GIP / GLP1 agonist compositions

Abstract

The present invention relates to a GIP / GLP1 agonist composition. The present invention relates to a GIP / GLP1 co-agonist peptide pharmaceutical composition for subcutaneous injection. The composition is prepared from tilpotide, NaCl and disodium hydrogen phosphate. The compositions provide commercially acceptable shelf-life stability, shelf-life stability, and are related to acceptable patient injection site experiences. Alternatively, the composition comprises tirpotide, propylene glycol, and disodium hydrogen phosphate, which also provides acceptable shelf life stability.

Description

[0001] This application is a divisional application, and the parent application is an application with a filing date of June 14, 2019, application number 201980042455.0, and invention name “GIP / GLP1 agonist composition”. 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 of the Invention

[0004] 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. Telportide is a GIP / GLP1 co-agonist peptide that can be used to treat diabetes. Telportide can be used to treat obesity.

[0005] US9474780 generally describes compositions containing a GIP / GLP1 agonist for administration by a parenteral route. US9474780 describes and claims telpotide. There is a need for telpotide compositions that provide acceptable stability and an acceptable patient injection site experience. Summary of the invention

[0006] The present invention meets these needs by providing a pharmaceutically acceptable composition of telpotide or a pharmaceutically acceptable salt thereof; the composition comprising: an agent selected from the group consisting of NaCl and propylene glycol; and disodium hydrogen phosphate.

[0007] In one embodiment, the reagent 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.

[0008] 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.

[0009] 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.

[0010] In one embodiment, the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL and the agent is NaCl. In one embodiment, the concentration of telpoitide is about 10 mg / mL to about 30 mg / mL. In one embodiment, the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL; the concentration of 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 telpoitide is about 5 mg / mL to about 30 mg / mL; the concentration of 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 disposable automatic injection device.

[0011] In one embodiment, the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL; and the agent is propylene glycol. In one embodiment, the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL; the concentration of propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL, and the concentration of sodium phosphate dibasic is about 1.34 mg / mL. In one embodiment, the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL; the concentration of propylene glycol is about 15.0 mg / mL, and the concentration of sodium phosphate dibasic is about 1.34 mg / mL.

[0012] In one embodiment, the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL. In certain embodiments, the concentration of telpoitide is about 10 mg / mL to about 30 mg / mL. In one embodiment, the concentration of telpoitide is selected from 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 telpoitide is selected from 10, 20 and 30 mg / mL.

[0013] In one embodiment, the composition of telpotide further comprises a preservative. In one embodiment, the composition of telpotide comprises telpotide, disodium hydrogen phosphate, propylene glycol and a preservative. In one embodiment, the preservative is selected from meta-cresol and phenol. In one embodiment, the concentration of the meta-cresol is about 2.0 mg / mL to about 4.0 mg / mL. In one embodiment, the concentration of the meta-cresol is about 3.0 mg / mL to about 3.5 mg / mL. In one embodiment, the concentration of the meta-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 telpoitide composition is provided, wherein the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL; the concentration of propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL; the concentration of sodium phosphate dibasic is about 0.67 mg / mL to about 2.68 mg / mL; and the concentration of m-cresol is about 2.0 mg / mL to about 4.0 mg / mL. In one embodiment, the concentration of m-cresol is about 3.15 mg / mL. In one embodiment, a telpoitide composition is provided, wherein the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL; the concentration of propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL; the concentration of sodium phosphate dibasic is about 0.67 mg / mL to about 2.68 mg / mL; and the concentration of phenol is about 3.0 mg / mL to about 7.0 mg / mL. In one embodiment, a telpoitide composition is provided, wherein the concentration of telpoitide is about 5 mg / mL to about 30 mg / mL; the concentration of propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL; the concentration of sodium phosphate dibasic is about 0.67 mg / mL to about 2.68 mg / mL; and the concentration of phenol is about 5.0 mg / mL.

[0014] In one embodiment, the dose of the telpotide composition is administered about once a week. In one embodiment, the dose of the telpotide composition is administered once every seven days.

