Pharmaceutical formulations

Abstract

The problem to be solved by the present invention is to provide a non-invasive treatment of obesity that approaches the efficacy of bariatric surgery.SOLUTION: The present invention relates to an aqueous pharmaceutical formulation of semaglutide and calyglintide that can be administered using a suitable drug delivery device. When co-administered, semaglutide and calyglintide, and pharmaceutical formulations comprising them as disclosed herein, may be used in the treatment of individuals with medical conditions such as diabetes and obesity, and their associated co-morbidities.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to aqueous pharmaceutical formulations of semaglutide and caglilintide, which can be administered using a suitable drug delivery device. When administered simultaneously, semaglutide and caglilintide, and the pharmaceutical formulations comprising them disclosed herein, can be used to treat individuals with medical conditions such as diabetes and obesity, and their associated comorbidities. [Background technology]

[0002] Obesity, defined as abnormal or excessive fat accumulation in the body, is now recognized by the World Health Organization (WHO) as a rapidly growing disorder worldwide. It is a major risk factor for death and a number of serious conditions, such as type 2 diabetes and cardiovascular disease.

[0003] When diet and exercise alone are not sufficient to reduce body mass index (BMI) to an acceptable level, treatment with active pharmaceutical ingredients such as liraglutide, orlistat, and naltrexone-bupropion has been shown to cause weight loss in obese individuals. Nevertheless, bariatric surgery is often required. Although bariatric surgery is currently the most effective treatment for achieving long-term weight loss, it is an invasive procedure associated with patient risks and high costs. Therefore, a minimally invasive treatment with efficacy comparable to bariatric surgery would be a significant improvement in the treatment of obesity.

[0004] Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist and the active pharmaceutical ingredient in the marketed product Ozempic®. Ozempic® is indicated (i) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, and (ii) to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease. Semaglutide was first described in U.S. Patent No. 5,629,999.

[0005] Caglilintide, also known as AM833, is an amylin receptor agonist first described in US Patent No. 5,629,999. Caglilintide monotherapy is currently in clinical development for the treatment of obesity.

[0006] Nevertheless, there remains a long-felt need in the art for a non-invasive treatment for obesity that approaches the effectiveness of bariatric surgery. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2006 / 097537 [Patent Document 2] International Publication No. 2012 / 168432 Summary of the Invention

[0008] Disclosed herein are aqueous formulations, which comprise: -caglilintide, a buffer solution, which is glutamic acid / glutamate at a concentration of about 2-10 mM, or lactic acid / lactate at a concentration of about 2-35 mM, or acetic acid / acetate at a concentration of about 2-10 mM; -90-99% w / w water, A pH of -3.5 to 4.5, preferably about pH 4.0.

[0009] Disclosed herein are aqueous formulations, which comprise: Caglilintide in a concentration of 0.1 to 20 mg / ml; a buffer solution, which is glutamic acid / glutamate at a concentration of about 2-10 mM, or lactic acid / lactate at a concentration of about 2-35 mM, or acetic acid / acetate at a concentration of about 2-10 mM; This includes a pH of -3.5 to 4.5, for example about pH 4.0.

[0010] Disclosed herein are aqueous formulations, which comprise: -Semaglutide, - Phosphate at a concentration of more than 15 mM and not more than 45 mM, for example 16 to 45 mM, for example 20 to 45 mM, for example 20 to 40 mM, for example 25 to 45 mM, for example 25 to 40 mM, for example 20 to 35 mM, for example 20 to 30 mM, for example about 25 to 35 mM, for example about 30 mM; -90-99% w / w water, and a pH of -7.0 to 8.0, for example about 7.4.

[0011] Disclosed herein are aqueous formulations, which comprise: Semaglutide in a concentration of 0.1 to 10 mg / ml; - Phosphate at a concentration of more than 15 mM and less than or equal to 45 mM, for example 16 to 45 mM, for example 20 to 45 mM, for example 20 to 40 mM, for example 25 to 45 mM, for example 25 to 40 mM, for example 20 to 35 mM, for example about 25 to 35 mM, for example about 30 mM; and a pH of -7 to 8, for example about 7.4.

[0012] Disclosed herein is a medical device comprising the above-mentioned pharmaceutical formulation comprising semaglutide in a first chamber and the above-mentioned pharmaceutical formulation comprising caglilintide in a second chamber.

[0013] Disclosed herein is a medical device comprising a single dose of semaglutide in a first chamber and a single dose of caglilintide in a second chamber.

[0014] Disclosed herein is a fixed dose combination of 0.025 to 5.0 mg of caglilintide and 0.05 to 5.0 mg of semaglutide for use in medicine. [Brief explanation of the drawings]

[0015] [Figure 1]Figure 1 shows a model of a preferred drug delivery device according to an embodiment of the present invention. Two liquids are separated by the front (distal) plunger until injection, during which both plungers are pushed toward the needle. When the front plunger reaches the bypass, the liquid in the rear (proximal) chamber is forced into the front (distal) chamber. [Figure 2] Figure 2 shows the solubility of semaglutide over the pH range 3.5 to 7.5. Concentrations of approximately 0.6 mM or greater (corresponding to approximately 2.5 mg / ml) indicate that all added semaglutide has dissolved, i.e., the maximum solubility is greater than 0.6 mM when the pH is above about 5.9. Concentrations below about 0.6 mM indicate that less than the analyzed amount of semaglutide can be dissolved when the pH is below about 5.9. [Figure 3] Figure 3 shows the weight loss observed in subjects co-administered caglilintide and semaglutide. DETAILED DESCRIPTION OF THE INVENTION

[0016] This paper discloses a combination therapy of semaglutide and caglilintide for use in medicine.The study of this combination therapy using both semaglutide, a GLP-1 receptor agonist, and caglilintide, an amylin receptor agonist, has shown a very strong potential for weight loss, and their simultaneous administration in humans can result in weight loss close to or at the same level as that of bariatric surgery.This combination therapy may be the answer to the long-standing need in the art for a minimally invasive treatment equivalent to bariatric surgery.Moreover, surprisingly, this combination therapy causes undesirable side effects, such as gastrointestinal disorders, that are comparable to those commonly seen with GLP-1 receptor agonists alone.

[0017] Unfortunately, semaglutide and caglilintide cannot be formulated in the same pharmaceutical formulation. To ensure chemical and physical stability, semaglutide must be formulated at a pH of 7-8, e.g., pH 7.4. To ensure chemical and physical stability, caglilintide must be formulated at a pH of 3.5-4.5, e.g., pH 4.0. The two pharmaceutical formulations containing semaglutide and caglilintide, respectively, must be stored separately until they are administered.

[0018] However, subcutaneous drug delivery is often associated with discomfort, as many people dislike the idea of ​​inserting a needle through the skin. An unknown number of people even suffer from needle phobia. For these individuals, receiving the desired combination of semaglutide and caglilintide would be much less uncomfortable and more convenient if they had to inject them only once with a single needle; one injection instead of two would result in better adherence to treatment (improved compliance) and ultimately improved patient outcomes. Furthermore, administering caglilintide and semaglutide in a single injection, rather than separately, may affect the efficacy of these active pharmaceutical ingredients.

[0019] Because dual-chamber devices are known in the art, an initial attempt was made to use such a device for the sequential administration of (1) either Ozempic® or a semaglutide pharmaceutical formulation currently in clinical development, and (2) a caglilintide pharmaceutical formulation currently in clinical development.

[0020] Ozempic® and pharmaceutical formulations of semaglutide in clinical development are buffered with 8 mM phosphoric acid / phosphate salt, stabilizing the pH at approximately 7.4. Marketed Ozempic® contains phenol (5.5 mg / ml) as a preservative.

[0021] The caglilintide pharmaceutical formulation used in the Phase 1 and 2 clinical trials was buffered with 5 mM acetic acid / acetate salt to stabilize the pH at approximately 4.0. The formulation in the Phase 1 and 2 clinical trials also contained 20 mM m-cresol as a preservative, 23 mg / ml glycerol as an isotonicity agent, HCl / NaOH for pH adjustment, and water for injection (WFI).

[0022] The inventors of the present invention have found that the known semaglutide and caglilintide formulations used in Phase 1 and Phase 2 (monotherapy) clinical trials cannot be stored and administered using the preferred dual-chamber medical device. First, the pharmaceutical formulations were not stable during storage in the dual-chamber device. Second, particles were formed when the pharmaceutical formulations were injected through the device.

