Gip / glpi agonist compositions

Abstract

The present invention relates to GIP / GLP1 agonist compositions. The present invention is a GIP / GLP1 co-agonist peptide pharmaceutical composition for subcutaneous injection. The composition comprises tirzepatide, NaCl, and disodium hydrogen phosphate. The composition provides commercially acceptable shelf-life stability, use-life stability, and an acceptable patient injection site experience. An alternative composition comprises tirzepatide, propylene glycol, and disodium hydrogen phosphate, which also provides acceptable shelf-life stability.

Description

[0001] This application is a divisional application of the parent application having the filing date of June 14, 2019, the application number 201980042455.0, and the title “GIP / GLP1 AGONIST COMPOSITIONS”. TECHNICAL FIELD

[0002] The present invention is a GIP / GLP1 co-agonist peptide pharmaceutical composition for subcutaneous injection. The composition comprises tirzepatide, NaCl, and disodium hydrogen phosphate. The composition provides commercially acceptable shelf-life stability, in-use stability, and is associated with an acceptable patient injection site experience. An alternative composition comprises tirzepatide, propylene glycol, and disodium hydrogen phosphate, which also provides acceptable shelf-life stability. BACKGROUND

[0003] Diabetes mellitus is a chronic disease characterized by hyperglycemia resulting from a deficiency 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 co-agonist peptide that can be used to treat diabetes. Tirzepatide can be used to treat obesity.

[0004] US9474780 broadly describes compositions containing GIP / GLP1 agonists for administration by parenteral routes. US9474780 describes and claims tirzepatide. There is a need to provide tirzepatide compositions that provide acceptable stability and an acceptable patient injection site experience. SUMMARY

[0005] The present invention meets these needs by providing a pharmaceutically acceptable composition of tirzepatide or a pharmaceutically acceptable salt thereof; the composition comprising: an agent selected from NaCl and propylene glycol; and disodium hydrogen phosphate.

[0006] In one embodiment, the agent is NaCl. In one embodiment, the concentration of the NaCl is about 6.2 mg / mL to about 9.5 mg / mL. In one embodiment, the concentration of the NaCl is about 7.0 mg / mL to about 9.0 mg / mL. In one embodiment, the concentration of the NaCl is about 8.2 mg / mL.

[0007] In one embodiment, the agent is propylene glycol. In one embodiment, the concentration of the propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL. In one embodiment, the concentration of the propylene glycol is about 14.0 mg / mL to about 16.0 mg / mL. In one embodiment, the concentration of the propylene glycol is about 15.0 mg / mL.

[0008] In one embodiment, the concentration of the sodium phosphate dibasic is about 0.67 mg / mL to about 2.68 mg / mL. In one embodiment, the concentration of the sodium phosphate dibasic is about 1.0 mg / mL to about 3.0 mg / mL. In one embodiment, the concentration of the sodium phosphate dibasic is about 1.34 mg / mL.

[0009] In one embodiment, the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL and the agent is NaCl. In one embodiment, the concentration of the telopeptide is about 10 mg / mL to about 30 mg / mL. In one embodiment, the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL; the concentration of the NaCl is about 8.2 mg / mL, and the concentration of sodium phosphate dibasic is about 0.67 mg / mL to about 2.68 mg / mL. In one embodiment, the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL; the concentration of the NaCl is about 8.2 mg / mL, the concentration of sodium phosphate dibasic is about 0.67 mg / mL to about 2.68 mg / mL, and the composition is provided in a single-use auto-injector device.

[0010] In one embodiment, the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL; and the agent is propylene glycol. In one embodiment, the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL; the concentration of the propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL, and the concentration of the sodium phosphate dibasic is about 1.34 mg / mL. In one embodiment, the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL; the concentration of the propylene glycol is about 15.0 mg / mL, and the concentration of the sodium phosphate dibasic is about 1.34 mg / mL.

