Spray Drying Process of GLP-1 Peptide

Abstract

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

Description

[0001] The present invention relates to the field of spray drying of feed solutions comprising GLP-1 peptides such as semaglutide. More specifically, the present invention relates to a process for spray drying of feed solutions comprising semaglutide, wherein improved purity is obtained, semaglutide obtainable by said process and its use in medicine.

[0002] background

[0003] In the manufacture of APIs and drug products, the stability of proteins and peptides during processing and on storage is extremely important. During the spray drying of APIs, impurities may be generated due to reactions between the solvent and the API. It is highly desirable to obtain a spray drying process for APIs in which as few impurities as possible are generated during the drying process and in which the highest possible drug stability and drug purity are achieved.

[0004] 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. In addition, it is known from the prior art that there are non-oxidative dehydrogenations of ethanol to acetaldehyde catalyzed by metal substances. Summary of the invention

[0005] In some aspects, the present invention relates to a process for spray drying a feed solution containing semaglutide, the process comprising introducing a feed solution containing semaglutide in a solvent into a spray dryer, and introducing an atomizing gas and a drying gas, characterized in that the spray dryer comprises a gas heater for the drying gas, the inner surface of the gas heater comprising iron and less than 18.5% chromium.

[0006] In some aspects, the present invention relates to products obtainable by the process of the present invention and uses of said products.

[0007] The inventors have observed that when the process for spray drying a feed solution containing semaglutide was moved from the first unit to the second unit, the amount of impurities generated increased. The need to increase production promoted the replacement of the units, and both units were standard units for spray drying. The impurities are characterized by having an increased molar weight, corresponding to the product of the reaction with acetaldehyde. The cause of the impurities is unclear, but after extensive research and consideration, it is clear 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. In addition, it seems that the increase in impurity generation is caused by the gas heater material, because passing ethanol doped with nitrogen through the same material as the gas heater material shows ethanol dehydrogenation, which depends on the gas temperature. The inventors have observed that when a gas heater made of stainless steel 316 is used in a spray drying process, a smaller amount of impurities is generated than when a gas heater made of Incoloy 800 is used in such a process. The present invention does not seem to be related to the scale of production. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 The acetaldehyde content (ppm) when a gas heater made of Incoloy 800 or stainless steel 316 was used in the spray drying process is shown.

[0009] Figure 2 The amount of impurities (%) generated during spray drying is shown as a function of the acetaldehyde content (ppm) when a gas heater made of Incoloy 800 or stainless steel 316 is used in the spray drying process. DETAILED DESCRIPTION

[0010] In some embodiments, the present invention relates to a process for spray drying a feed solution containing semaglutide, the process comprising introducing a feed solution containing semaglutide in a solvent into a spray dryer, and introducing an atomizing gas and a drying gas, characterized in that the spray dryer comprises a gas heater for the drying gas, the inner surface of the gas heater comprising iron and less than 18.5% chromium.

[0011] In some embodiments, the present invention relates to products obtainable by the process of the present invention and uses of said products.

[0012] Spray drying is commonly used as a step in the manufacturing of both APIs and drug products. The purity of the product obtained is critical to the overall product cost and subsequently the safety of the subjects who receive the final drug product.

[0013] Gas Heater Materials

[0014] Different materials can be used for gas heaters. Different materials have different properties and can be used for different purposes.

[0015] Incoloy 800 is an iron-nickel-chromium alloy having moderate strength and good resistance to oxidation, carburization and sulfidation at high temperatures, such as above 800°C. 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 and other components (Special Metals Corporation, 2004 (September 4), Publication No. SMC-046).

[0016] Stainless steel is a term used to describe an extremely versatile family of materials with 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, among other components (Specification sheet: Alloy 316 / 316L (UNS S31600, S31603) W.Nr. 1.4401, 1.4404, Sandmeyer Steel Company 06 / 2014).

