阅读说明：本技术 Glp-1肽的喷雾干燥工艺 (Spray drying process of GLP-1 peptide ) 是由 O·范格斯加德 M·H·汉森 于 2020-03-13 设计创作，主要内容包括：本发明涉及用于喷雾干燥包含司美格鲁肽的进料溶液的工艺,所述工艺包括将在溶剂中包含司美格鲁肽的进料溶液引入喷雾干燥器中,并引入雾化气体和干燥气体,其特征在于所述喷雾干燥器包括用于所述干燥气体的气体加热器,该气体加热器的内表面包含铁和少于18.5％的铬。(The present invention relates to a process for spray drying a feed solution comprising semaglutide, said process comprising introducing a feed solution comprising semaglutide in a solvent into a spray dryer, and introducing a nebulizing gas and a drying gas, characterized in that said spray dryer comprises a gas heater for said drying gas, the inner surface of which gas heater comprises iron and less than 18.5% chromium.)

1. Process for spray drying a feed solution comprising semaglutide, said process comprising introducing a feed solution comprising semaglutide in a solvent into a spray dryer and introducing a atomising gas and a drying gas, characterised in that said spray dryer comprises a gas heater for said drying gas, the inner surface of which gas heater comprises iron and less than 18.5% chromium.

2. The process according to claim 1, characterized in that the inner surface comprises 16-18% chromium.

3. Process according to any one of the preceding claims, characterized in that the internal surface comprises 10-14% nickel.

4. Process according to any one of the preceding claims, characterized in that the internal surface comprises 16-18% chromium and 10-14% nickel.

5. The process according to any of the preceding claims, characterized in that the inner surface has a depth of 0.001cm to 10 cm.

6. The process according to any of the preceding claims, characterized in that the feed solution solvent comprises ethanol.

7. The process according to any of the preceding claims, characterized in that the feed solution comprises 0.5-2.5% (w/w) semaglutide in 49-60% (w/w) aqueous ethanol.

8. Process according to any one of the preceding claims, characterized in that the drying gas is nitrogen.

9. Process according to any of the preceding claims, characterized in that the drying gas is recirculated.

10. The process according to any one of the preceding claims, further comprising the step of formulating the semaglutide obtained by the process into a pharmaceutical composition.

11. The process of claim 10, wherein the pharmaceutical composition is a tablet.

12. Product obtainable by the process according to any one of claims 1-11, characterized by comprising less than 0.3% of impurities.

13. A pharmaceutical composition according to claim 10, a tablet according to claim 11 or a product according to claim 12 for use in medicine.

14. Pharmaceutical composition according to claim 10, tablet according to claim 11 or product according to claim 12 for use in the prevention and/or treatment of obesity and/or diabetes.

15. Pharmaceutical composition according to claim 10, tablet according to claim 11 or product according to claim 12 for use in the prevention and/or treatment of overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes and/or NASH.

Background

In the manufacture of drug substances and pharmaceutical products, the stability of proteins and peptides during processing and upon storage is of utmost importance. During spray drying of a drug substance, impurities may be generated due to the reaction between the solvent and the drug substance. It is highly desirable to obtain a spray drying process for a drug substance wherein as few impurities as possible are produced during the drying process and wherein as high a drug stability and a drug purity as possible are obtained.

It is known from the prior art that amino groups and certain amino acids can be used to bind acetaldehyde, which can react with a variety of proteins to form stable and unstable products. Unstable products are easily reversible, while stable products are essentially irreversible products characterized by resistance to various treatments. Furthermore, it is known from the prior art that there are cases where non-oxygenated ethanol is dehydrogenated to acetaldehyde, catalyzed by a metal species.

Disclosure of Invention

In some aspects, the present invention relates to a process for spray drying a feed solution comprising semaglutide, said process comprising introducing a feed solution comprising semaglutide in a solvent into a spray dryer, and introducing an atomizing gas and a drying gas, characterised in that said spray dryer comprises a gas heater for said drying gas, the inner surface of which gas heater comprises iron and less than 18.5% chromium.

In some aspects, the invention relates to a product obtainable by the process of the invention and to uses of said product.