[0011] In one embodiment, the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL. In certain embodiments, the concentration of the telopeptide is about 10 mg / mL to about 30 mg / mL. In one embodiment, the concentration of the telopeptide is selected from the group consisting of 5, 10, 15, 20, 25, and 30 mg / mL. In one embodiment, 0.5 mL or less of the composition is administered as a dose. In one embodiment, the concentration of the telopeptide is selected from the group consisting of 10, 20, and 30 mg / mL.

[0012] In one embodiment, the composition of the telopeptide further comprises a preservative. In one embodiment, the composition of the telopeptide comprises a telopeptide, disodium hydrogen phosphate, propylene glycol, and a preservative. In one embodiment, the preservative is selected from the group consisting of m-cresol and phenol. In one embodiment, the concentration of the m-cresol is about 2.0 mg / mL to about 4.0 mg / mL. In one embodiment, the concentration of the m-cresol is about 3.0 mg / mL to about 3.5 mg / mL. In one embodiment, the concentration of the m-cresol is about 3.15 mg / mL. In one embodiment, the concentration of the phenol is about 3.0 mg / mL to about 7.0 mg / mL. In one embodiment, the concentration of the phenol is about 4.0 mg / mL to about 6.0 mg / mL. In one embodiment, the concentration of the phenol is about 5.0 mg / mL. In one embodiment, a telopeptide composition is provided, wherein the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL; the concentration of the propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL; the concentration of the disodium hydrogen phosphate is about 0.67 mg / mL to about 2.68 mg / mL; and the concentration of the m-cresol is about 2.0 mg / mL to about 4.0 mg / mL. In one embodiment, the concentration of the m-cresol is about 3.15 mg / mL. In one embodiment, a telopeptide composition is provided, wherein the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL; the concentration of the propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL; the concentration of the disodium hydrogen phosphate is about 0.67 mg / mL to about 2.68 mg / mL; and the concentration of the phenol is about 3.0 mg / mL to about 7.0 mg / mL. In one embodiment, a telopeptide composition is provided, wherein the concentration of the telopeptide is about 5 mg / mL to about 30 mg / mL; the concentration of the propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL; the concentration of the disodium hydrogen phosphate is about 0.67 mg / mL to about 2.68 mg / mL; and the concentration of the phenol is about 5.0 mg / mL.

[0013] In one embodiment, the dose of tirzepatide composition is administered about once a week. In one embodiment, the dose of tirzepatide composition is administered once every seven days.

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

[0015] In one embodiment, a method of treating obesity is provided, comprising administering to a person in need thereof an effective dose of one of the above compositions. In one embodiment, a method of providing therapeutic weight loss is provided, comprising administering to a person in need thereof 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, comprising administering to a person in need thereof an effective dose of one of the above compositions.

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

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

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

[0019] According to another aspect of the application, an article of manufacture comprising one of the above compositions is provided. In certain embodiments, the article of manufacture is a multi-use vial. In certain embodiments, the article of manufacture is a pre-filled syringe. In certain embodiments, the article of manufacture is an auto-injector device (“auto-injector”). As contemplated herein, an example of an auto-injector is set forth in U.S. Patent 8,734,394.

[0020] As used herein, “tirzepatide” means the GIP / GLP1 co-agonist peptide described in US 9,474,780 and by CAS Registry Number 2023788-19-2. Tirzepatide is described in Example 1 of US 9474,780, having the following sequence:

[0021] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0022] wherein X1is Aib; X2is Aib; K at position 20 is chemically modified by conjugation of the epsilon-amino group of the K side chain with (2-[2-(2-amino-ethoxy)-ethoxy]- acetyl)2-(yGlu)1-CO-(CH2) 18 -CO2H is chemically modified by conjugation with 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).

[0023] As used herein, "pharmaceutically acceptable salts" are well known to those skilled in the art. In one embodiment, the pharmaceutically acceptable salt is telotristat trifluoroacetate.

[0024] As used herein, the term "free of surfactant" means that the composition does not contain added surfactant, or contains only a de minimis amount of added surfactant.