[0023] Disclosed herein are pharmaceutical formulations of semaglutide and caglilintide that are suitable for storage in and administration using a medical device, such as a dual-chamber device. Also disclosed herein are medical devices that include a semaglutide pharmaceutical formulation in one chamber and a caglilintide pharmaceutical formulation in the other chamber. Disclosed herein are solutions for bringing patients closer to minimally invasive obesity treatments comparable to bariatric surgery.

[0024] Caglilintide Caglilintide is an amylin receptor agonist, also known as AM833. It is the compound of Example 53 of WO2012 / 168432: N-alpha-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyryl]-[Glu14,Arg17,Pro37]-pramlintide. Caglilintide can be prepared as described in WO2012 / 168432, pages 153-155.

[0025] In some embodiments, caglilintide is in the form of a salt. In some embodiments, caglilintide is in the form of a pharmaceutically acceptable salt.

[0026] Semaglutide Semaglutide is a 6.26 -{18-[N-(17-carboxyheptadecanoyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl}-[8-(2-amino-2-propanoic acid),34-L-arginine] is a GLP-1 receptor agonist, also known as human glucagon-like peptide 1(7-37). Semaglutide is also described in WHO Drug Information Vol. 24, No. 1, 2010, and can be prepared as described in Example 4 of WO2006 / 097537.

[0027] In some embodiments, semaglutide may be present in the composition in its fully or partially ionized form, for example, one or more carboxylic acid groups (-COOH) may be replaced by a carboxylate group (-COO - ), and / or one or more amino groups (—NH2) may be deprotonated to —NH3 + The group may be protonated.

[0028] In some embodiments, the semaglutide is in the form of a salt. In some embodiments, the semaglutide is in the form of a pharmaceutically acceptable salt.

[0029] Pharmaceutical preparations The terms "pharmaceutical formulation," "formulation," "pharmaceutical composition," and "composition" are used interchangeably herein and refer to a pharmaceutical preparation suitable for administration to a subject in need thereof. To those skilled in the art, pharmaceutical formulations and compositions are also known as "medicinal products." Two liquid pharmaceutical formulations suitable for parenteral injection, preferably subcutaneous injection, are disclosed herein. One of the pharmaceutical formulations contains caglilintide as the only active pharmaceutical ingredient. The other pharmaceutical formulation contains semaglutide as the only active pharmaceutical ingredient.

[0030] Pharmaceutical preparations containing caglilintide Disclosed herein is an aqueous liquid pharmaceutical formulation comprising caglilintide as the sole active pharmaceutical ingredient. Compared to known formulations, the caglilintide formulations disclosed herein have improved chemical and / or physical stability, such as a reduced tendency to form HMWPs during storage. Pharmaceutical formulations comprising caglilintide are suitable for storage in and administration using suitable medical devices, such as dual-chamber devices. The composition of the pharmaceutical formulation comprising caglilintide can be such that caglilintide is physically and chemically stable during storage in the medical device, even when in contact with the material of the chamber in which it is stored. The composition of the pharmaceutical formulation comprising caglilintide can be such that caglilintide is physically and chemically stable during discharge from the medical device in which it was stored.

[0031] In some embodiments, the pharmaceutical formulation comprising caglilintide is suitable for storage in and administration using a dual-chamber device, the latter also comprising, in a separate chamber, a pharmaceutical formulation comprising semaglutide as disclosed herein.

[0032] The pharmaceutical formulation comprising caglilintide may come into contact with the pharmaceutical formulation comprising semaglutide, since both formulations may, for example, pass through the same device outlet and the same needle of a dual-chamber device. The composition of the pharmaceutical formulation comprising caglilintide is preferably such that it does not adversely affect the chemical and / or physical stability of semaglutide during the time that passes between its discharge from the device in which it is stored and its injection into a subject.

[0033] In some embodiments the pharmaceutical formulation comprises 0.1 to 20 mg / ml of caglilintide, such as 0.32 to 18 mg / ml, for example 0.5 to 18 mg / ml, such as about 1.0 mg / ml, for example about 2.0 mg / ml, such as at least 2 mg / ml, for example about 4.0 mg / ml, such as about 4.8 mg / ml, for example about 6.8 mg / ml, for example about 9.6 mg / ml, such as about 18 mg / ml.

[0034] In some embodiments, the formulation contains 1 to 19 mg / ml of caglilintide. In some embodiments, the formulation contains 2 to 18 mg / ml of caglilintide. In some embodiments, the formulation contains 3 to 17 mg / ml of caglilintide. In some embodiments, the formulation contains 4 to 16 mg / ml of caglilintide. In some embodiments, the formulation contains 5 to 15 mg / ml of caglilintide. In some embodiments, the formulation contains 6 to 14 mg / ml of caglilintide. In some embodiments, the formulation contains 7 to 13 mg / ml of caglilintide. In some embodiments, the formulation contains 8 to 12 mg / ml of caglilintide. In some embodiments, the formulation contains 9 to 11 mg / ml of caglilintide. In a preferred embodiment, the formulation contains 9.6 mg / ml of caglilintide.

[0035] In some embodiments, the formulation contains 20 mg / ml or less of caglilintide. In some embodiments, the formulation contains 19 mg / ml or less of caglilintide. In some embodiments, the formulation contains 18 mg / ml or less of caglilintide. In some embodiments, the formulation contains 17 mg / ml or less of caglilintide. In some embodiments, the formulation contains 16 mg / ml or less of caglilintide. In some embodiments, the formulation contains 15 mg / ml or less. In some embodiments, the formulation contains 14 mg / ml or less of caglilintide. In some embodiments, the formulation contains 13 mg / ml or less of caglilintide. In some embodiments, the formulation contains 12 mg / ml or less of caglilintide. In some embodiments, the formulation contains 11 mg / ml or less of caglilintide. In some embodiments, the formulation contains 10 mg / ml or less of caglilintide. In some embodiments, the formulation contains 9 mg / ml or less of caglilintide. In some embodiments, the formulation contains 8 mg / ml or less of caglilintide. In some embodiments, the formulation contains 7 mg / ml or less of caglilintide. In some embodiments, the formulation contains 6 mg / ml or less of caglilintide. In some embodiments, the formulation contains 5 mg / ml or less of caglilintide.

[0036] In some embodiments, the formulation comprises at least 0.5 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 1 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 2 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 3 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 4 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 5 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 6 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 7 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 8 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 9 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 10 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 11 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 12 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 13 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 14 mg / ml of caglilintide. In some embodiments, the formulation comprises at least 15 mg / ml of caglilintide.

[0037] The formulation may include at least one pharmaceutically acceptable excipient.

[0038] Formulation of caglilintide at a pH of 3.5 to 4.5, for example at about pH 4, ensures chemical as well as physical stability of the active pharmaceutical ingredient.

[0039] In some embodiments, the pH is measured at room temperature, for example, 15-25° C. In some embodiments, the formulation includes a buffer with a pKa that is close to the desired pH of the solution.

[0040] In some embodiments, the buffer in the pharmaceutical formulation comprising caglilintide is lactate / lactic acid. In some embodiments, the buffer in the pharmaceutical formulation comprising caglilintide is lactate / lactic acid at a concentration of about 2 to 35 mM, such as 2 to 30 mM, for example, 2 to 25 mM, for example, 2 to 20 mM, for example, 2 to 15 mM, for example, 2 to 10 mM, for example, 2.5 to 10 mM, for example, 5 to 10 mM, for example, 2 to 9 mM, for example, 2 to 8 mM, about 2 to 7 mM, for example, about 2 to 6 mM, for example, about 2.5 to 5 mM, for example, about 5 mM.

[0041] In some embodiments, the buffer in the pharmaceutical formulation comprising caglilintide is glutamate / glutamic acid. In some embodiments, the buffer in the pharmaceutical formulation comprising caglilintide is glutamate / glutamic acid at a concentration of 2 to 10 mM, for example, 2.5 to 10 mM, for example, 5 to 10 mM, for example, 2 to 9 mM, for example, 2 to 8 mM, for example, 2.5 to 7.5 mM, for example, 2 to 7 mM, for example, 2 to 6 mM, for example, 4 to 6 mM, for example, about 2.5 to 5 mM, for example, about 5 mM.