The inventors have observed that the amount of impurities produced increases when the process for spray drying a feed solution comprising semaglutide is moved from a first unit to a second unit. The need to increase the production facilitates the replacement of the units and both units are standard units for spray drying. The impurities are characterized by having an increased molar weight, corresponding to the products of the reaction with acetaldehyde. The cause of the impurities is not clear, but it is evident from extensive research and consideration that there is a significant correlation between the gas inlet temperature and the level of free acetaldehyde in the spray-dried product, which can then react with the product. Further, it appears that the increase in the amount of impurity generation is caused by the gas heater material because the ethanol doped with nitrogen is made to show ethanol dehydrogenation by the same material as the gas heater material, depending on the gas temperature. The inventors have observed that a lower amount of impurities is generated when applying a gas heater made of stainless steel 316 in a spray drying process compared to applying a gas heater made of Incoloy 800 in such a process. The present invention appears to be independent of production scale.

Drawings

Fig. 1 shows acetaldehyde content (ppm) when a gas heater made of Incoloy 800 or stainless steel 316 is used in the spray drying process.

Fig. 2 shows the amount (%) of impurities generated during spray drying as a function of acetaldehyde content (ppm) when a gas heater made of Incoloy 800 or stainless steel 316 is used in the spray drying process.

Detailed Description

In some embodiments, the present invention relates to a process for spray drying a feed solution comprising semaglutide, said process comprising introducing a feed solution comprising semaglutide in a solvent into a spray dryer, and introducing a nebulizing gas and a drying gas, characterized in that said spray dryer comprises a gas heater for said drying gas, the inner surface of the gas heater comprising iron and less than 18.5% chromium.

In some embodiments, the invention relates to a product obtainable by the process of the invention and to uses of said product.

Spray drying is commonly used as a step in the manufacture of drug substances and pharmaceutical products. The purity of the obtained product is crucial for the overall product cost and the safety of the subject who subsequently receives the final pharmaceutical product.

Gas heater material

Different materials may be used for the gas heater. Different materials have different properties and can be used for different purposes.

Incoloy 800 is an iron-nickel-chromium alloy with moderate strength and good oxidation resistance, carburization and sulfidation at high temperatures, e.g., above 800 ℃. It is particularly useful and widely used in high temperature equipment such as heat treatment equipment and heat exchangers in chemical processes. Incoloy 800 contains iron, 30-35% nickel, and 19-23% chromium, as well as other components (Special Metals Corporation, 2004 (9/4), publication number SMC-046).

Stainless steel is a term used to describe an extremely versatile series of materials that have good corrosion and heat resistance. Stainless steel is generally considered to contain iron and at least 10.5% chromium. Stainless Steel 316 contains iron, 16-18% chromium, and 10-14% nickel, as well as other components (specification table: alloy 316/316L (UNS 31600, S31603) W. Nr.1.4401, 1.4404, Sandmeyer Steel Company 06/2014).

Spray drying process

The present invention relates to a process for spray drying a feed solution comprising a GLP-1 peptide. In one embodiment, the invention relates to a spray drying process of a feed solution comprising the GLP-1 peptide semaglutide, said process comprising a gas heater for drying a gas, the inner surface of the gas heater comprising iron and less than 18.5% chromium. As used herein, the definition "interior surface" refers to the interior surface of the gas heater that is in contact with the drying gas. In some embodiments, the inner surface may have a depth of 0.001 to 50cm, alternatively 0.01 to 30cm, alternatively 0.1 to 10 cm. In some embodiments, the interior surface may have a depth of 0.001 to 0.1cm, alternatively 0.001 to 0.5cm, alternatively 0.001 to 1cm, alternatively 0.001 to 2cm, alternatively 0.001 to 3cm, alternatively 0.001 to 4cm, alternatively 0.001 to 5cm, alternatively 0.001 to 6cm, alternatively 0.001 to 7cm, alternatively 0.001 to 8cm, alternatively 0.001 to 9cm, alternatively 0.001 to 10 cm. In some embodiments, the entire gas heater used to dry the gas comprises iron and less than 18.5% chromium.