[0025] As used herein, the term "propylene glycol" is well known to those skilled in the art. Propylene glycol is also represented by the formula C3H8O2.

[0026] The compositions of the present application have a telotristat concentration of 5 mg / mL to 30 mg / mL. The compositions of the present application can have specific concentrations of 5, 10, 15, 20, 25, and 30 mg / mL. Such compositions can be provided in pre-filled syringes. Such pre-filled syringes can be used for half-milliliter of such composition per patient per dose. The dose of telotristat composition can be administered using a dosing regimen determined by a clinician.

[0027] Upon initial production, the composition is sterile. If provided in a multi-use vial or cartridge, an antimicrobial preservative compound or mixture of compounds compatible with the other components of the composition can be added in sufficient concentration to meet applicable regulatory antimicrobial preservation requirements. Pharmaceutically acceptable preservatives are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy (D.B. Troy, Editor, 21stEd., Lippincott, Williams & Wilkins, 2006). In one embodiment, the preservative is m-cresol. In one embodiment, the preservative is phenol. Compositions for single-use pre-filled syringes do not require a preservative. In one embodiment, the composition is free of surfactant.

[0028] The pH of the tirzepatide compositions of the present application is typically 6.5 to 7.5, and physiologically appropriate acids and bases are used to adjust the pH as can be required to achieve the desired pH. In one embodiment, the pH target is 6.7 to 7.3. Patient injection site experience is a consideration for subcutaneous administration of the compositions. It is desirable to select compositions that are associated with acceptable patient injection site experience. For example, NaCl and citrate have been associated with painful irritation of the injection site. (Laursen, T.; Hansen, B.; Fisker, S. Pain perception after subcutaneous injections of media containing different buffers. Basic & Clinical Pharmacology & Toxicology 2006, 98, (2), 218-221.), (Fransson, J.; Espander-Jansson, Local tolerance of subcutaneous injections. Journal of Pharmacy and Pharmacology 1996, 48, (10), 1012-1015.) It is further desirable when administering the compositions to match as closely as possible the tonicity (i.e., osmolality) of the body fluids of the injection site, as solutions that are not approximately isotonic with body fluids can cause a painful stinging sensation upon administration. It is desirable that the compositions be approximately isotonic with the body fluids of the injection site. Compositions of the present application comprising tirzepatide, NaCl, and disodium hydrogen phosphate are associated with acceptable patient injection site experience. Likewise, compositions comprising tirzepatide, propylene glycol, and disodium hydrogen phosphate are associated with acceptable patient injection site experience.

[0029] In one embodiment, the pH is adjusted with a base to facilitate dissolution in the buffered solution. It can 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 dissolution of tirzepatide in the buffer. In one embodiment, HCl is added to adjust the pH of the composition containing dissolved tirzepatide to the desired pH range.

[0030] The compositions of the present application are typically administered subcutaneously. The compositions are typically administered using a pre-filled disposable pen-type, reusable pen-type, or auto-pen-type injector. The compositions can be administered using a multi-use vial or a pump device. In one embodiment, the device is an auto-injection device as claimed in U.S. Patent 8,734,394.

[0031] Compositions comprising tirzepatide, NaCl, and disodium hydrogen phosphate provide desirable shelf life stability and provide an acceptable injection site experience for patients. Likewise, compositions comprising tirzepatide, propylene glycol, and disodium hydrogen phosphate provide desirable shelf life stability and provide an acceptable injection site experience for patients. As used herein, "shelf life stability" is measured at about 5 degrees Celsius under controlled conditions. Compositions comprising tirzepatide, NaCl, and disodium hydrogen phosphate provide acceptable use life stability. Likewise, compositions comprising tirzepatide, propylene glycol, and disodium hydrogen phosphate provide acceptable use life stability. As used herein, the term "use life stability" refers to the stability of the composition measured at 25 degrees Celsius or about 25 degrees Celsius or at 40 degrees Celsius or about 40 degrees Celsius under controlled conditions. DETAILED DESCRIPTION

[0032] Embodiment 1. A pharmaceutical composition comprising:

[0033] tirzepatide or a pharmaceutically acceptable salt thereof;

[0034] a reagent selected from the group consisting of NaCl and propylene glycol; and

[0035] disodium hydrogen phosphate.