[0042] In some embodiments, the buffer in the pharmaceutical formulation comprising caglilintide is acetic acid / acetate. In some embodiments, the buffer in the pharmaceutical formulation comprising caglilintide is acetic acid / acetate at a concentration of about 2 to 10 mM, for example, 2.5 to 10 mM, for example, 2 to 9 mM, for example, 2 to 8 mM, for example, 2 to 7 mM, for example, 2 to 6 mM, for example, about 2.5 to 5.0 mM, for example, about 5 mM.

[0043] The concentration of the buffer in the pharmaceutical formulation containing caglilintide must be high enough to ensure sufficient pH stability during storage in the medical device, of about 3.5 to 4.5, for example about pH 4.0. The concentration of the buffer in the pharmaceutical formulation containing caglilintide must also be low enough to prevent the pH from dropping to a level that would cause semaglutide to precipitate or form particles during discharge from the device and injection into a subject (and therefore mixing with the pharmaceutical formulation containing semaglutide).

[0044] A pharmaceutical formulation comprising caglilintide may further comprise an isotonicity agent. The purpose of the isotonicity agent may be to protect living tissue when the formulation is injected into the body. For example, the presence of the isotonicity agent may make the injection relatively painless or prevent necrosis. The isotonicity agent may be selected from the group consisting of glycerol, mannitol, propylene glycol, sorbitol, sucrose, or trehalose. The isotonicity agent may be selected from the group consisting of glycerol, mannitol, sorbitol, sucrose, or trehalose. In some embodiments, the isotonicity agent is glycerol. In some embodiments, the isotonicity agent is mannitol. In some embodiments, the isotonicity agent is propylene glycol. In some embodiments, the isotonicity agent is sorbitol. In some embodiments, the isotonicity agent is sucrose. In some embodiments, the isotonicity agent is trehalose.

[0045] The concentration of the tonicity agent is such as to make the formulation isotonic.

[0046] When the tonicity agent is glycerol, it may be present at a concentration of 20-31 mg / ml, for example about 24 mg / ml.

[0047] When the tonicity agent is mannitol, it may be present at a concentration of 40-60 mg / ml, for example about 46 mg / ml.

[0048] When the tonicity agent is propylene glycol, it may be present in a concentration of 17 to 26 mg / ml, for example about 20 mg / ml.

[0049] When the tonicity agent is sorbitol, it may be present at a concentration of 40-60 mg / ml, for example about 46 mg / ml.

[0050] When the tonicity agent is sucrose, it may be present at a concentration of 73 to 105 mg / ml, for example about 83 mg / ml.

[0051] When the tonicity agent is trehalose, it may be present at a concentration of 73 to 105 mg / ml, for example about 83 mg / ml.

[0052] The pharmaceutical formulation may further include one or more agents for adjusting pH, such as NaOH and / or HCl.

[0053] The pharmaceutical formulation comprises water for injection (WFI). The pharmaceutical formulation may comprise more than 90% w / w water, such as 90-99% w / w water, for example 91-99% w / w water, for example 92-99% w / w water, for example 93-99% w / w water, for example 94-99% w / w water, for example more than 91% w / w water, such as more than 92% w / w water, for example more than 93% w / w water, for example more than 94% w / w water, such as about 95% w / w water, for example more than 95% w / w water, such as about 96% w / w water, for example more than 96% w / w water, for example about 97% w / w water, for example more than 97% w / w water, such as about 98% w / w water, for example more than 98% w / w water.

[0054] In some embodiments, the caglilintide formulation is preservative-free. In some embodiments, the pharmaceutical formulation is m-cresol-free.

[0055] The caglilintide formulations disclosed herein are suitable for use in medicines.

[0056] The caglilintide formulations disclosed herein are suitable for parenteral administration, such as subcutaneous administration.

[0057] Pharmaceutical preparations containing semaglutide Disclosed herein is an aqueous liquid pharmaceutical formulation comprising semaglutide as the only active pharmaceutical ingredient.The pharmaceutical formulation comprising semaglutide is suitable for storage in and administration using a suitable medical device, such as a dual-chamber device.The composition of the pharmaceutical formulation comprising semaglutide is preferably such that semaglutide is physically and chemically stable during storage in the device and in contact with the material of the chamber in which it is stored.The composition of the semaglutide pharmaceutical formulation is preferably such that semaglutide remains chemically and / or physically stable during discharge from the device and injection into a subject.

[0058] During parenteral injection, the pharmaceutical formulation containing semaglutide may come into contact with the pharmaceutical formulation containing caglilintide as both formulations are ejected through the same device outlet / needle of the dual-chamber device. The composition of the pharmaceutical formulation containing semaglutide may be such that it does not have a deleterious effect on the chemical and / or physical stability of semaglutide during the time that elapses during ejection from the device and injection into a subject.

[0059] Disclosed herein is a liquid pharmaceutical formulation comprising semaglutide, which comprises 0.1% (w / w) or less of phenol, sodium chloride, and / or potassium chloride.

[0060] In some embodiments, the pharmaceutical formulation comprising semaglutide is suitable for storage in and administration using a dual-chamber medical device, the latter also comprising, in a separate chamber, a pharmaceutical formulation comprising semaglutide as disclosed herein.

[0061] In some embodiments, the formulation contains 0.1 to 10 mg / ml semaglutide. In some embodiments, the formulation contains 1 to 9 mg / ml semaglutide. In some embodiments, the formulation contains 2 to 8 mg / ml semaglutide. In some embodiments, the formulation contains 3 to 7 mg / ml semaglutide. In some embodiments, the formulation contains 4 to 6 mg / ml semaglutide.

[0062] In some embodiments, the formulation contains 0.1 to 5 mg / ml semaglutide. In some embodiments, the formulation contains 0.5 to 5.0 mg / ml semaglutide. In some embodiments, the formulation contains 4.0 to 5.5 mg / ml semaglutide. In some embodiments, the formulation contains 4.5 to 6.0 mg / ml semaglutide. In some embodiments, the formulation contains 4.5 to 5.0 mg / ml semaglutide.

[0063] In preferred embodiments, the formulation contains about 0.5 mg / ml, about 1.0 mg / ml, about 2.0 mg / ml, about 3.4 mg / ml, or about 4.8 mg / ml of semaglutide.

[0064] In some embodiments, the concentration of semaglutide is 0.5 to 10 mg / ml or 0.01 to 3.5 mg / ml of the pharmaceutical formulation. In some embodiments, the concentration of semaglutide is 0.5 mg / ml, alternatively 1 mg / ml, alternatively 1.5 mg / ml, alternatively 2 mg / ml, alternatively 2.5 mg / ml, alternatively 3 mg / ml, alternatively 3.5 mg / ml.

[0065] In some embodiments, the formulation contains 10 mg / ml or less of semaglutide. In some embodiments, the formulation contains 9 mg / ml or less of semaglutide. In some embodiments, the formulation contains 8 mg / ml or less of semaglutide. In some embodiments, the formulation contains 7 mg / ml or less of semaglutide. In some embodiments, the formulation contains 6 mg / ml or less of semaglutide. In some embodiments, the formulation contains 5 mg / ml or less. In some embodiments, the formulation contains 4 mg / ml or less of semaglutide. In some embodiments, the formulation contains 3 mg / ml or less of semaglutide. In some embodiments, the formulation contains 2 mg / ml or less of semaglutide. In some embodiments, the formulation contains 1 mg / ml or less of semaglutide.

[0066] In some embodiments, the formulation contains at least 0.5 mg / ml semaglutide. In some embodiments, the formulation contains at least 1 mg / ml semaglutide. In some embodiments, the formulation contains at least 2 mg / ml semaglutide. In some embodiments, the formulation contains at least 3 mg / ml semaglutide. In some embodiments, the formulation contains at least 4 mg / ml semaglutide. In some embodiments, the formulation contains at least 5 mg / ml semaglutide. In some embodiments, the formulation contains at least 6 mg / ml semaglutide. In some embodiments, the formulation contains at least 7 mg / ml semaglutide. In some embodiments, the formulation contains at least 8 mg / ml semaglutide. In some embodiments, the formulation contains at least 9 mg / ml semaglutide.

[0067] In a preferred embodiment, the formulation contains 4.8 mg / ml semaglutide.

[0068] The formulation may include at least one pharmaceutically acceptable excipient.

[0069] The pH of pharmaceutical formulations containing semaglutide must always be above about 5.9 to ensure that semaglutide remains soluble in water (see Figure 2). The pH of pharmaceutical formulations containing semaglutide must be above about 5.9 during storage and administration.