In some embodiments of the invention, the inner surface comprises 1-18.5% chromium, alternatively 5-18.5% chromium, alternatively 10-18.5% chromium, alternatively 14-18.5% chromium, alternatively 16-18% chromium. In some embodiments of the invention, the inner surface comprises less than 29% nickel. In some embodiments, the inner surface comprises 1-29% nickel, alternatively 5-20% nickel, alternatively 6-18% nickel, alternatively 8-16% nickel, alternatively 10-14% nickel. In some embodiments of the invention, the inner surface comprises 16-18% chromium and 10-14% nickel. In some embodiments of the invention, the inner surface does not comprise aluminum. In some embodiments, the inner surface does not comprise titanium.

In some embodiments of the invention, the feed solution comprises a solution of the GLP-1 peptide in a solvent. In some embodiments of the invention, the feed solution comprises a solution of the GLP-1 peptide semaglutide in a solvent. In some embodiments of the invention, the solvent is an aqueous alcoholic solvent, such as an aqueous ethanol solution, i.e., comprising water and ethanol. In some embodiments of the invention, the feed solution consists essentially of semaglutide in an aqueous ethanol solution. In some embodiments, the concentration of the aqueous ethanol solution is 40-75% (w/w), alternatively 45-70% (w/w), alternatively 49-60% (w/w). The concentration of the aqueous ethanol solution is defined by the content of ethanol, i.e. a 70% (w/w) aqueous ethanol solution essentially consists of 70 wt% ethanol and 30 wt% water. In some embodiments of the invention, the concentration of semaglutide in the feed solution is from 0.1 to 10% (w/w), alternatively from 0.2 to 5% (w/w), alternatively from 0.3 to 3% (w/w), alternatively from 0.5 to 2.5% (w/w). In some embodiments of the invention, the feed solution comprises 0.1-10% (w/w) semaglutide in 40-75% (w/w) aqueous ethanol. In some embodiments of the invention, the feed solution comprises 0.5-2.5% (w/w) of semaglutide in 49-60% (w/w) aqueous ethanol. In some embodiments of the invention, the feed solution consists essentially of 0.5-2.5% (w/w) of semaglutide in 49-60% (w/w) aqueous ethanol. As used herein, "feed solution consists essentially of semaglutide" means that other agents from the manufacturing process, such as salt or peptide impurities, may be present; for example, the main component is semaglutide and no excipients are added. In some embodiments of the invention, the feed solution introduced into the spray dryer comes from the last chromatographic manufacturing step and will contain semaglutide (80-100%) as the major solid component, but also salts and impurities remaining from the manufacture.

In some embodiments of the invention, the drying gas is nitrogen. In some embodiments of the invention, the drying gas is recycled. In some embodiments of the invention, the atomizing gas is nitrogen. In some embodiments of the invention, the atomizing gas flow rate is from 18 to 77 kg/h. In some embodiments of the invention, the outlet temperature is from 57 to 79 ℃. In some embodiments of the invention, the inlet temperature is 100-162 ℃. In some embodiments of the invention, the feed flow rate is from 24 to 56 kg/h. In some embodiments of the invention, the condenser temperature is from-5 to 5 ℃. In some embodiments of the invention, the drying gas flow rate is 1250-. In some embodiments of the invention, the nozzle has an inner diameter of 1.0mm and an outer diameter of 5-6.5 mm.

In some embodiments of the invention, the process further comprises the step of formulating the semaglutide obtained by the process into a pharmaceutical composition. In some embodiments, the pharmaceutical composition is a solid or liquid pharmaceutical composition. In some embodiments, the pharmaceutical composition is a tablet.

Semetreutide

The compound semaglutide may be prepared as described in example 4 of WO 2006/097537. Semetreuptade is also known as N^6,26- {18- [ N- (17-carboxyheptadecacarbonyl) -L-gamma-glutamyl]-10-oxo-3, 6,12, 15-tetraoxa-9, 18-diazacyclooctadecanoyl } - [8- (2-amino-2-propionic acid), 34-L-arginine]Human glucagon-like peptide 1(7-37), see WHO Drug Information Vol.24, No.1,2010.