[0015] In one embodiment, a method for treating diabetes is provided, comprising administering an effective dose of the above composition to a person in need thereof.

[0016] In one embodiment, a method of treating obesity is provided, comprising administering an effective dose of one of the above compositions to a person in need thereof. In one embodiment, a method of providing therapeutic weight loss is provided, comprising administering an effective dose of one of the above compositions to a person in need thereof. In one embodiment, a method of treating a condition mediated by GIP / GLP1 co-agonist activity is provided, comprising administering an effective dose of one of the above compositions to a person in need thereof.

[0017] In one embodiment, there is provided one of the above compositions for use in the form of a medicament.

[0018] In one embodiment, one of the above compositions is provided for use in treating diabetes. In one embodiment, one of the above compositions is provided for use in treating obesity.

[0019] In one embodiment, one of the above compositions is provided for use in providing therapeutic weight loss. In one embodiment, one of the above compositions is provided for use in providing non-therapeutic weight loss.

[0020] According to another aspect of the present invention, there is provided an article of manufacture comprising one of the above compositions. In certain embodiments, the article is a multi-purpose vial. In certain embodiments, the article is a pre-filled syringe. In certain embodiments, the article is an automatic injection device ("auto-injector"). As contemplated herein, examples of auto-injectors are proposed in U.S. Patent No. 8,734,394.

[0021] As used herein, "telpotide" means a GIP / GLP1 co-agonist peptide described in US 9,474,780 and described by CAS Registry Number 2023788-19-2. Telpotide is described in Example 1 of US 9474,780 and has the following sequence:

[0022] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0023] wherein X1 is Aib; X2 is Aib; K at position 20 is replaced by (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H was chemically modified by conjugating to the ε-amino group of the K side chain; and the C-terminal amino acid was amidated to form a C-terminal primary amide (SEQ ID NO: 1).

[0024] As used herein, "pharmaceutically acceptable salts" are well known to those skilled in the art. In one embodiment, the pharmaceutically acceptable salt is telportide trifluoroacetate.

[0025] As used herein, the term "surfactant-free" means that the composition contains no added surfactants, or contains only de minimis amounts of added surfactants.

[0026] 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.

[0027] The compositions of the present invention have a telpoitide concentration of 5 mg / mL to 30 mg / mL. The compositions of the present invention may have specific concentrations of 5, 10, 15, 20, 25, and 30 mg / mL. Such compositions may be provided in pre-filled syringes. Such pre-filled syringes may be used for half a milliliter of such compositions / patient / dose. The dosage of the telpoitide composition may be administered using a dosing regimen determined by a clinician.

[0028] When initially produced, the composition is sterile. If provided in a vial or cartridge for multiple uses, an antimicrobial preservative compound or compound mixture 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, for example, Remington: The Science and Practice of Pharmacy (DB Troy, Editor, 21st edition, Lippincott, Williams & Wilkins, 2006). In one embodiment, the preservative is metacresol. In one embodiment, the preservative is phenol. No preservative is required for the composition of a disposable prefilled syringe. In one embodiment, the composition does not contain a surfactant.

[0029] The pH of the telpoitide compositions of the invention is typically 6.5 to 7.5, and the pH is adjusted using physiologically appropriate acids and bases, as may be necessary 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 subcutaneously administered compositions. It is desirable to select a composition that is associated with an acceptable patient injection site experience. For example, NaCl and citrate have been associated with painful irritation at 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.) When administering the composition, it is further desirable to match the body fluid tension (i.e., osmolality) at the injection site as closely as possible, because solutions that are not approximately isotonic with body fluids can produce a painful stinging sensation when administered. It is desirable that the composition be approximately isotonic with the body fluids at the injection site. The composition of the present invention comprising teilpotide, NaCl, and sodium hydrogen phosphate is associated with an acceptable patient injection site experience. Likewise, the composition comprising telpol, propylene glycol, and disodium hydrogen phosphate was associated with an acceptable patient injection site experience.