[0017] Spray drying process

[0018] The present invention relates to a spray drying process for a feed solution containing a GLP-1 peptide. In one embodiment, the present invention relates to a spray drying process for a feed solution containing the GLP-1 peptide semaglutide, the process comprising a gas heater for drying gas, the inner surface of the gas heater comprising iron and less than 18.5% chromium. As used herein, the definition "inner surface" refers to the inner surface of the gas heater in contact with the drying gas. In some embodiments, the inner surface may have a depth of 0.001-50 cm, or 0.01-30 cm, or 0.1-10 cm. In some embodiments, the inner surface may have a depth of 0.001-0.1 cm, or 0.001-0.5 cm, or 0.001-1 cm, or 0.001-2 cm, or 0.001-3 cm, or 0.001-4 cm, or 0.001-5 cm, or 0.001-6 cm, or 0.001-7 cm, or 0.001-8 cm, or 0.001-9 cm, or 0.001-10 cm. In some embodiments, the entire gas heater for drying gas contains iron and less than 18.5% chromium.

[0019] In some embodiments of the invention, the inner surface comprises 1-18.5% chromium, or 5-18.5% chromium, or 10-18.5% chromium, or 14-18.5% chromium, or 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, or 5-20% nickel, or 6-18% nickel, or 8-16% nickel, or 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.

[0020] In some embodiments of the present invention, the feed solution comprises a solution of the GLP-1 peptide in a solvent. In some embodiments of the present invention, the feed solution comprises a solution of the GLP-1 peptide semaglutide in a solvent. In some embodiments of the present invention, the solvent is an aqueous alcohol solvent, such as an ethanol aqueous solution, i.e., comprising water and ethanol. In some embodiments of the present invention, the feed solution consists essentially of semaglutide in an ethanol aqueous solution. In some embodiments, the concentration of the ethanol aqueous solution is 40-75% (w / w), or 45-70% (w / w), or 49-60% (w / w). The concentration of the ethanol aqueous solution is defined by the content of ethanol, i.e., a 70% (w / w) ethanol aqueous solution consists essentially of 70% by weight ethanol and 30% by weight water. In some embodiments of the present invention, the concentration of semaglutide in the feed solution is 0.1-10% (w / w), or 0.2-5% (w / w), or 0.3-3% (w / w), or 0.5-2.5% (w / w). In some embodiments of the invention, the feed solution comprises 0.1-10% (w / w) semaglutide in a 40-75% (w / w) ethanol-water solution. In some embodiments of the invention, the feed solution comprises 0.5-2.5% (w / w) semaglutide in a 49-60% (w / w) ethanol-water solution. In some embodiments of the invention, the feed solution consists essentially of 0.5-2.5% (w / w) semaglutide in a 49-60% (w / w) ethanol-water solution. As used herein, "the feed solution consists essentially of semaglutide" means that other reagents from the manufacturing process, such as salts 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 chromatography manufacturing step and will contain semaglutide (80-100%) as the main solid component, but will also contain salts and impurities remaining from the manufacturing.

[0021] In some embodiments of the present invention, the drying gas is nitrogen. In some embodiments of the present invention, the drying gas is recycled. In some embodiments of the present invention, the atomizing gas is nitrogen. In some embodiments of the present invention, the atomizing gas flow rate is 18-77kg / h. In some embodiments of the present invention, the outlet temperature is 57-79°C. In some embodiments of the present invention, the inlet temperature is 100-162°C. In some embodiments of the present invention, the feed flow rate is 24-56kg / h. In some embodiments of the present invention, the condenser temperature is -5 to 5°C. In some embodiments of the present invention, the drying gas flow rate is 1250-1550kg / h. In some embodiments of the present invention, the nozzle has an inner diameter of 1.0mm and an outer diameter of 5-6.5mm.

[0022] In some embodiments of the present 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.

[0023] Semaglutide

[0024] The compound semaglutide can be prepared as described in Example 4 of WO2006 / 097537. 6,26 -{18-[N-(17-carboxyheptadecanyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl}-[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.