In some embodiments, the semaglutide may be present in its fully or partially ionized form; for example, one or more carboxylic acid groups (-COOH) can be deprotonated to carboxylate groups (-COO)^-) And/or one or more amino groups (-NH)₂) Can be protonated as-NH₃ ⁺A group. In some embodiments, the semaphorinde is in the form of a salt.

Pharmaceutical composition

The compound semaglutide may be administered in the form of a pharmaceutical composition. The pharmaceutical composition may comprise semaglutide at a concentration of 0.01mg/ml to 100 mg/ml. In some embodiments, the pharmaceutical composition comprises 0.01 to 50mg/ml, or 0.01 to 20mg/ml, or 0.01 to 10mg/ml of semaglutide. In some embodiments, the pharmaceutical composition comprises 0.1-20mg/ml semaglutide.

The pharmaceutical compositions described herein may further comprise one or more pharmaceutically acceptable excipients, for example selected from the group consisting of buffer systems, preservatives, tonicity agents, chelating agents, stabilizers and surfactants. In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, for example one or more selected from the group consisting of buffers, isotonicity agents, and preservatives. The formulation of pharmaceutically active ingredients with various adjuvants is known in The art, see, e.g., Remington: The Science and Practice of Pharmacy (e.g., 19 th edition (1995) and any subsequent editions). The term "adjuvant" broadly refers to any component other than an active therapeutic ingredient, e.g., a compound of the invention. The adjuvants may be inert substances, inactive substances and/or non-pharmaceutically active substances.

In some embodiments, the pharmaceutical composition comprises a phosphate buffer, such as a sodium phosphate buffer, for example disodium phosphate. In some embodiments, the pharmaceutical composition comprises an isotonic agent, such as propylene glycol. In some embodiments, the pharmaceutical composition comprises a preservative, such as phenol.

The pharmaceutical composition may be in the form of a tablet. The pharmaceutical composition may comprise semaglutide in an amount of 0.01mg to 100 mg. In some embodiments, the pharmaceutical composition comprises 0.01-50mg, alternatively 0.01-20mg, alternatively 0.01-10mg of semaglutide. The pharmaceutical composition may be in the form of a solution or a suspension. The pharmaceutical composition may be adapted for sublingual and/or oral administration. The pharmaceutical composition may be suitable for subcutaneous administration.

Use of

The product obtainable by the process of the invention is intended to be used in a pharmaceutical composition together with one or more pharmaceutically acceptable adjuvants. In some embodiments, the product obtainable by the process of the present invention is characterized by comprising less than 0.5%, alternatively 0.4%, alternatively 0.3%, alternatively 0.2% impurities. In some embodiments, the products obtainable by the process of the invention are for subcutaneous administration. In some embodiments, the product obtainable by this process is for sublingual and/or oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet.

In some embodiments, the product obtainable by the process of the invention is for medical use. In some embodiments, the product obtainable by the process of the invention is used for the prevention and/or treatment of obesity and/or diabetes. In some embodiments, the product obtainable by the process of the invention is used for the treatment of obesity. In some embodiments, the product obtainable by the process of the invention is used for the treatment of diabetes. In some embodiments, the product obtainable by the process of the invention is for use in the prevention and/or treatment of overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and/or type 1 diabetes. In some embodiments, the product obtainable by the process of the invention is for use in the prevention and/or treatment of NASH.

In some embodiments, the pharmaceutical composition is for use in the prevention and/or treatment of obesity and/or diabetes. In some embodiments, the pharmaceutical composition is for use in treating obesity and/or diabetes. In some embodiments, the pharmaceutical composition is for treating obesity. In some embodiments, the pharmaceutical composition is for treating diabetes. In some embodiments, the pharmaceutical composition is for use in the prevention and/or treatment of overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and/or type 1 diabetes. In some embodiments, the pharmaceutical composition is for the prevention and/or treatment of NASH.

In some embodiments, the present invention relates to a method of preventing and/or treating obesity and/or diabetes by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of the present invention. In some embodiments, the present invention relates to a method of treating obesity and/or diabetes by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of the present invention. In some embodiments, the present invention relates to a method of treating obesity by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of the present invention. In some embodiments, the present invention relates to a method of treating diabetes by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of the present invention. In some embodiments, the present invention relates to a method for the prevention and/or treatment of overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and/or type 1 diabetes by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of the present invention. In some embodiments, the present invention relates to a method of preventing and/or treating NASH by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of the present invention.