[0036] Embodiment 2. The pharmaceutical composition as claimed in embodiment 1, wherein the concentration of the tirzepatide or a pharmaceutically acceptable salt thereof is about 5 mg / mL to about 30 mg / mL.

[0037] Embodiment 3. The pharmaceutical composition as claimed in embodiment 2, wherein the concentration of the disodium hydrogen phosphate is about 1.0 mg / mL to about 3.0 mg / mL.

[0038] Embodiment 4. The pharmaceutical composition as claimed in embodiment 3, wherein the concentration of the disodium hydrogen phosphate is about 0.67 mg / mL to about 2.68 mg / mL.

[0039] Embodiment 5. The pharmaceutical composition as claimed in embodiment 4, wherein the concentration of the disodium hydrogen phosphate is about 1.34 mg / mL.

[0040] Embodiment 6. The pharmaceutical composition as claimed in embodiment 1, wherein the concentration of the tirzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of 5, 10, 15, 20, 25, and 30 mg / mL.

[0041] Embodiment 7. The pharmaceutical composition as claimed in embodiment 6, wherein the concentration of the tirzepatide or a pharmaceutically acceptable salt thereof is selected from the group consisting of 10, 20, and 30 mg / mL.

[0042] Embodiment 8. The pharmaceutical composition as claimed in embodiment 7, wherein the agent is NaCl.

[0043] Embodiment 9. The pharmaceutical composition as claimed in embodiment 8, wherein the concentration of the NaCl is about 6.2 mg / mL to about 9.5 mg / mL.

[0044] Embodiment 10. The pharmaceutical composition as claimed in embodiment 9, wherein the concentration of the NaCl is about 7.0 mg / mL to about 9.0 mg / mL.

[0045] Embodiment 11. The pharmaceutical composition as claimed in embodiment 10, wherein the concentration of the NaCl is about 8.2 mg / mL.

[0046] Embodiment 12. The pharmaceutical composition as claimed in embodiment 1, wherein the concentration of telotristat or a pharmaceutically acceptable salt thereof is about 5 mg / mL to about 30 mg / mL; the concentration of disodium hydrogen phosphate is about 0.67 mg / mL to about 2.68 mg / mL; and the concentration of NaCl is about 6.2 mg / mL to about 9.5 mg / mL.

[0047] Embodiment 13. The pharmaceutical composition as claimed in embodiment 12, wherein the concentration of telotristat or a pharmaceutically acceptable salt thereof is about 5 mg / mL to about 30 mg / mL; the concentration of disodium hydrogen phosphate is about 1.34 mg / mL; and the concentration of NaCl is about 8.2 mg / mL.

[0048] Embodiment 14. The pharmaceutical composition as claimed in embodiment 13, wherein the composition is provided in an auto-injection device.

[0049] Embodiment 15. The pharmaceutical composition as claimed in embodiment 1, wherein the agent is propylene glycol.

[0050] Embodiment 16. The pharmaceutical composition as claimed in embodiment 15, wherein the concentration of the propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL.

[0051] Embodiment 17. The pharmaceutical composition as claimed in embodiment 16, wherein the concentration of the propylene glycol is about 14.0 mg / mL to about 16.0 mg / mL.

[0052] Embodiment 18. The pharmaceutical composition as claimed in embodiment 17, wherein the concentration of the propylene glycol is about 15.0 mg / mL.

[0053] Embodiment 19. The pharmaceutical composition as claimed in embodiment 1, wherein the concentration of telotristat or a pharmaceutically acceptable salt thereof is about 5 mg / mL to about 30 mg / mL; the concentration of disodium hydrogen phosphate is about 0.67 mg / mL to about 2.68 mg / mL; and the concentration of propylene glycol is about 14.0 mg / mL to about 16.0 mg / mL.

