCl containing 9 mg / mL benzyl alcohol; 30 mM NaCl; 15 mg / mL benzyl alcohol containing 0 mM NaCl and 9 mg / mL benzyl alcohol containing 0 mM NaCl.

[0010] Figure 6 . Static light scattering of tirzepatide in 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.

[0011] Figure 7 . Ligand-observed NMR of the preservative. In the upper left corner is 1.8 mg / mL benzyl alcohol; in the upper right corner is 1.8 mg / mL benzyl alcohol plus 1 mg / mL tirzepatide; in the lower left corner is 1.5 mg / mL phenol; in the lower right corner is 1.5 mg / mL phenol plus 1.0 mg / mL tirzepatide.

[0012] Figure 8 . 1 H- 13 1H- 1 H- 13 13CHSQC spectrum of tirzepatide (black) superimposed with the 1H-13CHSQC spectrum of tirzepatide with benzyl alcohol. No significant differences were observed between the spectra.

[0013] Figure 9 . The 1 H- 13 HSQC spectrum of tirzepatide (black) superimposed with that of tirzepatide containing phenol. Significant differences were observed between the spectra, indicating an interaction between phenol and tirzepatide. 1 H- 13 CHSQC spectrum.

[0014] The applicant has found that the NaCl concentration is an important aspect involved in the self-association of tirzepatide.

[0015] In one embodiment, a preservative-containing formulation is provided, wherein the oligomerization state of tirzepatide is considered matrix-equivalent to Mounjaro according to US regulatory standards. TM matrix equivalent.

[0016] In one embodiment, a preservative-containing tirzepatide formulation is provided, which has a lower risk of fibril formation.

[0017] The compositions herein seek to meet these needs by providing a pharmaceutically acceptable composition comprising tirzepatide or a pharmaceutically acceptable salt thereof; NaCl; glycerol; phenol; benzyl alcohol; and a phosphate buffer; wherein the NaCl concentration is less than or equal to about 3 mg / mL.

[0018] In one embodiment, the NaCl concentration is from about 1.5 mg / mL to about 3 mg / mL. In one embodiment, the NaCl concentration is from about 25 mM to about 50 mM. In one embodiment, the NaCl concentration is about 30 mM. In one embodiment, the NaCl concentration is about 1.75 mg / mL. In one embodiment, NaCl is a tonicity agent. In one embodiment, NaCl and glycerol are used as tonicity agents. In one embodiment, it is a composition wherein the glycerol concentration is from about 8 mg / mL to about 12 mg / mL. In one embodiment, the NaCl concentration is about 1.75 mg / mL and the glycerol concentration is about 8 mg / mL. In one embodiment, the NaCl concentration is about 50 mM and the glycerol concentration is about 8 mg / mL. In one embodiment, the NaCl concentration is about 30 mM and the glycerol concentration is about 8 mg / mL. In one embodiment, the NaCl concentration is about 50 mM and the glycerol concentration is about 12 mg / mL. In one embodiment, the phenol concentration is from about 2 mg / mL to about 5 mg / mL. In one embodiment, the phenol concentration is greater than about 5.5 mg / mL. In one embodiment, the phenol concentration is greater than about 5.5 mg / mL. In one embodiment, the preservative consists of phenol and benzyl alcohol. In one embodiment, the preservative comprises phenol and benzyl alcohol. In one embodiment, the preservative comprises 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 phenol concentration is less than about 6 mg / mL.

[0019] In one embodiment, the phosphate buffer is dibasic sodium phosphate. In one embodiment, the phosphate buffer concentration is from about 0.67 mg / mL to about 2.0 mg / mL. In one embodiment, the phosphate buffer concentration is about 1.34 mg / mL. In one embodiment, the phosphate buffer is about 5 mM.

[0020] In one embodiment, the concentration of tirzepatide is from 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 from 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 from 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 from 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 from about 10 mg / mL to about 30 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is from about 5 mg / mL to about 50.0 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is from about 2.5 mg / mL to about 30 mg / mL. In one embodiment, each dose administration delivers about 0.6 mL. In one embodiment, each dose administration delivers about 0.5 mL.

[0021] The concentration of tirzepatide or a pharmaceutically acceptable salt thereof can 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 a pharmaceutically acceptable salt thereof will be adjusted to ensure accurate delivery of the desired dose of tirzepatide or a pharmaceutically acceptable salt thereof. In one embodiment, the dose of tirzepatide or a pharmaceutically acceptable salt thereof is selected from 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg. In one embodiment, the dose of tirzepatide or a pharmaceutically acceptable salt thereof is selected from 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 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 10 mg and 15 mg. In one embodiment, the dose is selected from 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.

[0022] In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is from about 4.17 to about 25 mg / mL and the NaCl concentration is about 1.75 mg / mL. In one embodiment, the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is from about 2.09 mg / mL to about 25 mg / mL and the NaCl concentration is about 1.75 mg / mL.

[0023] In one embodiment, the composition of tirzepatide or a pharmaceutically acceptable salt thereof is administered approximately once a week. In one embodiment, the composition of tirzepatide or a pharmaceutically acceptable salt thereof is administered once every seven days.

[0024] In one embodiment, a method of treating diabetes is provided, which comprises administering to a person in need an effective dose of one of the above compositions.

[0025] In one embodiment, a method of treating obesity is provided, which comprises administering to a person in need an effective dose of one of the above compositions. In one embodiment, a method of providing therapeutic weight loss is provided, which comprises administering to a person in need an effective dose of one of the above compositions. In one embodiment, a method of improving long-term weight management is provided, which comprises administering to a person in need an effective dose of one of the above compositions. In one embodiment, a method of treating a condition mediated by GIP / GLP1 co-agonist activity is provided, which comprises administering to a person in need an effective dose of one of the above compositions.

[0026] In one embodiment, one of the above compositions is provided for use as a medicament.