In some embodiments, the present invention relates to a method for preventing and/or treating obesity and/or diabetes by administering a therapeutically effective amount of said pharmaceutical composition to a subject in need thereof. In some embodiments, the present invention relates to a method of treating obesity and/or diabetes by administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition. In some embodiments, the present invention relates to a method of treating obesity by administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition. In some embodiments, the present invention relates to a method of treating diabetes by administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition. In some embodiments, the present invention relates to a method for the prevention and/or treatment of overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and/or type 1 diabetes by administering a therapeutically effective amount of said pharmaceutical composition to a subject in need thereof. In some embodiments, the present invention relates to a method of preventing and/or treating NASH by administering a therapeutically effective amount of said pharmaceutical composition to a subject in need thereof.

Ranges herein include their endpoints unless otherwise specified. In some embodiments, the terms "a" or "an" mean "one or more". In some embodiments, and unless otherwise indicated in this specification, terms presented in the singular also include the plural. Herein, the term "about" refers to the value referred to ± 10%, and includes the value.

Non-limiting embodiments of the invention

The following are non-limiting embodiments of the invention:

1. process for spray drying a feed solution comprising semaglutide, said process comprising introducing a feed solution comprising semaglutide in a solvent into a spray dryer and introducing a atomising gas and a drying gas, characterised in that said spray dryer comprises a gas heater for said drying gas, the inner surface of which gas heater comprises iron and less than 18.5% chromium.

2. The process according to embodiment 1, characterized in that the inner surface comprises 1-18.5% chromium.

3. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 5-18.5% chromium.

4. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 10-18.5% chromium.

5. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 14-18.5% chromium.

6. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 16-18% chromium.

7. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises less than 29% nickel.

8. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 1-29% nickel.

9. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 5-20% nickel.

10. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 6-18% nickel.

11. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 8-16% nickel.

12. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 10-14% nickel.

13. The process according to any one of the preceding embodiments, characterized in that the inner surface comprises 16-18% chromium and 10-14% nickel.

14. The process according to any of the preceding embodiments, characterized in that the inner surface does not comprise aluminum.

15. The process according to any one of the preceding embodiments, characterized in that the inner surface does not comprise titanium.

16. The process according to any of the preceding embodiments, characterized in that the inner surface has a depth of 0.001-10 cm.

17. The process according to any of the preceding embodiments, characterized in that the entire gas heater for the drying gas contains iron and less than 18.5% chromium.

18. The process according to any of the preceding embodiments, characterized in that the feed solution consists essentially of semaglutide in a solvent.

19. The process according to any one of the preceding embodiments, characterized in that the feed solution solvent comprises an organic alcohol solvent.

20. The process according to any one of the preceding embodiments, characterized in that the feed solution solvent comprises ethanol.

21. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises an aqueous ethanol solution.

22. The process according to any of the preceding embodiments, characterized in that the feed solution solvent is 40-75% (w/w) aqueous ethanol.

23. The process according to any of the preceding embodiments, characterized in that the feed solution solvent is 45-70% (w/w) aqueous ethanol.

24. The process according to any of the preceding embodiments, characterized in that the feed solution solvent is 49-60% (w/w) aqueous ethanol.

25. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.1-10% (w/w) semaglutide.

26. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.2-5% (w/w) semaglutide.

27. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.3-3% (w/w) semaglutide.

28. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.5-2.5% (w/w) semaglutide.

29. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.1-10% (w/w) of semaglutide in 40-75% (w/w) aqueous ethanol.

30. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.5-2.5% (w/w) semaglutide in 49-60% (w/w) aqueous ethanol.

31. The process according to any of the preceding embodiments, characterized in that the feed solution consists essentially of 0.5-2.5% (w/w) of semaglutide in 49-60% (w/w) aqueous ethanol.