[0054] Embodiment 20. The pharmaceutical composition as claimed in embodiment 19, wherein the concentration of telotristat or a pharmaceutically acceptable salt thereof is about 5 mg / mL to about 30 mg / mL; the concentration of disodium hydrogen phosphate is about 1.34 mg / mL; and the concentration of propylene glycol is about 15.0 mg / mL.

[0055] Embodiment 21. The pharmaceutical composition as claimed in embodiment 20, wherein the composition is provided in an auto-injection device.

[0056] Embodiment 22. The pharmaceutical composition as claimed in embodiment 21, wherein the pH of the composition is about 6.5 to about 7.5.

[0057] Embodiment 23. The pharmaceutical composition as claimed in embodiment 22, wherein the pH is about 6.7 to about 7.3.

[0058] Embodiment 24. The pharmaceutical composition as claimed in embodiment 23, further comprising one or more preservatives.

[0059] Embodiment 25. The pharmaceutical composition as claimed in embodiment 24, wherein the composition further comprises a preservative selected from meta-cresol and phenol.

[0060] Embodiment 26. The pharmaceutical composition as claimed in embodiment 25, wherein the preservative is meta-cresol.

[0061] Embodiment 27. The pharmaceutical composition as claimed in embodiment 26, wherein the concentration of meta-cresol is about 2.0 mg / mL to about 4.0 mg / mL.

[0062] Embodiment 28. The pharmaceutical composition as claimed in embodiment 27, wherein the concentration of meta-cresol is about 3.15 mg / mL.

[0063] Embodiment 29. The pharmaceutical composition as claimed in embodiment 25, wherein the preservative is phenol.

[0064] Embodiment 30. The pharmaceutical composition as claimed in embodiment 29, wherein the concentration of phenol is about 3.0 mg / mL to about 7.0 mg / mL.

[0065] Implementation Scheme 31. The pharmaceutical composition claimed in Implementation Scheme 30, wherein the concentration of said phenol is about 5.0 mg / mL.

[0066] Implementation Scheme 32. The pharmaceutical composition claimed in Implementation Scheme 1, wherein the concentration of telpolide or a pharmaceutically acceptable salt thereof is from about 5 mg / mL to about 30 mg / mL; the concentration of disodium hydrogen phosphate is from about 0.67 mg / mL to about 2.68 mg / mL; the concentration of propylene glycol is from about 12.0 mg / mL to about 15.0 mg / mL; and further comprises about 2.0 mg / mL to about 4.0 mg / mL of m-cresol.

[0067] Implementation Scheme 33. The pharmaceutical composition claimed in Implementation Scheme 1, wherein the concentration of telpolide or a pharmaceutically acceptable salt thereof is from about 5 mg / mL to about 30 mg / mL; the concentration of disodium hydrogen phosphate is from about 0.67 mg / mL to about 2.68 mg / mL; the concentration of propylene glycol is from about 12.0 mg / mL to about 18.0 mg / mL; and further comprises phenol from about 3.0 mg / mL to about 7.0 mg / mL.

[0068] Implementation Scheme 34. The pharmaceutical composition claimed as in Implementation Scheme 33, wherein the volume of the dosage of the composition is about 0.5 mL.

[0069] Implementation Scheme 35. The pharmaceutical composition claimed in Implementation Scheme 34, wherein the composition is administered using an automated injection device.

[0070] Implementation Scheme 36. A method for treating diabetes, said method comprising administering to a person in need an effective dose of a pharmaceutical composition as claimed in Implementation Scheme 33.

[0071] Implementation Scheme 37. A method for treating diabetes as claimed in Implementation Scheme 36, wherein the dose is administered using an automated injection device.

[0072] Implementation Scheme 38. The method of treating diabetes as claimed in Implementation Scheme 37, wherein the said dose is administered once weekly.

[0073] Implementation Scheme 39. A method for treating obesity, said method comprising administering to a person in need an effective dose of a pharmaceutical composition as claimed in Implementation Scheme 33.