[0027] In one embodiment, one of the above compositions is provided for treating diabetes. In one embodiment, one of the above compositions is provided for treating obesity.

[0028] In one embodiment, one of the above compositions is provided for providing therapeutic weight loss. In one embodiment, one of the above compositions is provided for providing non-therapeutic weight loss. In one embodiment, one of the above compositions is provided for improving long-term weight management.

[0029] According to another aspect of the invention, an article comprising one of the above compositions is provided. In certain embodiments, the article is a multi-use vial. In certain embodiments, the article is a multi-use cartridge. In certain embodiments, the article is a multi-use pen. In certain embodiments, the article is a pre-filled syringe.

[0030] Mounjaro TM The drug is formulated as a once-weekly, preservative-free, single-use subcutaneous injection. As Mounjaro TMTirzepatide formulated in a certain form has been approved for the treatment of type 2 diabetes, and other indications (such as obesity) are being explored. Therefore, it is expected to develop a multi-use formulation of tirzepatide or its pharmaceutically acceptable salts containing preservatives so that this therapy can benefit and help more patients. The formulation containing preservatives is expected to be used in prefilled cartridges, pens, or vials designed for multi-use.

[0031] Antimicrobial preservatives are added to the formulation to inhibit or kill microorganisms that may be inadvertently introduced into the product. Such compounds usually contain an aromatic ring in their chemical structure, enabling them to interact with other molecules. For example, it has been reported that preservatives with an aromatic ring structure can cause instability of protein formulations through mechanisms including the unfolding of larger proteins with tertiary structures and the aggregation of polysorbates in pharmaceutical product compositions.

[0032] In the single-use drug Mounjaro TM the composition is 5 mM phosphate buffer, 140 mM NaCl, pH = 7.0 of tirzepatide at 5 mg / mL to 30 mg / mL. Under these conditions, the peptide reversibly self-associates, presenting a monomer-trimer-hexamer equilibrium. The single-use drug Mounjaro TM The equilibrium provided by the composition may be related to the product stability and the properties of the peptide. It is expected to maintain a substantially similar monomer-trimer-hexamer peptide self-association equilibrium to ensure a consistent patient experience between the preservative-free and preservative-containing formulations.

[0033] As shown in the figure, phenol, benzyl alcohol, and NaCl have varying degrees of interaction with tirzepatide. Although benzyl alcohol has been reported to interact with the peptide, Figure 7 、 8 and 9 show that it has no significant interaction with tirzepatide. In addition, sufficient preservatives and agents must be added to ensure stability and safety in the case of multiple uses by a single patient. Figure 1 、 2 、3, 4, 5, and 6 show the unpredictable oligomerization of tirzepatide under various excipients and conditions.

[0034] As used herein, "tirzepatide" refers to the GIP / GLP1 dual agonist peptide as described in US 9,474,780 and by CAS registration number: 2023788-19-2, and as the active pharmaceutical ingredient in the US FDA-approved product Mounjaro TM tirzepatide is described in Example 1 of US 9474,780 and has the following sequence:

[0035] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0036] Wherein X1 is Aib; X2 is Aib; the K at position 20 is chemically modified by coupling (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γGlu)1-CO-(CH2)18-CO2H to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO:1).

[0037] As used herein, "pharmaceutically acceptable salts" are well known to those skilled in the art. In one embodiment, it is a pharmaceutically acceptable salt, namely teplizumab trifluoroacetate. These compositions are sterile upon first production.

[0038] The pH of teplizumab or its pharmaceutically acceptable salts described herein is typically from about 6.5 to 7.5 and can be adjusted using physiologically suitable acids and bases as needed to achieve the desired pH. In one embodiment, the pH target is between 6.7 and 7.3. In one embodiment, the pH target is about 7.

[0039] In one embodiment, a base is used to adjust the pH to facilitate its dissolution in a buffer solution. In one embodiment, it may be necessary to add an acid to the composition to adjust the pH to the desired pH range. In one embodiment, NaOH is used to facilitate the dissolution of teplizumab or its pharmaceutically acceptable salts in a buffer. In one embodiment, HCl is added to adjust the pH of the composition containing dissolved teplizumab to the desired pH range.

[0040] The compositions of the invention are typically administered subcutaneously. The compositions are typically administered using a prefilled disposable pen, a reusable pen with a cartridge, or an autoinjector pen. The compositions can be administered using a multi-use vial or a pump device.

[0041] 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 measured under controlled conditions at 25 degrees Celsius or about 25 degrees Celsius or at 40 degrees Celsius or about 40 degrees Celsius.

[0042] In one embodiment, the term "phenol" refers to liquefied, distilled phenol, wherein the phenol is about 90% phenol containing about 10% water.

[0043] As used herein, the term "about" refers to a variable range permitted according to applicable regulatory guidelines. In one embodiment, "about" means plus or minus 10% of the stated value. In one embodiment, "about" means plus or minus 5% of the stated value. In one embodiment, "about" means plus or minus 2% of the stated value.

[0044] As used herein, benzyl alcohol with low peroxide content refers to benzyl alcohol having a peroxide value of about < 5 and / or about <1 Japanese Pharmacopoeia (JP) value and / or peroxide of about <4 ppm. In one embodiment, benzyl alcohol with a low peroxide value is used within one week of first opening the benzyl alcohol container. In one embodiment, benzyl alcohol with a low peroxide value is used within one day of first opening the benzyl alcohol container. In one embodiment, benzyl alcohol with a low peroxide value is stored refrigerated and used within 6 months of first opening the container. In one embodiment, benzyl alcohol with a low peroxide value is stored under a nitrogen blanket and used within 6 months of first opening. In one embodiment, benzyl alcohol with a low peroxide value is stored under a nitrogen blanket and used within 1 month.

[0045] Those skilled in the art will understand that these structures encompass both natural isotopic forms and other stable isotopes. For example, but not limited to, hydrogen can be deuterated.