[0025] In some embodiments, semaglutide may be present in its fully or partially ionized form; for example, one or more carboxylic acid groups (-COOH) may be deprotonated to carboxylate groups (-COO - ), and / or one or more amino groups (-NH2) may be protonated to -NH3 + In some embodiments, semaglutide is in the form of a salt.

[0026] Pharmaceutical composition

[0027] The compound semaglutide can be administered in the form of a pharmaceutical composition. The pharmaceutical composition may contain semaglutide at a concentration of 0.01 mg / ml to 100 mg / ml. In some embodiments, the pharmaceutical composition contains 0.01-50 mg / ml, or 0.01-20 mg / ml, or 0.01-10 mg / ml of semaglutide. In some embodiments, the pharmaceutical composition contains 0.1-20 mg / ml of semaglutide.

[0028] The pharmaceutical composition described herein may further include one or more pharmaceutically acceptable adjuvants, for example, selected from a buffer system, a preservative, a tonicity agent, a chelating agent, a stabilizer and a surfactant. In some embodiments, the pharmaceutical composition includes one or more pharmaceutically acceptable adjuvants, for example, selected from one or more of a buffer, an isotonic agent and a preservative. The formulation of pharmaceutically active ingredients and various adjuvants is known in the art, see, for example, Remington: The Science and Practice of Pharmacy (e.g., the 19th edition (1995) and any subsequent editions). The term "adjuvant" broadly refers to any component other than active therapeutic ingredients such as the compound of the present invention. An adjuvant can be an inert substance, an inactive substance and / or a non-pharmaceutically active substance.

[0029] In some embodiments, the pharmaceutical composition comprises a phosphate buffer, such as a sodium phosphate buffer, e.g., 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.

[0030] The pharmaceutical composition may be in the form of a tablet. The pharmaceutical composition may contain semaglutide in an amount of 0.01 mg to 100 mg. In some embodiments, the pharmaceutical composition contains 0.01-50 mg, or 0.01-20 mg, or 0.01-10 mg semaglutide. The pharmaceutical composition may be in the form of a solution or a suspension. The pharmaceutical composition may be suitable for sublingual and / or oral administration. The pharmaceutical composition may be suitable for subcutaneous administration.

[0031] use

[0032] The product obtainable by the process of the present invention is intended to be used in a pharmaceutical composition together with one or more pharmaceutically acceptable excipients. In some embodiments, the product obtainable by the process of the present invention is characterized in that it contains less than 0.5%, or 0.4%, or 0.3%, or 0.2% impurities. In some embodiments, the product obtainable by the process of the present invention is used for subcutaneous administration. In some embodiments, the product obtainable by the process is used for sublingual and / or oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet.

[0033] In some embodiments, the products obtainable by the process of the present invention are used for medical purposes. In some embodiments, the products obtainable by the process of the present invention are used to prevent and / or treat obesity and / or diabetes. In some embodiments, the products obtainable by the process of the present invention are used to treat obesity. In some embodiments, the products obtainable by the process of the present invention are used to treat diabetes. In some embodiments, the products obtainable by the process of the present invention are used to prevent and / or treat overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and / or type 1 diabetes. In some embodiments, the products obtainable by the process of the present invention are used to prevent and / or treat NASH.

[0034] In some embodiments, the pharmaceutical composition is used to prevent and / or treat obesity and / or diabetes. In some embodiments, the pharmaceutical composition is used to treat obesity and / or diabetes. In some embodiments, the pharmaceutical composition is used to treat obesity. In some embodiments, the pharmaceutical composition is used to treat diabetes. In some embodiments, the pharmaceutical composition is used to prevent and / or treat overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and / or type 1 diabetes. In some embodiments, the pharmaceutical composition is used to prevent and / or treat NASH.

[0035] In some embodiments, the present invention relates to a method for 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 for 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 for 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 for 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 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 the present invention. In some embodiments, the present invention relates to a method for 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.