[0070] In some embodiments, the semaglutide formulation has a pH in the range of 6 to 9. In some embodiments, the semaglutide formulation has a pH in the range of 6.5 to 8.5. In some embodiments, the semaglutide formulation has a pH in the range of 7.0 to 8.2, for example 7.0 to 8.0, for example 7.0 to 7.8. In some embodiments, the semaglutide formulation has a pH of about 7.4. Formulation of semaglutide at a pH of 7 to 8, for example about pH 7.4, ensures the chemical and physical stability of the active pharmaceutical ingredient.

[0071] In some embodiments, the pH is measured at room temperature, for example, 15-25° C. In some embodiments, the pharmaceutical formulation includes a buffer with a pKa that is close to the desired pH of the solution.

[0072] In some embodiments, the buffer is a phosphate buffer, which may be selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and / or tripotassium phosphate.

[0073] The concentration of the phosphate buffer may be more than 15 mM and not more than 45 mM, for example, 16 to 45 mM, for example, 20 to 45 mM, for example, 20 to 40 mM, for example, 25 to 45 mM, for example, 25 to 40 mM, for example, 20 to 35 mM, for example, about 25 to 35 mM, for example, about 30 mM.

[0074] In some embodiments, the pharmaceutical formulation includes a tonicity agent. The purpose of the tonicity agent may be to protect living tissue when the formulation is injected into the body. For example, the presence of the tonicity agent may make the injection relatively painless or prevent necrosis. The tonicity agent may be selected from the group consisting of propylene glycol, potassium chloride, and / or sodium chloride. In some embodiments, the formulation includes an isotonicity agent such as propylene glycol or sodium chloride. In some embodiments, the isotonicity agent is propylene glycol and / or sodium chloride. In some embodiments, the isotonicity agent is not propylene glycol. In some embodiments, the isotonicity agent is sodium chloride and / or potassium chloride. In some embodiments, the isotonicity agent is sodium chloride.

[0075] The concentration of the tonicity agent can be such to achieve isotonicity in vivo. In a preferred embodiment, the tonicity agent is sodium chloride at a concentration sufficient to achieve isotonicity.

[0076] In some embodiments, the tonicity agent is sodium chloride at a concentration of 4.5 to 8.5 mg / ml, such as 5.0 to 8.5 mg / ml, for example 5.5 to 8.5 mg / ml, for example 6.0 to 8.5 mg / ml, such as 7.0 to 8.25 mg / ml, for example 4.5 to 7.0, such as 5.0 to 7.5 mg / ml, for example 5.0 to 7.0 mg / ml, such as 5.5 to 7 mg / ml, for example 6.4 to 7.9 mg / ml, for example 6.4 to 7.5 mg / ml, such as 6 to 7 mg / ml, for example greater than 6.4 mg / ml, such as about 5.4 mg / ml, for example about 6.4 mg / ml, for example about 6.7 mg / ml.

[0077] In some embodiments, the tonicity agent is potassium chloride at a concentration of 5.5 to 11 mg / ml, for example, about 8.2 mg / ml.

[0078] In some embodiments, the formulation does not include an additional tonicity agent.

[0079] In some embodiments, the pharmaceutical formulation comprises histidine. In some embodiments, the concentration of histidine is 0-20 mM, alternatively 0.5-20 mM, alternatively 0.5-15 mM, alternatively 0.5-10 mM. In some aspects, the concentration of histidine is 1-20 mM, such as 2-20 mM, for example 2-15 mM, for example 2-10 mM, for example 5-20 mM, for example 5-15 mM, for example 5-10 mM, for example 10-20 mM, for example 10-15 mM. In some embodiments, the concentration of histidine is 5-15 mM, for example 8-12 mM, for example about 10 mM.

[0080] Aqueous semaglutide formulations comprise water for injection (WFI). The semaglutide formulation comprises more than 60% w / w water, such as more than 90% w / w water, for example 90-99% w / w water, for example 91-99% w / w water, for example 92-99% w / w water, for example 93-99% w / w water, such as 94-99% w / w water, for example 95-99% w / w water, for example 96-99% w / w water, such as 97-99% w / w water, for example 98-99% w / w water, for example at least 91% w / w water, such as at least 92% w / w water, for example at least 93% w / w water, such as at least 94% w / w water, for example about 95% w / w water, such as at least 95% w / w water, for example about 96% w / w water, such as at least 96% w / w water, for example about 97% w / w water, such as at least 97% w / w water, for example about 98% w / w, such as at least 98% w / w water.

[0081] The pharmaceutical formulation may further include one or more agents for adjusting pH, such as NaOH and / or HCl.

[0082] In some embodiments, the pharmaceutical formulations disclosed herein are preservative-free. In some embodiments, the formulations are essentially preservative-free. In some embodiments, the pharmaceutical formulations are phenol-free.

[0083] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, for example 0.01 to 3.5 mg / ml semaglutide or 0.5 to 10 mg / ml semaglutide, optionally b) 0.1% (w / w) or less phenol, c) a tonicity agent, d) a buffer, e) at least 60% water, and f) histidine. In some embodiments, the tonicity agent is sodium chloride.

[0084] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, for example 0.01 to 3.5 mg / ml semaglutide or 0.5 to 10 mg / ml semaglutide, optionally b) 0.1% (w / w) or less phenol, c) sodium chloride as an isotonicity agent, d) buffer, e) at least 60% water, and f) histidine.

[0085] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, for example 0.01 to 3.5 mg / ml semaglutide or 0.5 to 10 mg / ml semaglutide, optionally b) 0.1% (w / w) or less phenol, c) 2 to 12 mg / ml sodium chloride, for example 3 to 12 mg / ml, such as 4 to 12 mg / l, for example 5 to 12 mg / ml, for example 6 to 12 mg / ml sodium chloride, d) buffer, e) at least 60% water, and f) histidine.

[0086] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, for example 0.1 to 10 mg / ml semaglutide or 0.5 to 10 mg / ml semaglutide, optionally b) 0.1% (w / w) or less phenol, c) 5.0 to 7.0 mg / ml sodium chloride, for example 5.4 or 6.7 mg / ml, d) buffer, e) at least 60% water, and f) histidine.

[0087] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, for example 0.1 to 10 mg / ml semaglutide or 0.5 to 10 mg / ml semaglutide, optionally b) phenol at 0.1% (w / w) or less, c) sodium chloride, d) phosphate, e) water for injection, f) histidine, and optionally NaOH / HCl to reach a pH of 7 to 8, for example about pH 7.4.

[0088] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, for example 0.1 to 10 mg / ml semaglutide or 0.5 to 10 mg / ml semaglutide, optionally b) 0.1% (w / w) or less phenol, c) about 6.4 mg / ml or more than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, and f) histidine.

[0089] In some embodiments, the pharmaceutical formulation consists of, or consists essentially of, a) semaglutide, optionally b) 0.1% (w / w) or less phenol, c) greater than 6.4 mg / ml sodium chloride, d) buffer, e) at least 60% water, optionally f) histidine, and optionally g) one or more agents for adjusting pH such as HCl, NaOH, or acetate, and the formulation optionally has a pH of 6 to 10, for example 7 to 8.

[0090] In some embodiments, the pharmaceutical formulation consists of, or consists essentially of, a) semaglutide, optionally b) 0.1% (w / w) or less phenol, c) greater than 6.4 mg / ml sodium chloride, d) buffer, e) at least 97% water, optionally f) histidine, and optionally g) one or more agents to adjust pH such as HCl, NaOH, or acetate, and the formulation optionally has a pH of 7 to 8.

[0091] In some embodiments, the pharmaceutical formulation consists of, or consists essentially of, a) semaglutide, optionally b) 0.1% (w / w) or less phenol, c) greater than 6.4 mg / ml sodium chloride, d) buffer, e) at least 60% water, f) histidine, optionally g) one or more agents to adjust pH such as HCl, NaOH, or an acetate such as sodium acetate or acetic acid, and the formulation optionally has a pH of 6 to 10, for example 7 to 8.

[0092] In some embodiments, the pharmaceutical formulation consists of, or consists essentially of, a) semaglutide, optionally b) 0.1% (w / w) or less phenol, c) greater than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 60% water, and optionally f) one or more agents for adjusting pH, such as HCl, NaOH, or acetate, and the formulation optionally has a pH of 6 to 10, for example 7 to 8.