[0046] It has been reported that the hypothesis that antibacterial preservatives interact with the preservative through various peptides leads to formulation instability. A combination of multiple mechanisms may simultaneously promote the interaction between peptides and the preservative.

[0047] The interaction between tirzepatide and the preservative was investigated using static light scattering and solution NMR techniques.

[0048] Determination:

[0049] Light scattering of tirzepatide samples

[0050] Tirzepatide formulations were prepared for light scattering measurements, and their compositions are shown in detail in Tables 1.a and 1.b. Light scattering data were collected using a light scattering instrument based on an ALV-CGS3 goniometer (ALV-GmbH, Langen, Germany), which is an independent system with a 22 mW 633 nm HeNe laser.

[0051] Filter the sample into a disposable glass tube using a suitable filter. The corresponding pharmaceutical placebo is used as a scattering blank. In dynamic light scattering (DLS) mode, each sample is collected once for 15 or 30 seconds at a scattering angle of 90 degrees. Analyze the resulting DLS autocorrelation function using intensity-weighted regularized size distributions and demonstrate its monomodal nature before proceeding to the next step. The time-averaged scattering intensity values of the sample, placebo, and toluene are used to calculate the excess Rayleigh ratio.

[0052] The apparent weight-average molecular weight (WAMW) value is calculated using Equation (1):

[0053] WAMW = [(K · c) / R] -1 (1)

[0054] where K is the optical constant, c is the peptide mass concentration, and R is the excess Rayleigh ratio. Assume a refractive index increment (dn / dc) of 0.185 mL / g.

[0055] Table 1a.

[0056]

[0057] Table 1b.

[0058]

[0059]

[0060] Determination of the Tirzepatide Sample by Thioflavin T (ThT) Fluorescence

[0061] Collect ThT fluorescence using a SpectraMax Gemini EM microplate reader (Molecular Devices, San Jose, California). For each sample or placebo (Table 2), add 40 μL of the solution to three wells of a black clear-bottom 96-well plate, followed by 10 μL of a 20 mM ThT stock solution. Seal the plate and perform kinetic fluorescence measurements for 24 hours at an excitation wavelength of 450 nm and an emission wavelength of 480 nm. Set the temperature to 37 °C and perform measurements every 10 minutes, shaking for 3 seconds before each measurement. A positive control sample (Oxyntomodulin, 2 mg / mL, pH = 6.5) is included in the measurements.

[0062] Table 2. Composition of the Tirzepatide Formulations for ThT Fluorescence

[0063]

[0064] Effect of Preservatives and NaCl on the Self-Association of Tirzepatide

[0065] The higher-order structure of tirzepatide was characterized by far-ultraviolet circular dichroism (CD) spectroscopy and Fourier transform infrared spectroscopy (FTIR). In Mounjaro TM matrix (5 mM phosphate buffer, 140 mM NaCl, pH = 7.0), tirzepatide mainly had an α-helical structure. By light scattering method, it was shown that the self-association of tirzepatide in the dose and concentration range of 2.5 mg / 0.5 mL (5 mg / mL) and 15 mg / 0.5 mL (30 mg / mL) existed as a monomer-trimer-hexamer equilibrium.

[0066] To study the effect of preservatives, selected concentrations of m-cresol, phenol, or benzyl alcohol were added to the standard Mounjaro Tm composition. The concentrations of these preservatives were chosen such that the formulation met the passing criteria of the antibacterial efficacy test. The results of the light scattering experiments are summarized in Table 3. The WAMW of the Mounjaro TM composition (“Sample 5”) was 23.6 kDa. This value was consistent with the monomer-trimer-hexamer equilibrium described previously.

[0067] In the presence of 140 mM NaCl and preservatives, the WAMW of tirzepatide was determined to be 70 kDa or greater, consistent with oligomers of 14-mer to 16-mer (Table 3, “Samples 6 to 8”). Accordingly, the solution presented an opalescent state, in contrast to the “clear” appearance of the Mounjaro TM solution.

[0068] Table 3. Effect of Preservatives on the Self-Association of Tirzepatide

[0069]

[0070] Tendency of Tirzepatide to Form Fibrils in the Presence of Preservatives

[0071] Fibrils are large macromolecular self-assemblies of proteins or peptides with specific characteristics. Most notably, the individual peptide backbone transforms into a β-sheet-rich conformation. As a result, it may increase undesired physical, chemical, and therapeutic risks. Experimentally, fibril formation can be visually observed by increased turbidity, precipitation, or gelation, and can also be studied using a variety of techniques, including size-exclusion chromatography, analytical ultracentrifugation, light scattering, and microscopy imaging. These methods can be supplemented by spectroscopy, allowing conformational changes to the β-sheet and the formation of larger assemblies to be confirmed at the molecular level.

[0072] In the current study, using fluorescence spectroscopy with thioflavin T (ThT) as the binding dye, the risk of teplizumab fibril formation in the presence of preservatives was evaluated. ThT is a potent fluorescent marker for fibrils. Once selectively bound to fibril deposits, the fluorescence signal increases sharply, indicating the presence or increase of fibrils. This method has been applied to a variety of peptides to study their fibril-forming propensity. Teplizumab was formulated in matrices containing different teplizumab concentrations, tonicity agents, and preservatives (Table 2). A positive control known to form fibrils (gastrin-releasing peptide, 2 mg / mL, pH = 6.5) was included in the measurements. In the positive control, an enhancement of the ThT fluorescence signal was clearly visible. On the other hand, none of the teplizumab samples showed any statistically significant increase in signal, indicating a very low risk of fibrils.

[0073] Size-exclusion chromatography (SEC) shelf-life and use stability study

[0074] This method is an isocratic size-exclusion HPLC method with UV detection at 214 nm, aiming to determine the relative amount of high-molecular-weight substances. The SEC column is an 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, and the flow rate is 0.5 mL / min. The column temperature is 25 °C. High-molecular-weight substances are expressed as the percentage of the peak area in the total area. The stability of this method is measured by its ability to separate known impurities from teplizumab. This study compared alternative compositions with the compositions in the embodiments herein.