[0036] In some embodiments, the present invention relates to a method for preventing and / or treating obesity and / or diabetes, the method being by administering a therapeutically effective amount of the pharmaceutical composition to a subject in need. In some embodiments, the present invention relates to a method for treating obesity and / or diabetes, the method being by administering a therapeutically effective amount of the pharmaceutical composition to a subject in need. In some embodiments, the present invention relates to a method for treating obesity, the method being by administering a therapeutically effective amount of the pharmaceutical composition to a subject in need. In some embodiments, the present invention relates to a method for treating diabetes, the method being by administering a therapeutically effective amount of the pharmaceutical composition to a subject in need. In some embodiments, the present invention relates to a method for preventing and / or treating overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and / or type 1 diabetes, the method being by administering a therapeutically effective amount of the pharmaceutical composition to a subject in need. In some embodiments, the present invention relates to a method for preventing and / or treating NASH, the method being by administering a therapeutically effective amount of the pharmaceutical composition to a subject in need.

[0037] Unless otherwise stated, the ranges herein include their endpoints. In some embodiments, the term "a" means "one (kind) or more (kind)". In some embodiments, and unless otherwise stated in this specification, the terms presented in the singular also include plural cases. In this article, the term "about" refers to the value referred to ± 10%, and includes the value.

[0038] Non-limiting embodiments of the invention

[0039] The following are non-limiting embodiments of the present invention:

[0040] 1. A process for spray drying a feed solution containing semaglutide, the process comprising introducing a feed solution containing semaglutide in a solvent into a spray dryer, and introducing an atomizing gas and a drying gas, characterized in that the spray dryer comprises a gas heater for the drying gas, the inner surface of the gas heater comprising iron and less than 18.5% chromium.

[0041] 2. A process according to embodiment 1, characterised in that the inner surface comprises 1-18.5% chromium.

[0042] 3. Process according to any of the preceding embodiments, characterised in that the inner surface comprises 5-18.5% chromium.

[0043] 4. The process according to any of the preceding embodiments, characterized in that the inner surface comprises 10-18.5% chromium.

[0044] 5. The process according to any of the preceding embodiments, characterized in that the inner surface comprises 14-18.5% chromium.

[0045] 6. Process according to any of the preceding embodiments, characterised in that the inner surface comprises 16-18% chromium.

[0046] 7. A process according to any of the preceding embodiments, characterised in that the inner surface comprises less than 29% nickel.

[0047] 8. A process according to any of the preceding embodiments, characterised in that the inner surface comprises 1-29% nickel.

[0048] 9. The process according to any of the preceding embodiments, characterized in that the inner surface comprises 5-20% nickel.

[0049] 10. The process according to any of the preceding embodiments, characterized in that the inner surface comprises 6-18% nickel.

[0050] 11. The process according to any of the preceding embodiments, characterized in that the inner surface comprises 8-16% nickel.

[0051] 12. The process according to any of the preceding embodiments, characterized in that the inner surface comprises 10-14% nickel.

[0052] 13. Process according to any of the preceding embodiments, characterised in that the inner surface comprises 16-18% chromium and 10-14% nickel.

[0053] 14. The process according to any of the preceding embodiments, characterized in that the inner surface does not contain aluminum.

[0054] 15. The process according to any of the preceding embodiments, characterized in that the inner surface does not contain titanium.

[0055] 16. The process according to any one of the preceding embodiments, characterized in that the inner surface has a depth of 0.001-10 cm.

[0056] 17. Process according to any of the preceding embodiments, characterised in that the entire gas heater for the drying gas comprises iron and less than 18.5% chromium.

[0057] 18. The process according to any of the preceding embodiments, characterized in that the feed solution consists essentially of semaglutide in a solvent.

[0058] 19. The process according to any one of the preceding embodiments, characterized in that the feed solution solvent comprises an organic alcohol solvent.

[0059] 20. The process according to any one of the preceding embodiments, characterized in that the feed solution solvent comprises ethanol.

[0060] 21. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises an aqueous ethanol solution.