[0093] In some embodiments, the pharmaceutical formulation consists of, or consists essentially of, a) semaglutide, optionally b) 0.1% (w / w) or less phenol, c) greater than 6.4 mg / ml sodium chloride, d) a buffer, e) at least 97% water (e.g. 97-99%), optionally f) one or more agents for adjusting pH, such as HCl, NaOH, or acetate, and the formulation optionally has a pH of 6-10, for example 7-8.

[0094] In some embodiments, the semaglutide formulation is for parenteral administration, hi some embodiments, the semaglutide formulation is for subcutaneous administration.

[0095] In some embodiments, the semaglutide formulation is for use in an injection device.

[0096] Suitable medical devices The medical device can be used to administer a predetermined dose of caglilintide together with a predetermined dose of semaglutide in a single injection.The medical device can be used to administer a single dose of caglilintide, such as a single effective dose, together with a single dose of semaglutide, such as a single effective dose, in a single injection.The medical device can be used to administer a caglilintide pharmaceutical formulation together with a semaglutide pharmaceutical formulation in a single injection.The medical device can be or include a variable-volume drug reservoir or drug delivery device, and can include a first chamber and a second chamber, which are fluidly disconnected in the medical device before storage or injection.For example, the medical device can be a dual-chamber device including a tubular wall portion extending along a reference axis, and the first chamber and the second chamber are arranged consecutively along the reference axis.The dual-chamber device can extend between a distal end and a proximal end, and can further include a drug outlet portion arranged at the distal end.

[0097] A first elastomeric stopper can be disposed in sealing contact with the tubular wall between the drug exit portion and the proximal end to define the first chamber as a distal chamber, and a second elastomeric stopper can be disposed in sealing contact with the tubular wall between the first elastomeric stopper and the proximal end to define the second chamber as a proximal chamber.

[0098] Based on the desire to promote user convenience by providing a medical device with small physical dimensions, and taking into account the selected respective concentrations and clinically relevant expected ratios of the caglilintide pharmaceutical formulation and the semaglutide pharmaceutical formulation, the distal chamber may contain a semaglutide pharmaceutical formulation, and the proximal chamber may contain a caglilintide pharmaceutical formulation. From the standpoint of stability, this particular configuration may be even more advantageous when considering the process of filling the two chambers, because the caglilintide pharmaceutical formulation has a higher surface reactivity than the semaglutide pharmaceutical formulation, making it difficult to avoid introducing a certain amount of air into the distal chamber by conventional filling methods.

[0099] The dual-chamber device may further include a passage means for allowing passage of fluid from the proximal chamber to the distal chamber through and / or through the first elastomeric stopper. For example, the tubular wall may include a bypass shape that allows passage of fluid from the proximal chamber to the distal chamber through the first elastomeric stopper when the first elastomeric stopper is in a particular bypass position relative to the tubular wall. In this case, the first elastomeric stopper is disposed proximal to the bypass shape in the dual-chamber device in a pre-injection state and is adapted to move to the bypass position for a dose administration event.

[0100] The drug outlet portion can be configured to allow the liquid drug to be ejected as a high-pressure jet through a syringe needle or through a nozzle. In the former case, the syringe needle can be pre-attached at the drug outlet portion, e.g., attached thereto, or the drug outlet portion can be adapted to receive the syringe needle. The drug outlet portion can be fluid-tight, e.g., by a pierceable self-sealing septum.

[0101] The dual chamber device may further comprise a drug ejection means including a piston rod actuatable to apply a driving force to the second elastomeric stopper. The drug ejection means may further comprise an energy means, for example a releasable spring member, to actuate the piston rod.

[0102] In some embodiments, the dual chamber device is a syringe device. In some embodiments, the dual chamber device is a pen injection device. Examples of different dual chamber devices are disclosed in WO2010 / 139793, WO2012 / 089445, and US 4,394,863.

[0103] Alternatively, the medical device may be a dual-reservoir device including a first reservoir defining a first chamber and a second reservoir defining a second chamber. The first reservoir may include a first tubular wall portion extending along a first reference axis, a first drug outlet portion, and a first elastomeric stopper disposed in sealing contact with the first tubular wall. The second reservoir may include a second tubular wall portion extending along a second reference axis, a second drug outlet portion, and a second elastomeric stopper disposed in sealing contact with the second tubular wall. The first reference axis may be parallel to the second reference axis.

[0104] The dual reservoir device may further include a needle manifold for enabling fluid transport from the first drug outlet portion and the second drug outlet portion to a single skin interface element.

[0105] The needle manifold may include a plurality of fluidly interconnected channels, including a first inlet channel configured for fluid communication with a first drug outlet portion, a second inlet channel configured for fluid communication with a second drug outlet portion, and an outlet channel in the form of a hypodermic needle.

[0106] The dual reservoir device may further include a drug expulsion means for sequential or simultaneous advancement of the first elastomeric stopper in the first tubular wall portion and the second elastomeric stopper in the second tubular wall portion.

[0107] An exemplary embodiment of a dual reservoir device is disclosed in WO2017 / 114921.

[0108] In some embodiments, the tubular wall portion of any one of the devices described above is made of glass. In some embodiments, the tubular wall portion narrows toward the drug outlet portion. In some embodiments, the drug outlet portion comprises a glass wall portion.

[0109] Thus, using the medical device as described above, the caglintide and semaglutide pharmaceutical formulations are physically separated during storage and prevented from mixing until the user initiates a dose administration event, causing the expulsion of both pharmaceutical formulations through a single injection needle. The medical device provides convenience to subjects in need of treatment, thereby promoting compliance.

[0110] For the avoidance of any doubt, in this context, the terms "distal" and "proximal" refer to a position on or a direction along a drug delivery device, medical reservoir, or needle unit, with "distal" referring to the drug outlet end and "proximal" referring to the end opposite the drug outlet end. Also, the terms "stopper," "piston," and "plunger" are used interchangeably throughout this document to refer to a movable sealing component within a reservoir body.

[0111] 1 is a longitudinal cross-sectional view of a drug reservoir 1 according to an exemplary embodiment of the present invention. The drug reservoir 1 is shown in a pre-injection state.

[0112] The drug reservoir 1 has a generally cylindrical reservoir body 2 having a bypass channel 3 and a narrow distal end portion 4. An injection needle 5 is secured to the distal end portion 4 and establishes fluid communication with the reservoir outlet 6. A front piston 8 is disposed within the reservoir body 2 between the reservoir outlet 6 and the open proximal end 7, thereby defining a front chamber 10 by the reservoir outlet 6, the front portion of the reservoir body 2 including the bypass channel 3, and the front piston 8. A rear piston 9 is disposed within the reservoir body 2 between the front piston 8 and the open proximal end 7, thereby defining a rear chamber 11 by the front piston 8, a central portion of the reservoir body 2, and the rear piston 9. The rear piston 9 has a recess 13 adapted to receive an end portion of a piston rod (not shown). Notably, in other exemplary embodiments, the rear piston does not have a recess, thereby resembling the front piston. In these embodiments, the piston rod is adapted to abut against a lateral end face of the rear piston.

[0113] The front chamber 10, which constitutes the distal chamber, holds a neutral or slightly basic liquid pharmaceutical formulation 18 containing semaglutide, and the rear chamber 11, which constitutes the proximal chamber, holds an acidic liquid pharmaceutical formulation 19 containing caglilintide.

[0114] In use, the piston rod is inserted into the recess 13, and when a sufficiently large distal force is applied via the piston rod to the rear piston 9, the rear piston 9 is put into operation, and due to the incompressibility of the acidic liquid pharmaceutical formulation, the force is transferred to the front piston 8, which is also actuated as a result. In this way, the rear chamber 11 is displaced within the reservoir body 2, while a volume of the neutral or slightly basic liquid pharmaceutical formulation 18 is forced out through the injection needle 5 until the front piston 8 reaches the bypass channel 3, at which point the acidic liquid pharmaceutical formulation 19 is forced into the bypass channel 3 and past the front piston 8 as the piston rod continues to apply a driving force to the rear piston 9.

[0115] As the rear piston 9 approaches the front piston 8, the rear chamber 11 eventually collapses and the acidic liquid pharmaceutical formulation 19 is gradually transferred to the front chamber 10 where it mixes with the remainder of the neutral or slightly basic liquid pharmaceutical formulation 18.