[0074] Implementation Scheme 40. The method for treating diabetes as claimed in Implementation Scheme 39, wherein the dose is administered using an automated injection device.

[0075] Implementation Scheme 41. The method for treating obesity as claimed in Implementation Scheme 40, wherein the said dose is administered once weekly.

[0076] Embodiment 42. A pharmaceutical composition as claimed in embodiment 33 for use in the treatment of diabetes.

[0077] Embodiment 43. A pharmaceutical composition as claimed in embodiment 33 for use in the treatment of obesity.

[0078] Example

[0079] Example #1 - Compositions containing NaCl

[0080] Compositions were prepared essentially as described herein. Compositions containing 5, 10, 15, 20, 15, and 30 mg / mL tirzepatide each contained the ingredients listed in Table 1. Acid or base was optionally added to achieve the desired pH range. Water was added q.s. to a total final volume of one milliliter.

[0081] Table 1. Formulations of tirzepatide, phosphate, and NaCl

[0082] Ingredient Concentration (mg / mL) Tirzepatide 5, 10, 15, 20, 15, and 30 Sodium phosphate dibasic* 1.34 NaCl 8.2

[0083] *Using 5 mM phosphate buffer

[0084] Example #2 - Compositions containing propylene glycol

[0085] Compositions were prepared essentially as described herein. Compositions providing 5, 10, 15, 20, 15, and 30 mg / mL tirzepatide per mL of composition each contained the ingredients listed in Table 2. Acid or base was optionally added to achieve the desired pH range. Water was added q.s. to a total final volume of one milliliter.

[0086] Table 2. Formulations of tirzepatide, phosphate, and propylene glycol

[0087] Ingredient Concentration (mg / mL) Tirzepatide 5, 10, 15, 20, 15, and 30 Sodium phosphate dibasic* 1.34 Propylene glycol Ingredient Concentration (mg / mL) Tirzepatide 5, 10, 15, 20, 15, and 30 Sodium phosphate dibasic* NaCl Ingredient Concentration (mg / mL) Tirzepatide 5, 10, 15, 20, 15, and 30 Sodium phosphate dibasic* Prop 15

[0088] *Using 5 mM phosphate buffer

[0089] Stability studies using size exclusion chromatography (SEC)

[0090] This procedure is an isocratic size exclusion HPLC method using UV detection at 214 nm designed to determine the relative amounts of tirzepatide monomer and total aggregate. Monomer and aggregate are reported as peak area percent compared to total area. This procedure is an indication of stability determined by its ability to resolve known impurities from tirzepatide. This study compared alternative compositions to the compositions of the present invention prepared as shown in Table 3. The stability of this study is shown in Table 4.

[0091] Stability study comparing alternative compositions:

[0092] Table 3

[0093]

[0094] **Using 10 mM Phosphate Buffer

[0095] Table 4. Teriparatide monomer (% peak area) determined using size exclusion chromatography (SEC)

[0096]

[0097] Storage Stability Study

[0098] RP-HPLC:

[0099] The procedure is a gradient reverse phase HPLC method using UV detection at 214 nm, designed to determine the amount, identity, and purity of teriparatide in a drug product. Identity is determined by matching the retention time of the main peak to that of the main peak of an external reference standard. The amount is determined by comparing the area of the main peak to that of the corresponding peak in an external reference standard. Impurities and related substances are reported as peak area percent compared to the total peak area. The procedure is an indication of stability by its ability to resolve known impurities from teriparatide. As shown in Table 4, compositions containing NaCl as a tonicity agent provide acceptable shelf life stability.

[0100] Size Exclusion Chromatography (SEC) Shelf Life Stability Study

[0101] The size exclusion stability study method and RP-HPLC described above were used to compare compositions containing NaCl as a tonicity and stabilizing agent to compositions containing propylene glycol as a tonicity and stabilizing agent. This study illustrates acceptable shelf life stability of compositions of the present invention containing either NaCl agent or containing propylene glycol as an agent. The compositions used in this study are listed in Table 5. The stability from this study is given in Table 6.