[0061] 22. The process according to any one of the preceding embodiments, characterized in that the feed solution solvent is 40-75% (w / w) ethanol in water.

[0062] 23. The process according to any one of the preceding embodiments, characterized in that the feed solution solvent is 45-70% (w / w) ethanol in water.

[0063] 24. The process according to any one of the preceding embodiments, characterized in that the feed solution solvent is 49-60% (w / w) ethanol in water.

[0064] 25. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.1-10% (w / w) semaglutide.

[0065] 26. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.2-5% (w / w) semaglutide.

[0066] 27. The process according to any of the preceding embodiments, characterized in that the feed solution comprises 0.3-3% (w / w) semaglutide.

[0067] 28. The process according to any of the preceding embodiments, characterized in that the feed solution comprises 0.5-2.5% (w / w) semaglutide.

[0068] 29. The process according to any one of the preceding embodiments, characterized in that the feed solution comprises 0.1-10% (w / w) semaglutide in 40-75% (w / w) ethanol in water.

[0069] 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) ethanol in water.

[0070] 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) semaglutide in 49-60% (w / w) ethanol in water.

[0071] 32. The process according to any of the preceding embodiments, characterized in that the drying gas is nitrogen.

[0072] 33. The process according to any of the preceding embodiments, characterized in that the drying gas is recycled.

[0073] 34. The process according to any of the preceding embodiments, characterized in that the atomizing gas is nitrogen.

[0074] 35. The process according to any one of the preceding embodiments, characterized in that the atomizing gas flow rate is 18-77 kg / h.

[0075] 36. The process according to any of the preceding embodiments, characterized in that the outlet temperature is 57-79°C.

[0076] 37. The process according to any of the preceding embodiments, characterized in that the inlet temperature is 100-162°C.

[0077] 38. The process according to any of the preceding embodiments, characterized in that the feed flow rate is 24-56 kg / h.

[0078] 39. The process according to any of the preceding embodiments, characterized in that the condenser temperature is between -5 and 5°C.

[0079] 40. The process according to any of the preceding embodiments, characterized in that the drying gas flow rate is 1250-1550 kg / h.

[0080] 41. The process according to any of the preceding embodiments, characterized by having a nozzle with an inner diameter of 1.0 mm and an outer diameter of 5-6.5 mm.

[0081] 42. The process according to any one of the preceding embodiments, further comprising the step of formulating semaglutide obtained by the process into a pharmaceutical composition.

[0082] 43. The process of embodiment 42, wherein the pharmaceutical composition is a solid or liquid pharmaceutical composition.

[0083] 44. The process of embodiment 42, wherein the pharmaceutical composition is a tablet.

[0084] 45. A product obtainable by a process according to any one of the preceding embodiments.

[0085] 46. ​​The product according to embodiment 45, characterized in that it contains less than 0.5%, or 0.4%, or 0.3%, or 0.2% impurities.

[0086] 47. A pharmaceutical composition comprising a therapeutically effective amount of a product according to any one of embodiments 45-46.

[0087] 48. The pharmaceutical composition according to embodiment 47, further comprising one or more pharmaceutically acceptable excipients.

[0088] 49. The pharmaceutical composition according to any one of embodiments 47-48, which is suitable for sublingual and / or oral administration.

[0089] 50. The pharmaceutical composition according to any one of embodiments 47-49, which is suitable for subcutaneous administration.

[0090] 51. The pharmaceutical composition according to any one of embodiments 47-50, which is in the form of a tablet.

[0091] 52. The product according to any one of embodiments 45-46 or the pharmaceutical composition according to any one of embodiments 47-51 for use in medicine.

[0092] 53. The product according to any one of embodiments 45-46 or the pharmaceutical composition according to any one of embodiments 47-51 for use in preventing and / or treating obesity and / or diabetes.

[0093] 54. The product according to any one of embodiments 45-46 or the pharmaceutical composition according to any one of embodiments 47-51 for use in the treatment of obesity and / or diabetes.