[0075] RP-HPLC shelf-life and use stability study

[0076] This method is a gradient reversed-phase HPLC method, using a C18 reversed-phase chromatographic column with a 2.6 μm dimension, 4.6 x 250 mm or equivalent specification, and performing UV detection at 214 nm. Mobile phase A is an aqueous solution of 0.1% trifluoroacetic acid, and mobile phase B is a solution of 0.1% trifluoroacetic acid in acetonitrile (ACN). The gradient profile is shown in Table 4.

[0077] Table 4: RP-HPLC Gradient Profile

[0078] Time (min) Flow rate (mL / min) 0.1% TFA aqueous solution 0.1% TFA acetonitrile solution 0 1.0 or 1.2 75.0 25.0 0.1 1.2 75.0 25.0 1.0 1.2 75.0 25.0 11.0 1.2 57.5 42.5 51.0 1.2 47.5 52.5 52.0 1.2 10.0 90.0 54.0 1.2 10.0 90.0 54.1 1.2 75.0 25.0 59.8 1.2 75.0 25.0 59.9 1.0 or 1.2 75.0 25.0 60.0 1.0 or 1.2 75.0 25.0

[0079] The column temperature is controlled at 60 °C. This method aims to determine the assay, identity, and purity of tirzepatide in the drug product. Identity is confirmed by comparing the retention time of the main peak with that of the external reference standard. Assay is determined by comparing the main peak area with the corresponding peak area in the external reference standard. Impurities and related substances are reported as a percentage of the total peak area. The stability of this method is judged by its ability to separate known impurities from tirzepatide. The composition contains 30 mM to 50 mM NaCl, 8 mg / mL glycerol; 5 mM phosphate buffer, and uses phenol as a preservative, providing acceptable stability for use.

[0080] Stability Studies

[0081] The primary stability studies included multi-dose tirzepatide injection drug products in 6 batches of prefilled pen (PFP) devices. The drug products in each of these batches were filled into 3 mL clear glass cartridges, sealed at one end by an elastomeric piston and at the other end by a disc seal composed of a bilayer elastomeric disc and an aluminum shell.

[0082] Each batch of samples was stored stably for at least 24 months under long-term storage conditions at 5 °C (2 °C - 8 °C) and for 6 months under accelerated conditions at 25 °C / 60% relative humidity (RH). In addition, the samples were also stored under stress stability conditions at 30 °C / 65% RH. An overview of the drug stability test protocol is shown in Table 5.

[0083] Samples from each batch were stored stably for at least 24 months under long-term storage conditions at 5 °C (2 °C - 8 °C) and for 6 months under accelerated conditions at 25 °C / 60% relative humidity (RH). In addition, the samples were also stored under stress stability conditions at 30 °C / 65% RH. An overview of the drug stability test protocol is shown in Table 5.

[0084] Table 5. Main Stability Protocol for the Drug

[0085]

[0086]

[0087] Table 5 (continued). Main Stability Protocol for the Drug

[0088]

[0089] In addition to the long-term (5°C), accelerated (25°C / 60% RH), and stress (30°C / 65% RH) condition studies summarized in Table 5, a use stability study was also conducted to demonstrate acceptable stability during the use of the multi-dose drug by patients under non-refrigerated conditions. In this study, two main stability batches were selected according to the concentration bracketing approach, with one batch selected at the low end (2.5 mg / 0.6 mL) of the proposed drug concentration range and the other at the high end (15 mg / 0.6 mL). This study was conducted on prefilled pen batches at concentrations of 2.5 mg / 0.6 mL and 15 mg / 0.6 mL, and was carried out after storage at 2°C to 8°C for approximately 2 - 3 months 1 For the use study, both batches were stored under the use condition of 30°C and tested for 30 days as shown in Table 6 below. At the four time points (0, 14, 22, and 30 days) of the use study, the samples were removed from the storage condition of 30°C and the needles were fixed on the prefilled pens. After priming was completed, the drug solution was discharged from the prefilled pens, and then the needles were removed. The samples were tested or returned to the 30°C condition for liquid discharge and testing at subsequent time points. In this way, the samples reaching the end of the in-use study had been exposed to conditions (such as 30°C) and operations (such as fixing the needle, discharging the drug solution, removing the needle) simulating the expected use by patients. The stability study protocol for the multi-dose product is shown in Table 6

[0090] Table 6. Main Stability Protocol for the Use of the Drug

[0091]

[0092] a T0 is the date when the sample is removed from the long-term storage condition of 5°C and tested, which is 30 days before the end of the use study

[0093] These tests included attributes of the drug product that are liable to change during storage and may affect quality, safety and / or efficacy. Tests for color, clarity and pH were carried out to confirm that, as with the single-dose product, no significant changes were observed with regard to stability and that these changes were not attributes limiting the shelf-life. Antimicrobial effectiveness testing (AET) was carried out on samples exposed to the conditions of use. The AET test, in combination with the preservative content test, demonstrated the microbiological safety of the drug product during use.

[0094] RP-HPLC purity

[0095] Purity was evaluated under long-term (5 °C), accelerated (25 °C / 60% RH) and stress stability (30 °C / 65% RH) storage conditions. Under accelerated conditions, the purity of each batch decreased slightly. Based on the available data, all batches met the end of shelf-life acceptance criteria under long-term and accelerated storage conditions.

[0096] Total impurities

[0097] Total impurities were evaluated under long-term (5 °C), accelerated (25 °C / 60% RH) and stress stability (30 °C / 65% RH) storage conditions. Under accelerated conditions, the total impurities in each batch increased slightly. Based on the available data, all batches met the end of shelf-life acceptance criteria under long-term and accelerated storage conditions.