[0116] Upon complete collapse of the rear chamber 11, the mixture is expelled from the front chamber 10 through the injection needle 5 as the rear piston 9, under the influence of the piston rod, pushes the front piston 8 further distally within the reservoir body 2. Expulsion continues until the front piston 8 reaches the retraction of the reservoir body 2 at the reservoir outlet 6.

[0117] In a preferred embodiment, the pharmaceutical formulation containing semaglutide is stored in the distal chamber (closest to the needle) of the dual-chamber device. The volume of the semaglutide pharmaceutical formulation present in the distal chamber may be 400 to 600 μl, for example about 500 to 550 μl. The volume of the semaglutide pharmaceutical formulation present in the distal chamber may be such as to ensure an extractable volume of about 500 μl.

[0118] In some embodiments, the extractable volume of the semaglutide pharmaceutical formulation provides a dose of about 0.125 to about 5.0 mg of semaglutide. In some embodiments, the extractable volume provides a dose of about 0.125 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of 0.2 to 0.3 mg of semaglutide, for example, about 0.25 mg. In some embodiments, the extractable volume corresponds to a dose of about 0.3 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 0.4 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of 0.4 to 0.6 mg of semaglutide, for example, about 0.5 mg. In some embodiments, the extractable volume corresponds to a dose of about 0.6 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 0.7 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 0.8 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 0.85 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 0.9 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of 0.9 to 1.1 mg of semaglutide, for example, a dose of about 1.0 mg. In some embodiments, the extractable volume corresponds to a dose of about 1.1 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.2 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.3 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.4 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.5 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.6 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of 1.6 to 1.8 mg of semaglutide, for example, a dose of about 1.7 mg. In some embodiments, the extractable volume corresponds to a dose of about 1.8 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.9 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 2.0 mg of semaglutide.In some embodiments, the extractable volume corresponds to a dose of about 2.1 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 2.2 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 2.3 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of 2.3 to 2.5 mg of semaglutide, for example about 2.4 mg. In some embodiments, the extractable volume corresponds to a dose of about 2.5 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 2.6 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 2.7 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 2.8 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 2.9 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.0 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.1 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.2 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.3 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.4 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.5 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.6 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.7 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.8 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 3.9 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.0 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.1 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.2 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.3 mg of semaglutide.In some embodiments, the extractable volume corresponds to a dose of about 4.4 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.5 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.6 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.7 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.8 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 4.9 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 5.0 mg of semaglutide.

[0119] In a preferred embodiment, the pharmaceutical preparation containing caglilintide is stored in the proximal chamber (farthest from the needle) of the dual-chamber device. The volume of the caglilintide pharmaceutical preparation present in the proximal chamber can be 200 to 300 μl, for example, 250 to 300 μl. The volume of the caglilintide pharmaceutical preparation present in the proximal chamber can be such that an extractable volume of approximately 250 μl is ensured.

[0120] In some embodiments, the extractable volume corresponds to a dose of about 0.08 to about 5.0 mg of caglilintide, for example, a dose of about 0.125 mg to about 5.0 mg. In some embodiments, the extractable volume corresponds to a dose of about 0.08 mg of caglilintide. In some embodiments, the extractable volume provides a dose of about 0.125 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.25 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.3 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.4 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.5 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.6 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.7 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.8 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.85 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 0.9 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.0 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.1 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.2 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.3 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.4 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.5 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.6 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.7 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.8 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 1.9 mg of caglilintide.In some embodiments, the extractable volume corresponds to a dose of about 2.0 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.1 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.2 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.3 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.4 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.5 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.6 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.7 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.8 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 2.9 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.0 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.1 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.2 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.3 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.4 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.5 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.6 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.7 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.8 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 3.9 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.0 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.1 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.2 mg of caglilintide.In some embodiments, the extractable volume corresponds to a dose of about 4.3 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.4 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.5 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.6 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.7 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.8 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 4.9 mg of caglilintide. In some embodiments, the extractable volume corresponds to a dose of about 5.0 mg of caglilintide.

[0121] In some embodiments, the concentration of semaglutide in the semaglutide formulation present in one chamber of the device is higher than the concentration of semaglutide in the semaglutide formulation in the other chamber of the device.

[0122] Medical Utility The formulations disclosed herein are for use in medicine.

[0123] The aqueous pharmaceutical formulation comprising caglintide disclosed herein and the aqueous pharmaceutical formulation comprising semaglutide disclosed herein are for use in medicine.

[0124] Disclosed herein is caglilintide in combination with semaglutide for use in medicine.

[0125] Disclosed herein are methods for the prevention or treatment of a medical disorder or disease, such as diabetes or obesity, wherein caglilintide in combination with semaglutide is administered to a subject in need thereof.

[0126] Disclosed herein are methods for the prevention or treatment of a medical disorder or disease, in which the liquid pharmaceutical formulations disclosed herein are administered to a subject in need thereof.

[0127] As used herein, the term "treatment" refers to the medical therapy of any human or other vertebrate subject in need thereof. The subject is expected to have undergone a physical examination by a physician or veterinarian who has provided a provisional or definitive diagnosis indicating that the use of the particular treatment will be beneficial to the health of the human or other vertebrate. The timing and purpose of the treatment may vary from individual to individual, depending on the subject's current health status. Thus, the treatment may be prophylactic (preventative), palliative, symptomatic, and / or curative.

[0128] Caglilintide in combination with semaglutide, and / or the caglilintide and semaglutide formulations disclosed herein may be used for: (i) prevention and / or treatment of all forms of diabetes and related conditions, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity-onset diabetes of the young), gestational diabetes, and / or reduction of HbA1c; (ii) delaying or preventing the progression of diabetic disease, such as the progression of type 2 diabetes, delaying the progression from impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delaying the progression from insulin-nonrequiring type 2 diabetes to insulin-requiring type 2 diabetes; (iii) for example, reducing food intake, reducing weight, suppressing appetite, inducing satiety; treating or preventing antipsychotic or steroid-induced binge eating disorder, food cravings, bulimia nervosa, and / or obesity; and / or preventing and / or treating eating disorders such as obesity by slowing gastric emptying, (iv) prevention and / or treatment of cardiovascular disease, such as delaying or reducing the occurrence of major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, hospitalization for unstable angina, and hospitalization for heart failure; (v) prevention and / or treatment of nonalcoholic fatty liver disease (NAFLD) and / or nonalcoholic steatohepatitis (NASH); (vi) prevention and / or treatment of cognitive disorders such as Alzheimer's disease.

[0129] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In still further particular aspects, the indication is (iii). In still further particular aspects, the indication is (iv). In still further particular aspects, the indication is (v). In still further particular aspects, the indication is (vi). In some embodiments, the indication is type 2 diabetes and / or obesity.

[0130] Generally, all subjects suffering from obesity are considered to be overweight.Disclosed herein is a method for treating or preventing obesity.Disclosed herein is the use of the formulations disclosed herein for treating or preventing obesity.In some embodiments, the subject suffering from obesity is a human, such as an adult human or a pediatric human (including infants, children, and adolescents).

[0131] Body mass index (BMI) is a measure of body fat based on height and weight. The formula is BMI = weight in kilograms / height in meters. 2 A human subject suffering from obesity may have a BMI of ≧30, and the subject may also be referred to as being obese. In some embodiments, a human subject suffering from obesity may have a BMI of ≧35 or a BMI in the range of ≧30 to <40. In some embodiments, the obesity is severe obesity or morbid obesity, and the human subject may have a BMI of ≧40.

[0132] Disclosed herein are methods for the treatment or prevention of overweight, optionally in the presence of at least one weight-related comorbidity.Disclosed herein are uses of the formulations disclosed herein for the treatment or prevention of overweight, optionally in the presence of at least one weight-related comorbidity.

[0133] In some embodiments, the overweight subject is a human, such as an adult human or a pediatric human (including infants, children, and adolescents). In some embodiments, the overweight human subject can have a BMI of ≧25, such as a BMI of ≧27. In some embodiments, the overweight human subject has a BMI in the range of 25 to <30 or 27 to <30.

[0134] Increased BMI increases an individual's risk of developing any one of a wide range of diseases or comorbidities. The weight-related comorbidity can be one or a combination of the diseases described above. In some embodiments, the weight-related comorbidity is selected from the group consisting of hypertension, diabetes (such as type 2 diabetes), dyslipidemia, high cholesterol, and obstructive sleep apnea.