[0094] 55. The product according to any one of embodiments 45-46 or the pharmaceutical composition according to any one of embodiments 47-51 for use in treating obesity.

[0095] 56. The product according to any one of embodiments 45-46 or the pharmaceutical composition according to any one of embodiments 47-51 for use in the treatment of diabetes.

[0096] 57. The product according to any one of embodiments 45-46 or the pharmaceutical composition according to any one of embodiments 47-51, for use in preventing and / or treating overweight, obesity, hyperglycemia, type 2 diabetes, impaired glucose tolerance and / or type 1 diabetes.

[0097] 58. The product according to any one of embodiments 45-46 or the pharmaceutical composition according to any one of embodiments 47-51 for use in preventing and / or treating NASH.

[0098] 59. A method for 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 1-44, a product according to any one of embodiments 45-46, or a pharmaceutical composition according to any one of embodiments 47-51.

[0099] 60. A method for 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.

[0100] 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.

[0101] 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.

[0102] 63. A method for 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.

[0103] 64. A method for 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.

[0104] Example

[0105] General Methods

[0106] Spray drying experiments were carried out on a PSD4 production-scale spray dryer using a two-fluid nozzle with an inner diameter of 1 mm and an outer diameter of 5-6.5 mm. The atomizing gas was nitrogen and the drying gas was nitrogen. The drying gas was recirculated through a condensing unit at -5 to 5 °C and then heated using a gas heater whose inner surface was made of Incoloy 800 or stainless steel 316.

[0107] Feed solution preparation

[0108] The feed solution was either 1) received as semaglutide in a water / ethanol solution from a previous manufacturing step, or 2) was a spray dried powder comprising semaglutide that was redissolved in an appropriate water / ethanol composition prior to processing. When tested, semaglutide was tested in a concentration range of 7.8 to 24 g / l, and the ethanol weight percentage of the solvent system ranged from 49-60%.

[0109] Spray drying process:

[0110] The solvent used for stabilization matched the water / ethanol composition of the semaglutide-containing solution (49-60% (w / w) ethanol).

[0111] Prior to batch start, the spray dryer was stabilized with solvent at the desired set point values ​​(predefined from Table 1 below) for drying gas flow, outlet temperature, feed flow, atomizing gas flow and condenser temperature, and the inlet temperature was adjusted to obtain the desired outlet temperature.

[0112] parameter Test lower limit Testing upper limit Outlet temperature[℃] 57 79 Atomizing gas flow rate [kg / h] 18 77 Feed flow rate [kg / h] 24 56 Inlet temperature [℃] 100 162 Condenser temperature -5 5 Drying gas flow rate [kg / h] 1250 1550 Semaglutide concentration [mg / ml] 7.8 24.0 Ethanol concentration in solvent [%] 49 60

[0113] Table 1: Lower and upper limits of parameters tested in the spray drying process.

[0114] Once stable parameters are reached, switch from the stabilizing solvent to the semaglutide feed solution to start the spray drying process. Collect the product at predetermined intervals using a filter bag sleeve with bag backflushing or using a cyclone as the primary powder separation technique. At the end of the spray drying run, switch the semaglutide feed solution to the stabilizing solvent before the unit is shut down or stabilized for the next batch.

[0115] Example 1: Spray drying of semaglutide using different heater materials

[0116] Purpose: The purpose of this experiment is to determine the causes of impurity formation and means to prevent impurity formation.

[0117] Data Analysis:

[0118] Standard least squares analysis was performed using SAS Software version 12.2 Analysis Table 2, Figure 1 and Figure 2 The data presented in . The acetaldehyde level in the spray-dried powder was modeled as the response, which was positively affected by the gas heater material and inlet temperature, and negatively affected by the feed flow rate. By modeling the impurity increase as the response, it was positively affected by both the acetaldehyde level in the spray-dried powder and the inlet temperature, although the relationship between these two parameters was not deconvoluted.

[0119]

[0120]

[0121] Table 2: Acetaldehyde and impurity levels in response to different gas heater materials.