[0098] High molecular weight substances

[0099] High molecular weight substances (HMWS) were evaluated under long-term (5 °C), accelerated (25 °C / 60% RH) and stress stability (30 °C / 65% RH) storage conditions. Under accelerated conditions, the HMWS in each batch increased slightly. Based on the available data, all batches met the end of shelf-life acceptance criteria for HMWS under long-term and accelerated storage conditions.

[0100] Benzyl alcohol

[0101] The benzyl alcohol content was evaluated under long-term (5 °C) and accelerated (25 °C / 60% RH) storage conditions. Under accelerated conditions, the data showed no clear trend in the stability of benzyl alcohol. Based on the available data, all batches met the end of shelf-life acceptance criteria for benzyl alcohol under long-term and accelerated storage conditions.

[0102] Phenol

[0103] The phenol content was evaluated under long-term (5 °C) and accelerated (25 °C / 60% RH) storage conditions. Under accelerated conditions, the data showed no obvious trend in the stability of phenol. Based on the available data, all batches met the acceptance criteria for the shelf life of phenol under long-term and accelerated storage conditions.

[0104] Color

[0105] 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 acceptance criteria for color under long-term and accelerated conditions. Color is not a shelf life limiting parameter for this composition.

[0106] Clarity

[0107] The clarity was evaluated by instrumental analysis (ratio nephelometry) under long-term (5 °C) and accelerated (25 °C / 60% RH) storage conditions. No trends or significant variability outside of method variability were observed.

[0108] Sterility

[0109] All major stability batches met the sterility requirements. Container closure integrity (CCI) testing can be used in place of sterility testing. All CCI results for the major stability study were "pass".

[0110] pH

[0111] The pH was evaluated under long-term (5 °C), accelerated (25 °C / 60% RH), and stress stability (30 °C / 65% RH) storage conditions. Based on the available data, all batches met the acceptance criteria for the shelf life of pH under long-term and accelerated conditions. No trend in the results was observed, demonstrating that the pH was well controlled throughout storage.

[0112] Particulates

[0113] The particulate content 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 long-term and accelerated conditions.

[0114] Injection (bolus) force

[0115] The injection (bolus) force was evaluated by compression testing under long-term (5 °C) and accelerated (25 °C / 60% RH) storage conditions. No trends or significant variability outside of method variability were observed under either condition. All batches in the study met the acceptance criteria for injection force under long-term and accelerated conditions. Injection force is not expected to be a shelf life limiting parameter.

[0116] Dose Accuracy

[0117] Dose accuracy was evaluated using the gravimetric volume by weight method under long-term (5°C) and accelerated (25°C / 60% RH) storage conditions. No trends or significant variability outside of method variability were observed under either condition. All batches in the study met the acceptance criteria for dose accuracy under long-term and accelerated conditions. Dose accuracy is not expected to be a shelf-life limiting parameter.

[0118] Antimicrobial Effectiveness Testing (AET)

[0119] Characterization study: Antimicrobial effectiveness testing (AET) was performed on samples from in-use samples at the 22-day and 30-day time points. This in-use study was designed to verify the effectiveness of the antimicrobial preservative. Samples from in-use samples at the 22-day and 30-day time points were tested according to USP. These results support that the multi-dose product meets the pharmacopeial AET criteria at the end of the entire use period when stored under in-use conditions and at the end of the use period after 6 months of storage under accelerated stability conditions.

[0120] The results support that the shelf life of the multi-dose telotristat injection product is 24 months when stored under long-term storage conditions of approximately 5°C (2°C - 8°C) and the use period is 30 days at up to approximately 30°C. The use stability results are summarized in Table 7.

[0121] Table 7. Use Stability Results (30°C)

[0122]

[0123]

[0124] Table 7 (continued). Use Stability Results (30°C)

[0125]

[0126] a Representative samples were tested using an acceptance sampling plan defined by internal quality standards. The reported mean values are for reference only. Storage stability results at 0 and 3 months are shown in Table 8 at storage temperatures of 2 to 8°C.

[0127] Table 8. Long-Term Condition Stability

[0128]

[0129]

[0130] * Pass = clear, transparent solution, no visible particles.

[0131] ***The CCI test was conducted on the cartridges of batch D589770.

[0132] NMR studies and self-association

[0133] Preparations of tirzepatide were made for light scattering measurements and NMR, and their compositions are shown in Tables 9, 10, and 11.

[0134] Table 9. Compositions of tirzepatide preparations for static light scattering

[0135]

[0136]

[0137] Table 10. Compositions of tirzepatide preparations for NMR

[0138]

[0139] Table 11. Compositions of tirzepatide preparations for NMR

[0140] Examples

[0141] Example preparations of tirzepatide containing preservatives

[0142] Table 12 lists the example preparations of the formulations containing preservatives. In addition to 50 mM NaCl, an appropriate amount of glycerol was added as a second tonicity agent. The formulations were studied to verify the antibacterial efficacy of the formulations and the physical and chemical stability required for the drug.

[0143] Table 12. Compositions of tirzepatide drugs containing preservatives

[0144]

[0145] The NaCl concentration plays a key role in determining the association state of tirzepatide, that is, as the NaCl concentration increases, the WAMW is higher. After adding the preservative, the self-association of the peptide is enhanced. In the preparations of Examples 1 and 2, at 50 mM NaCl, the oligomerization state of tirzepatide is considered to be the same as that in TM the Mounjaro matrix. These results indicate that the risk of fibril formation of tirzepatide in the preservative-containing formulation with 50 mM NaCl is low.

[0146] In the preparations of Examples 1 and 2, synergy was found at 50 mM NaCl. At 50 mM NaCl, in Examples 1 and 2, the oligomeric state of tirzepatide is considered to be the same as that of TM the 30 mg / mL tirzepatide oligomeric state in the Mounjaro matrix.