[0030] In one embodiment, the pH is adjusted with a base to facilitate dissolution in a buffered solution. It may be necessary to add an acid to the composition to adjust the pH to a desired pH range. In one embodiment, NaOH is used to facilitate dissolution of telpotide in a buffer. In one embodiment, HCl is added to adjust the pH of the composition containing dissolved telpotide to a desired pH range.

[0031] The compositions of the present invention are typically administered subcutaneously. Pre-filled disposable pen-type, reusable pen-type or automatic pen-type syringes are typically used to administer the compositions. Multiple-use vials or pump devices may be used to administer the compositions. In one embodiment, the device is an automatic injection device as claimed in U.S. Patent No. 8,734,394.

[0032] The composition comprising telpotide, NaCl and disodium hydrogen phosphate provides the desired shelf-life stability and provides an acceptable injection site experience for the patient. Similarly, the composition comprising telpotide, propylene glycol and disodium hydrogen phosphate provides the desired shelf-life stability and provides an acceptable injection site experience for the patient. As used herein, "shelf-life stability" is measured at about 5 degrees Celsius under controlled conditions. The composition comprising telpotide, NaCl and disodium hydrogen phosphate provides acceptable use-life stability. Similarly, the composition comprising telpotide, propylene glycol and disodium hydrogen phosphate provides acceptable use-life stability. As used herein, the term "use-life stability" refers to the stability of a composition measured at or about 25 degrees Celsius or at or about 40 degrees Celsius under controlled conditions. Example

[0033] Example #1 - Compositions containing NaCl

[0034] The compositions were prepared essentially as described herein. The compositions containing 5, 10, 15, 20, 15 and 30 mg / mL telpotide each contained the ingredients listed in Table 1. Acid or base was optionally added to achieve the desired pH range. Water was added qs to a total final volume of one milliliter.

[0035] Table 1. Formulations of telpotide, phosphate, and NaCl

[0036] Element Concentration (mg / mL) Telportide 5, 10, 15, 20, 15 and 30 Disodium hydrogen phosphate* 1.34 NaCl 8.2

[0037] *Use 5mM phosphate buffer

[0038] Example #2 - Compositions containing propylene glycol

[0039] The compositions were prepared essentially as described herein. Compositions providing 5, 10, 15, 20, 15 and 30 mg of telpotide 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 qs to a total final volume of one milliliter.

[0040] Table 2. Formulations of telpotide, phosphate and propylene glycol

[0041] Element Concentration (mg / mL) Telportide 5, 10, 15, 20, 15 and 30 Disodium hydrogen phosphate* 1.34 Propylene glycol 15

[0042] *Use 5mM phosphate buffer

[0043] Study on the stability of size exclusion chromatography (SEC) during its shelf life

[0044] The procedure is an isocratic size exclusion HPLC method using UV detection at 214 nm designed to determine the relative amounts of telpotide monomer and total aggregates. Monomer and aggregates are reported as percentage of peak area compared to total area. The procedure is an indicator of stability as measured by its ability to resolve known impurities from telpotide. 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.

[0045] Stability studies comparing alternative compositions:

[0046] Table 3

[0047]

[0048] **Use 10mM phosphate buffer

[0049] Table 4. Telpotide monomer (% peak area) determined using size exclusion chromatography (SEC)

[0050]

[0051] Storage stability study

[0052] RP-HPLC:

[0053] The procedure is a gradient reverse phase HPLC method using UV detection at 214 nm designed to determine the amount, identity and purity of telpotide in drug products. Identity is determined by matching the retention time of the major peak with that of the major peak of an external reference standard. Quantity is determined by comparing the major peak area with the corresponding peak in the external reference standard. Impurities and related substances are reported as percentage of peak area compared to the total peak area. The procedure is an indicator of stability as judged by its ability to resolve known impurities from telpotide. As shown in Table 4, the composition comprising NaCl as a tonicity agent provides acceptable shelf life stability.

[0054] Study on the Storage Stability of Size Exclusion Chromatography (SEC)

[0055] The size exclusion stability study method and RP-HPLC described above were used to compare compositions comprising NaCl as tonicity and stabilizers with compositions comprising propylene glycol as tonicity and stabilizers. This study illustrates the acceptable shelf life stability of compositions of the present invention comprising either NaCl reagent or propylene glycol as reagent. The compositions used for this study are listed in Table 5. The stability from this study is given in Table 6.