32. The process according to any of the preceding embodiments, characterized in that the drying gas is nitrogen.

33. The process according to any of the preceding embodiments, characterized in that the drying gas is recycled.

34. The process according to any one of the preceding embodiments, characterized in that the atomizing gas is nitrogen.

35. The process according to any of the preceding embodiments, characterized in that the atomizing gas flow rate is from 18 to 77 kg/h.

36. The process according to any of the preceding embodiments, characterized in that the outlet temperature is 57-79 ℃.

37. The process according to any of the preceding embodiments, characterized in that the inlet temperature is 100-162 ℃.

38. The process according to any of the preceding embodiments, characterized in that the feed flow rate is 24-56 kg/h.

39. The process according to any of the preceding embodiments, characterized in that the condenser temperature is from-5 to 5 ℃.

40. The process according to any of the preceding embodiments, characterized in that the drying gas flow rate is 1250-.

41. The process according to any of the preceding embodiments, characterized by having a nozzle with an inner diameter of 1.0mm and an outer diameter of 5-6.5 mm.

42. The process according to any one of the preceding embodiments, further comprising the step of formulating the semaglutide obtained by the process into a pharmaceutical composition.

43. The process of embodiment 42, wherein the pharmaceutical composition is a solid or liquid pharmaceutical composition.

44. The process of embodiment 42, wherein the pharmaceutical composition is a tablet.

45. A product obtainable by the process according to any one of the preceding embodiments.

46. The product of embodiment 45, comprising less than 0.5%, alternatively 0.4%, alternatively 0.3%, alternatively 0.2% impurities.

47. A pharmaceutical composition comprising a therapeutically effective amount of a product according to any one of embodiments 45-46.

48. The pharmaceutical composition according to embodiment 47, further comprising one or more pharmaceutically acceptable excipients.

49. A pharmaceutical composition according to any one of embodiments 47-48, which is suitable for sublingual and/or oral administration.

50. The pharmaceutical composition according to any one of embodiments 47-49, which is suitable for subcutaneous administration.

51. The pharmaceutical composition of any one of embodiments 47-50, in the form of a tablet.

52. A product according to any one of embodiments 45-46 or a pharmaceutical composition according to any one of embodiments 47-51 for use in medicine.

53. A product according to any one of embodiments 45 to 46 or a pharmaceutical composition according to any one of embodiments 47 to 51 for use in the prevention and/or treatment of obesity and/or diabetes.

54. A product according to any one of embodiments 45-46 or a pharmaceutical composition according to any one of embodiments 47-51 for use in the treatment of obesity and/or diabetes.

55. A product according to any one of embodiments 45-46 or a pharmaceutical composition according to any one of embodiments 47-51 for use in the treatment of obesity.

56. A product according to any one of embodiments 45-46 or a pharmaceutical composition according to any one of embodiments 47-51 for use in the treatment of diabetes.

57. A product according to any one of embodiments 45-46 or a pharmaceutical composition according to any one of embodiments 47-51 for use in the prevention and/or treatment of overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and/or type 1 diabetes.

58. The product according to any one of embodiments 45 to 46 or the pharmaceutical composition according to any one of embodiments 47 to 51 for use in the prevention and/or treatment of NASH.

59. A method of preventing and/or treating obesity and/or diabetes by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of any one of embodiments 1 to 44, a product according to any one of embodiments 45 to 46 or a pharmaceutical composition according to any one of embodiments 47 to 51.

60. A method of treating obesity and/or diabetes by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of any one of embodiments 1-44, a product according to any one of embodiments 45-46 or a pharmaceutical composition according to any one of embodiments 47-51.

61. A method of treating obesity by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of any one of embodiments 1-44, a product according to any one of embodiments 45-46, or a pharmaceutical composition according to any one of embodiments 47-51.

62. A method of treating diabetes by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of any one of embodiments 1-44, a product according to any one of embodiments 45-46, or a pharmaceutical composition according to any one of embodiments 47-51.

63. A method of preventing and/or treating overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and/or type 1 diabetes by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of any one of embodiments 1-44, a product according to any one of embodiments 45-46 or a pharmaceutical composition according to any one of embodiments 47-51.

64. A method of preventing and/or treating NASH by administering to a subject in need thereof a therapeutically effective amount of a product obtainable by the process of any one of embodiments 1-44, a product according to any one of embodiments 45-46 or a pharmaceutical composition according to any one of embodiments 47-51.