[0147] Examples 3 and 4

[0148] The formulations of Examples 3 and 4 were prepared substantially as described herein, as shown in Table 13.

[0149] Table 13.

[0150]

[0151] a : The concentration of tirzepatide in the formulation containing the preservative was adjusted based on a 0.6 mL injection volume. The dose range of 2.5 mg to 15 mg remained unchanged. As shown below, the concentration depends on the injection volume.

[0152] Table 14 gives examples of the concentration of tirzepatide using the formulations herein.

[0153] Table 14

[0154]

[0155] Embodiments:

[0156] Embodiment 1. A pharmaceutical composition comprising SEQ ID NO:2 or a pharmaceutically acceptable salt thereof; NaCl; glycerol; phenol; and a phosphate buffer; wherein the NaCl concentration is less than or equal to about 3 mg / mL.

[0157] 2. The pharmaceutical composition of Embodiment 1, wherein the phosphate buffer concentration is about 5 mM.

[0158] 3. The pharmaceutical composition according to any one of Embodiment 1 or 2, wherein the phosphate buffer concentration is about 1.34 mg / mL.

[0159] 4. The pharmaceutical composition according to any one of Embodiments 1 to 3, wherein the NaCl concentration is about 30 mM to about 50 mM.

[0160] 5. The pharmaceutical composition according to any one of Embodiments 1 to 4, wherein the NaCl concentration is about 30 mM.

[0161] 6. The pharmaceutical composition according to any one of Embodiments 1 to 5, wherein the NaCl concentration is about 1.75 mg / mL.

[0162] 7. The pharmaceutical composition according to any one of Embodiments 1 to 6, wherein the glycerol concentration is about 8 mg / mL to 12 mg / mL.

[0163] 8. The pharmaceutical composition according to any one of Embodiments 1 to 7, wherein the glycerol concentration is about 8 mg / mL.

[0164] 9. The pharmaceutical composition according to any one of embodiments 1 to 8, wherein the phenol concentration is from about 1.5 mg / mL to about 6 mg / mL.

[0165] 10. The pharmaceutical composition according to any one of embodiments 1 to 9, wherein the phenol concentration is from about 2 mg / mL to about 5.5 mg / mL.

[0166] 11. The pharmaceutical composition according to any one of embodiments 1 to 10, wherein the phenol concentration is about 5.5 mg / mL.

[0167] 12. The pharmaceutical composition according to any one of embodiments 1 to 11, wherein the composition further comprises benzyl alcohol.

[0168] 13. The pharmaceutical composition according to any one of embodiments 1 to 12, wherein the preservative comprises phenol and benzyl alcohol.

[0169] 14. The pharmaceutical composition according to any one of embodiments 1 to 12, wherein the preservative comprises about 9 mg / mL of benzyl alcohol.

[0170] 15. The pharmaceutical composition of embodiment 14, wherein the preservative comprises about 2 mg / mL of phenol and about 9 mg / mL of benzyl alcohol.

[0171] 16. The pharmaceutical composition according to any one of embodiments 1 to 15, wherein the preservative comprises low peroxide benzyl alcohol.

[0172] 17. The pharmaceutical composition according to any one of embodiments 1 to 16, wherein the preservative comprises benzyl alcohol having a peroxide content of less than about 4 parts per million.

[0173] 18. The pharmaceutical composition according to any one of embodiments 1 to 17, wherein the pH of the composition is from about 6.5 to about 7.5.

[0174] 19. The pharmaceutical composition according to any one of embodiments 1 to 18, wherein the pH of the composition is from about 6.7 to about 7.3.

[0175] 20. The pharmaceutical composition according to any one of embodiments 1 to 19, wherein the composition is about pH 7.

[0176] 21. The pharmaceutical composition of embodiment 1, wherein:

[0177] the phosphate buffer concentration is about 5 mM; NaCl is about 2.93 mg / mL; phenol is about 2 mg / mL; glycerol is about 8 mg / mL; and benzyl alcohol is about 9 mg / mL.

[0178] 22. The pharmaceutical composition of embodiment 1, wherein the phosphate buffer concentration is about 5 mM; the NaCl concentration is about 30 mM glycerol; and phenol.

[0179] 23. The pharmaceutical composition of embodiment 22, wherein the glycerol is about 8 mg / mL.

[0180] 24. The pharmaceutical composition of any one of embodiments 22 to 23, wherein the phenol is about 2 mg / mL to about 5.5 mg / mL.

[0181] 25. The pharmaceutical composition of any one of embodiments 22 to 24, wherein the phenol is about 5.5 mg / mL.

[0182] 26. The pharmaceutical composition of any one of embodiments 22 to 24, wherein the phenol is about 2 mg / mL.

[0183] 27. The pharmaceutical composition of any one of embodiments 1 to 26, wherein the composition is provided in the form of a multi - use injection device.

[0184] 28. The pharmaceutical composition of any one of embodiments 1 to 26, wherein the composition is administered in the form of a multi - use injection device.

[0185] 29. A pharmaceutical composition comprising SEQ ID NO:3 or a pharmaceutically acceptable salt thereof; NaCl; glycerol; phenol; and a phosphate buffer; wherein the NaCl concentration is less than or equal to about 3 mg / mL.

[0186] 30. The pharmaceutical composition of embodiment 29, wherein the concentration of the phosphate buffer is about 5 mM.

[0187] 31. The pharmaceutical composition of any one of embodiments 29 or 30, wherein the concentration of the phosphate buffer is about 1.34 mg / mL.

[0188] 32. The pharmaceutical composition of any one of embodiments 29 to 31, wherein the NaCl concentration is about 30 mM to about 50 mM.

[0189] 33. The pharmaceutical composition of any one of embodiments 29 to 32, wherein the NaCl concentration is about 30 mM.

[0190] 34. The pharmaceutical composition of any one of embodiments 29 to 33, wherein the NaCl concentration is about 1.75 mg / mL.