[0056] Table 5. Comparison between NaCl and propylene glycol

[0057]

[0058]

[0059] *5 mM phosphate buffer was used in this study

[0060] Table 6. Comparison of NaCl and propylene glycol as reagents in telpotide formulations as determined by SEC for monomer (% peak area) and by RP-HPLC for purity

[0061]

[0062] Injection pain studies:

[0063] All compositions were prepared as described in Table 7. Each solution composition vial was kept at room temperature for about 30 minutes, but not more than 4 hours. The reconstituted lyophilized composition was used immediately. All injections were rotated between the four quadrants of the abdomen in the following order: lower left quadrant; lower right quadrant; upper left quadrant; and upper right quadrant. A syringe with a 29-gauge needle was used to administer the composition from the vial. The subject grasped the skin fold at the injection site and then inserted the needle at an angle of about 45 degrees. A second person used a stopwatch to measure the length of the injection. The subject slowly pushed the plunger of the syringe until 0.5 mL of the composition was injected. The target time for the injection was 4 seconds, but not more than 5 seconds. After the injection, the needle was pulled from the skin to release the skin from the subject's grasp. The subject assessed the pain immediately after each injection. Pain measurements were assessed using a 100-mm validated visual analog scale (VAS). VAS is a well-validated tool for assessing injection site pain (Williamson, A.; Hoggart, Pain: A review of three commonly used pain rating scales. Journal of Clinical Nursing 2005, 14, (7), 798-804). VAS is expressed as a 10-cm (100-mm) line anchored by verbal descriptors, usually "no pain" and "worst imaginable pain". Subjects are asked to mark the 100-mm line to indicate the intensity of pain at the time point and to do so as clinically indicated. Staff use a vernier caliper to measure the distance from 0 to the mark placed by the subject on the VAS and record the measurement in the source file. The results from this study are shown in Table 8. Mild pain intensity indications (compared to moderate or severe) reflect acceptable patient injection site experience.

[0064] Table 7

[0065]

[0066]

[0067]

[0068]

[0069] *5 mM phosphate buffer was used in this study

[0070] Table 8. VAS pain scores

[0071]

[0072] sequence

[0073] SEQ ID NO:1

[0074] Telportide

[0075] YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS

[0076] wherein X1 is Aib; X2 is Aib; K at position 20 is replaced by (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO-(CH2) 18 -CO2H was chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid was amidated to form a C-terminal primary amide.

Claims

1. A pharmaceutical composition, comprising: Tielpotide or a pharmaceutically acceptable salt thereof; an agent selected from the group consisting of NaCl and propylene glycol; and Disodium hydrogen phosphate.

2. The pharmaceutical composition as claimed in claim 1, wherein the concentration of telpotide or a pharmaceutically acceptable salt thereof is about 5 mg / mL to about 30 mg / mL.

3. A pharmaceutical composition as claimed in claim 2, wherein the concentration of said sodium hydrogen phosphate is from about 1.0 mg / mL to about 3.0 mg / mL.

4. A pharmaceutical composition as claimed in claim 3, wherein the concentration of said sodium hydrogen phosphate is from about 0.67 mg / mL to about 2.68 mg / mL.

5. A pharmaceutical composition as claimed in claim 4, wherein the concentration of disodium hydrogen phosphate is about 1.34 mg / mL.

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

7. The pharmaceutical composition as claimed in claim 6, wherein the concentration of teilpotide or a pharmaceutically acceptable salt thereof is selected from 10, 20 and 30 mg / mL.

8. A pharmaceutical composition as claimed in claim 7, wherein the agent is NaCl.

9. A pharmaceutical composition as claimed in claim 8, wherein the concentration of NaCl is from about 6.2 mg / mL to about 9.5 mg / mL.

10. The pharmaceutical composition as claimed in claim 9, wherein the concentration of NaCl is about 7.0 mg / mL to about 9.0 mg / mL.