[0135] Disclosed herein is a method for reducing body weight.The person who will be reduced in body weight can have a BMI of ≧25, for example, a BMI of ≧27 or a BMI of ≧30.In some embodiments, the person who will be reduced in body weight can have a BMI of ≧35 or a BMI of ≧40.The term " reducing body weight " can include the treatment or prevention of obesity and / or overweight.

[0136] In some embodiments, administration of the semaglutide and caglilintide pharmaceutical formulations disclosed herein may be used as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg / m2 or greater or 27 kg / m2 or greater (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, or dyslipidemia).

[0137] In some embodiments, administration of the semaglutide and caglilintide pharmaceutical formulations disclosed herein may result in >15% weight loss, such as >20% weight loss, for example >25% weight loss, such as >30% weight loss, for example about 15-40% weight loss, such as about 20-35% weight loss, for example about 25-30% weight loss, within 26 weeks of initiating treatment.

[0138] In some embodiments, the fixed dose combination of semaglutide and caglilintide disclosed herein may result in >15% weight loss, such as >20% weight loss, for example >25% weight loss, such as >30% weight loss, for example about 15-40% weight loss, such as about 20-35% weight loss, for example about 25-30% weight loss, within 26 weeks of starting treatment.

[0139] dose As described above, semaglutide and caglilintide may be administered to an individual in need thereof using a suitable medical device.

[0140] In some embodiments, an effective amount of semaglutide may be administered to an individual in need thereof together with an effective amount of caglilintide.

[0141] In some embodiments, the dose is administered approximately once a week. In some embodiments, the interval between two fixed doses can be about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days. In a preferred embodiment, the fixed maintenance dose is administered approximately once every 7 days (once a week).

[0142] In some embodiments, the dose is administered to an individual with any one of the indications listed above. In some preferred embodiments, the dose is administered to an individual with obesity (body mass index [BMI] ≥ 30 kg / m 2 In some preferred embodiments, the dose is administered to individuals who are overweight (BMI > 27 kg / m 2 ~<30kg / m 2) and is administered to an individual who has at least one weight-related comorbidity.

[0143] In some embodiments, weekly treatment results in statistically significant, dose-dependent weight reduction.

[0144] At the start of treatment, it may be beneficial to administer increasing doses of caglilintide and / or semaglutide to individuals in need thereof. Once individuals have adapted to treatment, it may be beneficial to administer maintenance doses of caglilintide and semaglutide to individuals in need thereof.

[0145] In some embodiments, treatment is weekly and the dose escalation period is 16 weeks.

[0146] In some embodiments, treatment is weekly and dose escalation is approximately weekly.

[0147] In some embodiments, treatment is once weekly and dose escalation is once every two weeks.

[0148] In some embodiments, treatment is once weekly with dose escalation approximately once every three weeks.

[0149] In some embodiments, treatment is once weekly with dose escalation approximately once every four weeks.

[0150] In some embodiments, escalating doses of caglilintide are administered together with escalating doses of semaglutide.

[0151] In some embodiments, the escalating doses of caglilintide are administered together with a fixed dose of semaglutide.

[0152] In some embodiments, the escalating dose of caglilintide is administered together with 2.4 mg of semaglutide.

[0153] The administered dose of caglilintide may be 0.025 to 5.0 mg.

[0154] The administered dose of caglilintide may be 0.08 to 5.0 mg.

[0155] In some embodiments, the dose of caglilintide administered is 0.08 mg.

[0156] In some embodiments, the dose of caglilintide administered is 0.125 mg.

[0157] In some embodiments, the dose of caglilintide administered is 0.16 mg.

[0158] In some embodiments, the dose of caglilintide administered is 0.25 mg.

[0159] In some embodiments, the dose of caglilintide administered is 0.5 mg.

[0160] In some embodiments, the dose of caglilintide administered is at least 0.6 mg.

[0161] In some embodiments, the dose of caglilintide administered is 0.85 mg.

[0162] In some embodiments, the dose of caglilintide administered is 1.0 mg.

[0163] In some embodiments, the dose of caglilintide administered is 1.1 mg.

[0164] In some embodiments, the dose of caglilintide administered is 1.2 mg.

[0165] In some embodiments, the maintenance dose of caglilintide is 1.2 mg.

[0166] In some embodiments, the dose of caglilintide administered is 1.3 mg.

[0167] In some embodiments, the dose of caglilintide administered is 1.4 mg.

[0168] In some embodiments, the dose of caglilintide administered is 1.5 mg.

[0169] In some embodiments, the dose of caglilintide administered is 1.6 mg.

[0170] In some embodiments, the dose of caglilintide administered is 1.7 mg.

[0171] In some embodiments, the dose of caglilintide administered is 1.8 mg.

[0172] In some embodiments, the dose of caglilintide administered is 1.9 mg.

[0173] In some embodiments, the dose of caglilintide administered is 2.0 mg.

[0174] In some embodiments, the dose of caglilintide administered is 2.1 mg.

[0175] In some embodiments, the dose of caglilintide administered is 2.2 mg.

[0176] In some embodiments, the dose of caglilintide administered is 2.3 mg.

[0177] In some embodiments, the dose of caglilintide administered is 2.4 mg.

[0178] In some embodiments, the maintenance dose of caglilintide is 2.4 mg.

[0179] In some embodiments, the dose of caglilintide administered is 2.5 mg.

[0180] In some embodiments, the dose of caglilintide administered is 2.6 mg.

[0181] In some embodiments, the dose of caglilintide administered is 2.7 mg.

[0182] In some embodiments, the dose of caglilintide administered is 2.8 mg.

[0183] In some embodiments, the dose of caglilintide administered is 2.9 mg.

[0184] In some embodiments, the dose of caglilintide administered is 3.0 mg.

[0185] In some embodiments, the dose of caglilintide administered is 3.1 mg.

[0186] In some embodiments, the dose of caglilintide administered is 3.2 mg.

[0187] In some embodiments, the dose of caglilintide administered is 3.3 mg.

[0188] In some embodiments, the dose of caglilintide administered is 3.4 mg.

[0189] In some embodiments, the dose of caglilintide administered is 3.5 mg.

[0190] In some embodiments, the dose of caglilintide administered is 3.6 mg.

[0191] In some embodiments, the dose of caglilintide administered is 3.7 mg.

[0192] In some embodiments, the dose of caglilintide administered is 3.8 mg.

[0193] In some embodiments, the dose of caglilintide administered is 3.9 mg.

[0194] In some embodiments, the dose of caglilintide administered is 4.0 mg.

[0195] In some embodiments, the dose of caglilintide administered is 4.1 mg.

[0196] In some embodiments, the dose of caglilintide administered is 4.2 mg.

[0197] In some embodiments, the dose of caglilintide administered is 4.3 mg.

[0198] In some embodiments, the dose of caglilintide administered is 4.4 mg.

[0199] In some embodiments, the dose of caglilintide administered is 4.5 mg.

[0200] In some embodiments, the maintenance dose of caglilintide is 4.5 mg.

[0201] In some embodiments, the dose of caglilintide administered is 4.6 mg.

[0202] In some embodiments, the dose of caglilintide administered is 4.7 mg.

[0203] In some embodiments, the dose of caglilintide administered is 4.8 mg.

[0204] In some embodiments, the dose of caglilintide administered is 4.9 mg.

[0205] In some embodiments, the dose of caglilintide administered is 5.0 mg.

[0206] The dose of semaglutide administered may be about 0.05 to 5 mg, for example at least 0.5 mg of semaglutide.

[0207] The dose of semaglutide administered may be about 0.25 to 3.0 mg.

[0208] In some embodiments, the dose of semaglutide administered is 0.25 mg.

[0209] In some embodiments, the dose of semaglutide administered is 0.5 mg.

[0210] In some embodiments, the dose of semaglutide administered is at least 0.6 mg.

[0211] In some embodiments, the dose of semaglutide administered is 0.85 mg.

[0212] In some embodiments, the dose of semaglutide administered is 1.0 mg.

[0213] In some embodiments, the dose of semaglutide administered is 1.2 mg.

[0214] In some embodiments, the dose of semaglutide administered is 1.5 mg.

[0215] In some embodiments, the dose of semaglutide administered is 1.7 mg.

[0216] In some embodiments, the dose of semaglutide administered is 2.4 mg.

[0217] In some embodiments, the dose of semaglutide administered is 3.0 mg.

[0218] In some embodiments, the ratio of caglilintide to semaglutide administered is 1:2.