[0191] 35. The pharmaceutical composition of any one of embodiments 29 to 34, wherein the glycerol concentration is about 8 mg / mL to 12 mg / mL.

[0192] 36. The pharmaceutical composition of any one of embodiments 29 to 35, wherein the glycerol concentration is about 8 mg / mL.

[0193] 37. The pharmaceutical composition according to any one of embodiments 29 to 36, wherein the phenol concentration is from about 1.5 mg / mL to about 6 mg / mL.

[0194] 38. The pharmaceutical composition according to any one of embodiments 29 to 37, wherein the phenol concentration is from about 2 mg / mL to about 5.5 mg / mL.

[0195] 39. The pharmaceutical composition according to any one of embodiments 29 to 38, wherein the phenol concentration is about 5.5 mg / mL.

[0196] 40. The pharmaceutical composition according to any one of embodiments 29 to 39, wherein the composition further comprises benzyl alcohol.

[0197] 41. The pharmaceutical composition according to any one of embodiments 29 to 40, wherein the preservative comprises phenol and benzyl alcohol.

[0198] 42. The pharmaceutical composition according to any one of embodiments 29 to 41, wherein the preservative comprises about 9 mg / mL of benzyl alcohol.

[0199] 43. The pharmaceutical composition according to embodiment 42, wherein the preservative comprises about 2 mg / mL of phenol and about 9 mg / mL of benzyl alcohol.

[0200] 44. The pharmaceutical composition according to any one of embodiments 29 to 43, wherein the preservative comprises low peroxide benzyl alcohol.

[0201] 45. The pharmaceutical composition according to any one of embodiments 29 to 44, wherein the preservative comprises benzyl alcohol having a peroxide content of less than about 4 parts per million.

[0202] 46. The 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.

[0203] 47. The 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.

[0204] 48. The pharmaceutical composition according to any one of embodiments 29 to 47, wherein the composition is about pH 7.

[0205] 49. The pharmaceutical composition according to embodiment 29, wherein:

[0206] the phosphate buffer concentration is about 5 mM; NaCl is about 2.93 mg / mL; phenol is about 2 mg / mL; glycerol is about 8 mg / mL; and benzyl alcohol is about 9 mg / mL.

[0207] 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; glycerol; and phenol.

[0208] 51. The pharmaceutical composition of embodiment 50, wherein the glycerol is about 8 mg / mL.

[0209] 52. The pharmaceutical composition of any one of embodiments 50 to 51, wherein the phenol is from about 2 mg / mL to about 5.5 mg / mL

[0210] 53. The pharmaceutical composition of any one of embodiments 50 to 52, wherein the phenol is about 5.5 mg / mL.

[0211] 54. The pharmaceutical composition of any one of embodiments 50 to 52, wherein the phenol is about 2 mg / mL.

[0212] 55. The pharmaceutical composition of any one of embodiments 29 to 54, wherein the composition is provided in the form of a multi - use injection device.

[0213] 56. The pharmaceutical composition of any one of embodiments 29 to 54, wherein the composition is administered in the form of a multi - use injection device.

[0214] 57. A pharmaceutical composition, comprising SEQ ID NO:4 or a pharmaceutically acceptable salt thereof; NaCl; glycerol; phenol; and a phosphate buffer; wherein the NaCl concentration is less than or equal to about 3 mg / mL.

[0215] 58. The pharmaceutical composition of embodiment 57, wherein the concentration of the phosphate buffer is about 5 mM.

[0216] 59. The pharmaceutical composition of any one of embodiments 57 or 58, wherein the concentration of the phosphate buffer is about 1.34 mg / mL.

[0217] 60. The pharmaceutical composition of any one of embodiments 57 to 59, wherein the NaCl concentration is from about 30 mM to about 50 mM.

[0218] 61. The pharmaceutical composition of any one of embodiments 57 to 60, wherein the NaCl concentration is about 30 mM.

[0219] 62. The pharmaceutical composition of any one of embodiments 57 to 61, wherein the NaCl concentration is about 1.75 mg / mL.

[0220] 63. The pharmaceutical composition of any one of embodiments 57 to 62, wherein the glycerol concentration is from about 8 mg / mL to 12 mg / mL.

[0221] 64. The pharmaceutical composition according to any one of embodiments 57 to 63, wherein the glycerol concentration is about 8 mg / mL.

[0222] 65. The pharmaceutical composition according to any one of embodiments 57 to 64, wherein the phenol concentration is from about 1.5 mg / mL to about 6 mg / mL.

[0223] 66. The pharmaceutical composition according to any one of embodiments 57 to 65, wherein the phenol concentration is from about 2 mg / mL to about 5.5 mg / mL.

[0224] 67. The pharmaceutical composition according to any one of embodiments 57 to 66, wherein the phenol concentration is about 5.5 mg / mL.

[0225] 68. The pharmaceutical composition according to any one of embodiments 57 to 67, wherein the composition further comprises benzyl alcohol.

[0226] 69. The pharmaceutical composition according to any one of embodiments 57 to 68, wherein the preservative comprises phenol and benzyl alcohol.

[0227] 70. The pharmaceutical composition according to any one of embodiments 57 to 69, wherein the preservative comprises about 9 mg / mL of benzyl alcohol.

[0228] 71. The pharmaceutical composition of embodiment 70, wherein the preservative comprises about 2 mg / mL of phenol and about 9 mg / mL of benzyl alcohol.

[0229] 72. The pharmaceutical composition according to any one of embodiments 57 to 71, wherein the preservative comprises low peroxide benzyl alcohol.

[0230] 73. The pharmaceutical composition according to any one of embodiments 57 to 72, wherein the preservative comprises benzyl alcohol having a peroxide content of less than about 4 parts per million.

[0231] 74. The pharmaceutical composition according to any one of embodiments 57 to 73, wherein the pH of the composition is from about 6.5 to about 7.5.