11. A pharmaceutical composition as claimed in claim 10, wherein the concentration of NaCl is about 8.2 mg / mL.

12. The pharmaceutical composition as claimed in claim 1, wherein the concentration of teilpotide 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; and the concentration of NaCl is from about 6.2 mg / mL to about 9.5 mg / mL.

13. A pharmaceutical composition as claimed in claim 12, wherein the concentration of teilpotide 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.

14. A pharmaceutical composition as claimed in claim 13, wherein the composition is provided in an automatic injection device.

15. A pharmaceutical composition as claimed in claim 1, wherein the agent is propylene glycol.

16. The pharmaceutical composition as claimed in claim 15, wherein the concentration of propylene glycol is from about 12.0 mg / mL to about 18.0 mg / mL.

17. The pharmaceutical composition as claimed in claim 16, wherein the concentration of propylene glycol is from about 14.0 mg / mL to about 16.0 mg / mL.

18. A pharmaceutical composition as claimed in claim 17, wherein the concentration of propylene glycol is about 15.0 mg / mL.

19. The pharmaceutical composition as claimed in claim 1, wherein the concentration of teilpotide 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.

20. The pharmaceutical composition as claimed in claim 19, wherein the concentration of teilpotide 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.

21. A pharmaceutical composition as claimed in claim 20, wherein the composition is provided in an automatic injection device.

22. A pharmaceutical composition as claimed in claim 21, wherein the pH of the composition is from about 6.5 to about 7.

5.

23. A pharmaceutical composition as claimed in claim 22, wherein the pH is from about 6.7 to about 7.

3.

24. A pharmaceutical composition as claimed in claim 23, further comprising one or more preservatives.

25. A pharmaceutical composition as claimed in claim 24, wherein the composition further comprises a preservative selected from the group consisting of m-cresol and phenol.

26. A pharmaceutical composition as claimed in claim 25, wherein the preservative is m-cresol.

27. A pharmaceutical composition as claimed in claim 26, wherein the concentration of m-cresol is from about 2.0 mg / mL to about 4.0 mg / mL.

28. A pharmaceutical composition as claimed in claim 27, wherein the concentration of m-cresol is about 3.15 mg / mL.

29. A pharmaceutical composition as claimed in claim 25, wherein the preservative is phenol.

30. The pharmaceutical composition as claimed in claim 29, wherein the concentration of phenol is about 3.0 mg / mL to about 7.0 mg / mL.

31. A pharmaceutical composition as claimed in claim 30, wherein the concentration of phenol is about 5.0 mg / mL.

32. The pharmaceutical composition as claimed in claim 1, wherein the concentration of teilpoitide 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; the concentration of propylene glycol is 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.

33. The pharmaceutical composition as claimed in claim 1, wherein the concentration of teilpotide 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; the concentration of propylene glycol is about 12.0 mg / mL to about 18.0 mg / mL; and further comprises about 3.0 mg / mL to about 7.0 mg / mL of phenol.

34. A pharmaceutical composition as claimed in claim 33, wherein the volume of the composition dose is about 0.5 mL.

35. A pharmaceutical composition as claimed in claim 34, wherein the composition is administered using an automatic injection device.

36. A method for treating diabetes, the method comprising administering an effective dose of the pharmaceutical composition as claimed in claim 33 to a person in need thereof.

37. A method of treating diabetes as claimed in claim 36, wherein the dose is administered using an automatic injection device.

38. A method for treating diabetes as claimed in claim 37, wherein the dose is administered once a week.

39. A method for treating obesity, the method comprising administering an effective dose of the pharmaceutical composition as claimed in claim 33 to a person in need thereof.

40. A method of treating diabetes as claimed in claim 39, wherein the dose is administered using an automatic injection device.

41. A method for treating obesity as claimed in claim 40, wherein the dose is administered once a week.

42. A pharmaceutical composition as claimed in claim 33 for use in the treatment of diabetes.

43. A pharmaceutical composition as claimed in claim 33 for use in the treatment of obesity.

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