[0122] Table 2 and Figure 1 The results in show that a small amount of acetaldehyde is generated when the spray drying process is performed in the first unit including a gas heater made of stainless steel 316. When the spray drying process is performed in the second unit including a gas heater made of Incoloy 800, an increased amount of acetaldehyde is generated. When the Incoloy 800 gas heater material in the second unit is replaced with stainless steel 316, a small amount of acetaldehyde is generated. This indicates that a reduced amount of acetaldehyde is generated when a gas heater made of stainless steel 316 is used in the spray drying process compared to when a gas heater made of Incoloy 800 is used.

[0123] Table 2 and Figure 2The results in show that no impurity levels were measured for the first unit because no problems had been found. When the spray drying process was performed in the second unit including a gas heater made of Incoloy 800, a large amount of impurities were generated. When the Incoloy 800 gas heater material in the second unit was replaced with stainless steel 316, a small amount of impurities were generated. This indicates that the use of a gas heater made of stainless steel 316 in the spray drying process generates a reduced amount of impurities compared to the use of a gas heater made of Incoloy 800. In addition, Figure 2 The correlation between the acetaldehyde generated and the impurities generated is shown.

[0124] Although certain features of the present invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents will now occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and changes that fall within the true scope of the invention.

Claims

1. A process for spray drying a feed solution comprising semaglutide, the process comprising introducing a feed solution comprising semaglutide in a solvent into a spray dryer, and introducing an atomizing gas and a drying gas, characterized in that The spray dryer includes a gas heater for the drying gas, the inner surface of the gas heater comprises iron, 16-18% chromium and 10-14% nickel, and the feed solution solvent comprises an organic alcohol solvent, and the drying gas is recycled.

2. The process according to claim 1, characterized in that The inner surface has a depth of 0.001 cm to 10 cm.

3. A process according to any one of the preceding claims 1 to 2, characterised in that The feed solution solvent includes ethanol.

4. The process according to claim 3, characterized in that The feed solution solvent includes ethanol aqueous solution.

5. Process according to claim 4, characterised in that The feed solution solvent is 40-75% (w / w) ethanol aqueous solution.

6. The process according to any one of the preceding claims 1-2 and 4-5, characterized in that The feed solution contains 0.1-10% (w / w) semaglutide.

7. Process according to claim 6, characterised in that The feed solution contains 0.1-10% (w / w) semaglutide in 40-75% (w / w) ethanol in water.

8. Process according to claim 7, characterised in that The feed solution contains 0.5-2.5% (w / w) semaglutide in 49-60% (w / w) ethanol in water.

9. The process according to any one of the preceding claims 1-2, 4-5 and 7-8, characterized in that The drying gas is nitrogen.

10. The process according to any one of the preceding claims 1-2, 4-5 and 7-8, characterized in that The atomizing gas was nitrogen.

11. A process according to any one of the preceding claims 1-2, 4-5 and 7-8, characterised in that The nebulizing gas flow rate was 18-77 kg / h.

12. The process according to any one of the preceding claims 1-2, 4-5 and 7-8, characterized in that The outlet temperature is 57-79°C.

13. The process according to any one of the preceding claims 1-2, 4-5 and 7-8, characterized in that Inlet temperature is 100-162˚C.

14. A process according to any one of the preceding claims 1-2, 4-5 and 7-8, characterised in that The feed flow rate was 24-56 kg / h.

15. The process according to any one of the preceding claims 1-2, 4-5 and 7-8, characterized in that The condenser temperature is -5 to 5˚C.

16. A process according to any one of the preceding claims 1-2, 4-5 and 7-8, characterised in that The drying gas flow rate is 1250-1550 kg / h.

17. The process according to any one of the preceding claims 1-2, 4-5 and 7-8, further comprising the step of formulating semaglutide obtained by the process into a pharmaceutical composition.

18. The process according to claim 17, wherein the pharmaceutical composition is a tablet.

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