[0102] Table 5. Comparison between NaCl and propylene glycol

[0103]

[0104]

[0105] *5 mM Phosphate Buffer was used in this study

[0106] Table 6. Comparison of NaCl and propylene glycol as an agent in teriparatide formulations by determination of monomer (% peak area) with SEC and purity by RP-HPLC

[0107]

[0108] Injection pain study:

[0109] All compositions were prepared as described in Table 7. Each solution composition vial was held at room temperature for approximately 30 minutes, but no more than 4 hours. Reconstituted lyophilized compositions were used immediately. All injections were rotated between the four quadrants of the abdomen in the following order: left lower quadrant; right lower quadrant; left upper quadrant; and right upper quadrant. A syringe with a 29 gauge needle was used to administer the composition from the vial. The subject grasped the skin fold over the injection site and then inserted the needle at an angle of approximately 45 degrees. A second person used a stopwatch to measure the length of time of the injection. The subject slowly advanced the plunger of the syringe until 0.5 mL of the composition was injected. The target time for the injection was 4 seconds, but no more than 5 seconds. The needle was removed from the skin after the injection and the skin was released from the subject's grasp. The subject assessed pain immediately after each injection. Pain measurements were assessed using a 100-mm validated pain visual analog scale (VAS). The VAS is a well-validated tool for assessing pain at an injection site (Williamson, A.; Hoggart, Pain: A review of three commonly used pain rating scales. Journal of Clinical Nursing 2005, 14, (7), 798-804). The VAS is represented as a 10-cm (100-mm) line anchored by verbal descriptors, typically "no pain" and "worst imaginable pain." The subject was asked to mark the 100-mm line to indicate the intensity of pain at the time point and as clinically indicated. The staff member measured the distance from 0 to the mark placed by the subject on the VAS using a vernier caliper and the measurement was recorded in the source document. Results from this study are found in Table 8. Mild pain intensity indication (as compared to moderate or severe) reflects an acceptable patient injection site experience.

[0110] Table 7

[0111]

[0112]

[0113] * 5 mM Phosphate Buffer used in this study

[0114] Table 8. VAS Pain Scores

[0115]

[0116] Sequence

[0117] SEQ ID NO: 1

[0118] thymopentin

[0119] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0120] wherein X1is Aib; X2is Aib; K at position 20 is chemically modified by conjugation of the ε-amino group of the side chain of K with (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)ι-CO- (CH2) 18 -CO2H to the ε-amino group of the side chain of K; and the C-terminal amino acid is amidated to a C-terminal primary amide.

Claims

1. A pharmaceutical composition comprising: tirzepatide, or a pharmaceutically acceptable salt thereof; NaCl at a concentration of 6.2 mg / mL to 9.5 mg / mL; and disodium hydrogen phosphate, wherein the concentration of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5 mg / mL to 30 mg / mL, and wherein the concentration of disodium hydrogen phosphate is 0.67 mg / mL to 3 mg / mL.

2. The pharmaceutical composition as claimed in claim 1, wherein the concentration of disodium hydrogen phosphate is 0.67 mg / mL to 2.68 mg / mL.

3. The pharmaceutical composition as claimed in claim 2, wherein the concentration of disodium hydrogen phosphate is 1.34 mg / mL.

4. The pharmaceutical composition as claimed in claim 1, wherein the concentration of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from 5, 10, 15, 20, 25, and 30 mg / mL.

5. The pharmaceutical composition as claimed in claim 4, wherein the concentration of tirzepatide, or a pharmaceutically acceptable salt thereof, is selected from 10, 20, and 30 mg / mL.

6. The pharmaceutical composition as claimed in any one of claims 1 to 5, wherein the concentration of NaCl is 7 mg / mL to 9 mg / mL.