Examples

General procedure

Spray drying experiments were carried out on a PSD4 production scale spray dryer using a two-fluid nozzle with an internal diameter of 1mm and an external diameter of 5-6.5 mm. The atomizing gas is nitrogen, and the drying gas is nitrogen. The dry gas was recirculated through a condensing unit at-5 to 5 ℃ and then heated using a gas heater whose inner surface was made of Incoloy 800 or stainless steel 316.

Feed solution preparation

The feed solution 1) is received as semaglutide in a water/ethanol solution from a previous manufacturing step, or 2) is a spray-dried powder comprising semaglutide, redissolved in a suitable water/ethanol composition, and then processed. When tested, the concentration range tested for semaglutide was 7.8 to 24g/l, and the solvent system had a range of 49-60% ethanol by weight.

The spray drying process comprises the following steps:

the solvent used for stabilization was matched to the water/ethanol composition (49-60% (w/w) ethanol) of the solution containing semaglutide.

Prior to the start of the batch, the spray dryer was stabilized with solvent at the desired set point value (predefined from table 1 below) for the drying gas stream, outlet temperature, feed stream, atomization gas stream, and condenser temperature, and the inlet temperature was adjusted to obtain the desired outlet temperature.

Parameter(s)	Lower limit of test	Upper limit of test
			Outlet temperature [ deg.C ]]	57	79
Flow rate of atomizing gas [ kg/h]	18	77
			Feed flow rate [ kg/h]	24	56
Inlet temperature [ deg.C]	100	162
			Condenser temperature	-5	5
Flow rate of drying gas [ kg/h]	1250	1550
			Concentration of semaglutide [ mg/ml ]]	7.8	24.0
Concentration of ethanol in solvent [% ]]	49	60

Table 1: lower and upper limits for the parameters tested in the spray drying process.

Once stable parameters were reached, the spray drying process was started by switching from the stabilizing solvent to the semaglutide feed solution. The product is collected at predetermined intervals using a filter bag sleeve with a filter bag blowback, or using a cyclone separator as the primary powder separation technique. At the end of the spray drying run, the semaglutide feed solution was switched to the stabilizing solvent before the unit was shut down or stabilized for the next batch.

Example 1: spray drying of semaglutide using different heater materials

The purpose is as follows: the purpose of this experiment was to determine the cause of impurity generation and the means to prevent impurity generation.

And (3) data analysis:

analysis using standard least squares, using SASSoftware version 12.2 analyzes the data presented in table 2, fig. 1 and fig. 2. The acetaldehyde level in the spray dried powder was modeled as a response that was positively affected by the gas heater material and inlet temperature, but negatively affected by the feed flow rate. By modeling the impurity increase as a response, it is positively influenced by both the acetaldehyde level and the inlet temperature in the spray dried powder, although the correlation between these two parameters is not deconvoluted.

Table 2: in response to acetaldehyde and impurity levels of the different gas heater materials.

The results in table 2 and fig. 1 show that performing the spray drying process in the first unit including the gas heater made of stainless steel 316 generates a small amount of acetaldehyde. When the spray drying process was performed in the second unit comprising a gas heater made of Incoloy 800, increased amounts of acetaldehyde were generated. When the Incoloy 800 gas heater material in the second cell was replaced with stainless steel 316, a small amount of acetaldehyde was generated. This shows that applying a gas heater made of stainless steel 316 in the spray drying process generates a reduced amount of acetaldehyde compared to applying a gas heater made of Incoloy 800.

The results in table 2 and fig. 2 show that no impurity levels were measured for the first unit, as no problems have been found. When the spray drying process was performed in the second unit including the gas heater made of Incoloy 800, a large amount of impurities were generated. When the Incoloy 800 gas heater material in the second cell was replaced with stainless steel 316, a small amount of impurities was generated. This shows that applying a gas heater made of stainless steel 316 in the spray drying process generates a reduced amount of impurities compared to applying a gas heater made of Incoloy 800. In addition, FIG. 2 shows the correlation between the acetaldehyde produced and the impurities produced.

While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true scope of the invention.