[0232] 75. The pharmaceutical composition according to any one of embodiments 57 to 74, wherein the pH of the composition is from about 6.7 to about 7.3.

[0233] 76. The pharmaceutical composition according to any one of embodiments 57 to 75, wherein the composition is about pH 7.

[0234] 77. The pharmaceutical composition of embodiment 57, wherein:

[0235] The phosphate buffer concentration is about 5 mM; NaCl is about 2.93 mg / mL; phenol is about 2 mg / mL; glycerol is about 8 mg / mL; and benzyl alcohol is about 9 mg / mL.

[0236] 78. The pharmaceutical composition of embodiment 57, wherein the concentration of the phosphate buffer is about 5 mM; the concentration of NaCl is about 30 mM; glycerol; and phenol.

[0237] 79. The pharmaceutical composition of embodiment 78, wherein the glycerol is about 8 mg / mL.

[0238] 80. The pharmaceutical composition of any one of embodiments 78 to 79, wherein the phenol is from about 2 mg / mL to about 5.5 mg / mL

[0239] 81. The pharmaceutical composition of any one of embodiments 78 to 80, wherein the phenol is about 5.5 mg / mL.

[0240] 82. The pharmaceutical composition of any one of embodiments 78 to 80, wherein the phenol is about 2 mg / mL.

[0241] 83. The pharmaceutical composition of any one of embodiments 57 to 82, wherein the composition is provided in the form of a multi - use injection device.

[0242] 84. The pharmaceutical composition of any one of embodiments 57 to 82, wherein the composition is administered in the form of a multi - use injection device.

[0243] Sequence

[0244] SEQ ID NO:1 Tirzepatide

[0245] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0246] wherein X1 is Aib; X2 is Aib; the K at position 20 is chemically modified by conjugating the ε - amino group of the K side chain with (2 - [2 - (2 - amino - ethoxy) - ethoxy] - acetyl) 2 - (γGlu) 1 - CO - (CH2) 18 -CO2H; and the C - terminal amino acid is amidated to a C - terminal primary amide.

[0247] SEQ ID NO:2

[0248] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0249] wherein X1 is Aib; X2 is Aib; the K at position 20 is chemically modified by conjugating the ε - amino group of the K side chain with a C16 - C20 fatty acid or its derivative; and the C - terminal amino acid is optionally amidated to a C - terminal primary amide.

[0250] SEQ ID NO:3

[0251] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0252] (SEQ ID NO:3) wherein X1 is Aib; X2 is Aib; K at position 20 is chemically modified by conjugating the ε-amino group of the K side chain with a fatty acid selected from:

[0253]

[0254] and the C-terminal amino acid is optionally amidated to a C-terminal primary amide; or a pharmaceutically acceptable salt thereof.

[0255] SEQ ID NO:4

[0256]

Claims

1. A pharmaceutical composition comprising tirzepatide or a pharmaceutically acceptable salt thereof; NaCl; glycerol; phenol; and a phosphate buffer; wherein the NaCl concentration is less than or equal to about 3 mg / mL.

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

3. The pharmaceutical composition claimed in any one of claims 1 or 2, wherein the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is selected from about 5, about 10, about 15, about 20, about 25, about 30, about 40, and about 50 mg / mL.

4. The pharmaceutical composition claimed in any one of claims 1 to 3, wherein the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is selected from about 10, about 20, and about 30 mg / mL.

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

6. The pharmaceutical composition claimed in claim 5, wherein the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is selected from 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 claimed in any one of claims 5 or 6, wherein the concentration of tirzepatide or a pharmaceutically acceptable salt thereof is selected from about 4.17, about 8.33, about 12.50, about 16.67, about 20.83, and about 25 mg / mL.

8. The pharmaceutical composition claimed in any one of claims 1 to 7, which is presented in unit dose, wherein the unit dose of tirzepatide or a pharmaceutically acceptable salt thereof is selected from about 5, about 7.5, about 10, about 12.5, about 15, about 20, and about 25 mg.

9. The pharmaceutical composition claimed in any one of claims 1 to 7, which is presented in unit dose, wherein the unit dose of tirzepatide or a pharmaceutically acceptable salt thereof is selected from 5, 7.5, 10, 12.5, and 15 mg.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

24. The pharmaceutical composition claimed in any one of claims 1 to 23, wherein the composition further comprises low peroxide grade benzyl alcohol.

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

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

5.

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

3.

28. The pharmaceutical composition claimed in any one of claims 1 to 27, wherein the composition is about pH 7.

29. The pharmaceutical composition claimed in claim 1, wherein the concentration of teplizumab 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 5.5 mg / mL; and glycerol is about 12 mg / mL.

30. The pharmaceutical composition claimed in claim 1, wherein: The concentration of teplizumab 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; glycerol is about 8 mg / mL; and the composition further comprises about 9 mg / mL of benzyl alcohol.

31. The pharmaceutical composition claimed in claim 1, wherein the concentration of teplizumab 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 NaCl concentration is about 30 mM; glycerol; and phenol.

32. The pharmaceutical composition claimed in claim 31, wherein the glycerol concentration is about 8 mg / mL.

33. The pharmaceutical composition claimed in any one of claims 31 to 32, wherein the phenol concentration is about 2 mg / mL to about 5.5 mg / mL.

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

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

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

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

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

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

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

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

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

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

47. A method for improving long-term weight management in a person in need thereof, comprising administering an effective amount of the composition claimed in any one of claims 1 to 44.

48. The method claimed in claim 47, wherein the person in need thereof is obese.

49. The pharmaceutical composition claimed in any one of claims 1 to 44, which is used for treating type 2 diabetes.

50. The pharmaceutical composition claimed in any one of claims 1 to 44, which is used for improving long-term weight management.

51. The pharmaceutical composition claimed in any one of claims 1 to 44, which is used for treating obesity.

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