7. The pharmaceutical composition as claimed in claim 6, wherein the concentration of NaCl is 8.2 mg / mL.

8. The pharmaceutical composition as claimed in claim 1, wherein the concentration of tirzepatide, or a pharmaceutically acceptable salt thereof, is 5 mg / mL to 30 mg / mL; the concentration of disodium hydrogen phosphate is 1.34 mg / mL; and the concentration of NaCl is 8.2 mg / mL.

9. The pharmaceutical composition as claimed in claim 8, wherein the pH of the composition is 6.5 to 7.

5.

10. The pharmaceutical composition as claimed in claim 9, wherein the pH is 6.7 to 7.

3.

11. The pharmaceutical composition as claimed in claim 1, further comprising one or more preservatives.

12. The pharmaceutical composition as claimed in claim 11, wherein the pharmaceutical composition comprises at least one of m-cresol and phenol.

13. The pharmaceutical composition as claimed in claim 11, wherein the pharmaceutical composition comprises m-cresol.

14. The pharmaceutical composition as claimed in claim 13, wherein the concentration of m-cresol is 2 mg / mL to 4 mg / mL.

15. The pharmaceutical composition as claimed in claim 14, wherein the concentration of m-cresol is 3.15 mg / mL.

16. The pharmaceutical composition as claimed in claim 11, wherein the pharmaceutical composition comprises phenol.

17. The pharmaceutical composition as claimed in claim 16, wherein the concentration of phenol is 3 mg / mL to 7 mg / mL.

18. The pharmaceutical composition as claimed in claim 17, wherein the concentration of phenol is 5 mg / mL.

19. A pharmaceutical composition as claimed in claim 1, wherein the concentration of taspoglutide or a pharmaceutically acceptable salt thereof is 5 mg / mL to 30 mg / mL; the concentration of disodium hydrogen phosphate is 0.67 mg / mL to 2.68 mg / mL; and the pharmaceutical composition further comprises 2 mg / mL to 4 mg / mL of m-cresol.

20. A pharmaceutical composition as claimed in claim 1, wherein the concentration of taspoglutide or a pharmaceutically acceptable salt thereof is 5 mg / mL to 30 mg / mL; the concentration of disodium hydrogen phosphate is 0.67 mg / mL to 2.68 mg / mL; and the pharmaceutical composition further comprises 3 mg / mL to 7 mg / mL of phenol.

21. A pharmaceutical composition as claimed in claim 20, wherein the volume of the composition dose is 0.5 mL.

22. A pharmaceutical composition as claimed in claim 21, wherein the composition is suitable for administration using an automatic injection device.

23. A pharmaceutical composition as claimed in claim 20 for use in the treatment of diabetes.

24. A pharmaceutical composition as claimed in claim 20 for use in the treatment of obesity.

25. A pharmaceutical composition as claimed in claim 1, wherein the concentration of NaCl is 8.2 mg / mL to 8.8 mg / mL.

26. A pharmaceutical composition as claimed in claim 6, wherein the concentration of NaCl is 8.8 mg / mL.

27. A pharmaceutical composition comprising: taspoglutide or a pharmaceutically acceptable salt thereof at a concentration selected from 5, 10, 15, 20, 25 and 30 mg / mL; NaCl at a concentration of 8.2 mg / mL; and disodium hydrogen phosphate at a concentration of 0.67 mg / mL to 2.68 mg / mL, and having a pH of 6.5 to 7.

5.

28. The pharmaceutical composition of claim 26, wherein the concentration of disodium hydrogen phosphate is 1.34 mg / mL.

29. Use of an effective dose of a pharmaceutical composition as claimed in claim 20 in the manufacture of a medicament for the treatment of diabetes.

30. The use as claimed in claim 29, wherein the dose is administered using an automatic injection device.

31. The use as claimed in claim 30, wherein the dose is administered once a week.

32. Use of an effective dose of a pharmaceutical composition as claimed in claim 20 in the manufacture of a medicament for the treatment of obesity.

33. The use as claimed in claim 32, wherein the dose is administered using an automatic injection device.

34. The use as claimed in claim 33, wherein the dose is administered once a week.

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