[0219] In some embodiments, the dose of caglilintide is 0.125 mg and the dose of semaglutide is 0.25 mg.

[0220] In some embodiments, the dose of caglilintide is 0.25 mg and the dose of semaglutide is 0.5 mg.

[0221] In some embodiments, the dose of caglilintide is 0.5 mg and the dose of semaglutide is 1.0 mg.

[0222] In some embodiments, the dose of caglilintide is 0.85 mg and the dose of semaglutide is 1.7 mg.

[0223] In some embodiments, the dose of caglilintide is 1.2 mg and the dose of semaglutide is 2.4 mg.

[0224] In some embodiments, the maintenance dose of caglilintide is 1.2 mg and the maintenance dose of semaglutide is 2.4 mg.

[0225] In some embodiments, the ratio of caglilintide to semaglutide administered is 1:1.

[0226] In some embodiments, the dose of caglilintide is 0.25 mg and the dose of semaglutide is 0.25 mg.

[0227] In some embodiments, the dose of caglilintide is 0.5 mg and the dose of semaglutide is 0.5 mg.

[0228] In some embodiments, the dose of caglilintide is 1.0 mg and the dose of semaglutide is 1.0 mg.

[0229] In some embodiments, the dose of caglilintide is 1.7 mg and the dose of semaglutide is 1.7 mg.

[0230] In some embodiments, the dose of caglilintide is 0.16 mg and the dose of semaglutide is 2.4 mg.

[0231] In some embodiments, the dose of caglilintide is 0.3 mg and the dose of semaglutide is 2.4 mg.

[0232] In some embodiments, the dose of caglilintide is 0.6 mg and the dose of semaglutide is 2.4 mg.

[0233] In some embodiments, the dose of caglilintide is 1.2 mg and the dose of semaglutide is 2.4 mg.

[0234] In some embodiments, the maintenance dose of caglilintide is 1.2 mg and the maintenance dose of semaglutide is 2.4 mg.

[0235] In some embodiments, the dose of caglilintide is 2.4 mg and the dose of semaglutide is 2.4 mg.

[0236] In some embodiments, the maintenance dose of caglilintide is 2.4 mg and the maintenance dose of semaglutide is 2.4 mg.

[0237] In some embodiments, the dose of caglilintide is 4.5 mg and the dose of semaglutide is 2.4 mg.

[0238] In some embodiments, the maintenance dose of caglilintide is 4.5 mg and the maintenance dose of semaglutide is 2.4 mg.

[0239] In some embodiments, caglilintide is administered at an initial dose of 0.16 mg once weekly, then titrated to subsequent dose levels of 0.3 mg, 0.6 mg, 1.2 mg, and 2.4 mg every other week until a target / maintenance dose of 2.4 mg once weekly is reached.

[0240] In some embodiments, caglilintide is administered at an initial dose of 0.3 mg once weekly, then titrated to subsequent dose levels of 0.6 mg, 1.2 mg, and 2.4 mg every other week until a target / maintenance dose of 2.4 mg once weekly is reached.

[0241] In some embodiments, caglilintide is administered at an initial dose of 0.3 mg once weekly, then titrated to subsequent dose levels of 0.6 mg, 1.2 mg, 2.4 mg, and 4.5 mg until a target / maintenance dose of 4.5 mg once weekly is reached.

[0242] In some embodiments, 0.25 mg of caglilintide is administered once weekly and titrated every four weeks to a subsequent dose level of 0.5 mg, then to a target / maintenance dose of 1.0 mg once weekly.

[0243] In some embodiments, 0.25 mg of caglilintide is administered once weekly and titrated every four weeks to subsequent dose levels of 0.5 mg and then to a target / maintenance dose of 1.2 mg once weekly.

[0244] In some embodiments, 0.25 mg of caglilintide is administered once weekly and titrated every four weeks to subsequent dose levels of 0.5 mg, 1.0 mg, and 1.7 mg until a target / maintenance dose of 2.4 mg once weekly is reached.

[0245] In some embodiments, 0.25 mg of semaglutide is administered once weekly and titrated every four weeks to subsequent dose levels of 0.5 mg, 1.0 mg, and 1.7 mg until a target / maintenance dose of 2.4 mg once weekly is reached.

[0246] In some embodiments, 0.25 mg of caglilintide and 0.25 mg of semaglutide are administered once weekly for 4 weeks (weeks 0-3) and titrated every 4 weeks to subsequent dose levels of 0.5 mg of caglilintide and 0.5 mg of semaglutide (weeks 4-7), 1.0 mg of caglilintide and 1.0 mg of semaglutide (weeks 8-11), and 1.7 mg of caglilintide and 1.7 mg of semaglutide (weeks 12-15) until a target / maintenance dose of 2.4 mg of caglilintide and 2.4 mg of semaglutide once weekly is reached (week 16 and thereafter).

[0247] As used herein, specific values ​​given in terms of numbers or intervals may be interpreted as being the specific value or as being an approximation (e.g., plus or minus 10, 15, or 20 percent of the specific value when amounts may be provided by weight; e.g., plus or minus 0.4 when pH is measured).

[0248] Embodiment The following are non-limiting embodiments of the present invention.

[0249] 1. An aqueous formulation of caglilintide, -caglilintide, a buffer solution, which is glutamic acid / glutamate at a concentration of about 2-10 mM, or lactic acid / lactate at a concentration of about 2-35 mM, or acetic acid / acetate at a concentration of about 2-10 mM; -90-99% w / w water, - A pH of 3.5 to 4.5, for example, about pH 4.0. 2. An aqueous formulation of caglilintide, Caglilintide in a concentration of 0.1 to 20 mg / ml; a buffer solution, which is glutamic acid / glutamate at a concentration of about 2-10 mM, or lactic acid / lactate at a concentration of about 2-35 mM, or acetic acid / acetate at a concentration of about 2-10 mM; - Aqueous formulations of caglilintide having a pH of 3.5 to 4.5, for example pH 4.0. 3. A formulation according to embodiment 1 or 2, which is a pharmaceutical formulation comprising caglilintide in a concentration of 0.1 to 20 mg / ml, such as about 1.0 mg / ml, for example about 2.0 mg / ml, such as at least 2 mg / ml, for example about 4.0 mg / ml, such as about 4.8 mg / ml, for example about 6.8 mg / ml, such as about 9.6 mg / ml, for example about 18 mg / ml. 4. A formulation according to any one of embodiments 1 to 3, which is a pharmaceutical formulation comprising a single dose of caglilintide. 5. A formulation according to any one of embodiments 1 to 4, which is a pharmaceutical formulation comprising an effective dose of caglilintide. 6. An aqueous formulation of caglilintide, - A single dose of caglilintide and a buffer solution, which is glutamic acid / glutamate at a concentration of about 2-10 mM, or lactic acid / lactate at a concentration of about 2-35 mM, or acetic acid / acetate at a concentration of about 2-10 mM; -Having a pH of 3.5 to 4.5, for example about pH 4.0. 7. An aqueous formulation of caglilintide, a single effective dose of caglilintide and a buffer solution, which is glutamic acid / glutamate at a concentration of about 2-10 mM, or lactic acid / lactate at a concentration of about 2-35 mM, or acetic acid / acetate at a concentration of about 2-10 mM; -Having a pH of 3.5 to 4.5, for example about pH 4.0. 8. The dose of caglilintide is 0.025 to 5.0 mg, for example 0.08 to 5.0 mg, for example about 0.125 mg, for example about 0.16 mg, for example about 0.25 mg, for example about 0.5 mg, such as at least about 0.6 mg, for example about 0.85 mg, for example about 1.0 mg, for example about 1.1 mg, for example about 1.2 mg, for example about 1.3 mg, for example about 1.4 mg, for example about 1.5 mg, for example about 1.6 mg, such as about 1.7 mg, for example about 1.8 mg, for example about 1.9 mg, for example about 2.0 mg, for example about 2.1 mg, for example about 2.2 mg, for example about 2.3 mg, mg, such as about 2.5 mg, for example about 2.6 mg, for example about 2.7 mg, such as about 2.8 mg, for example about 2.9 mg, for example about 3.0 mg, such as about 3.1 mg, for example about 3.2 mg, such as about 3.3 mg, for example about 3.4 mg, such as about 3.5 mg, for example about 3.6 mg, for example about 3.7 mg, such as about 3.8 mg, for example about 3.9 mg, such as about 4.0 mg, for example about 4.1 mg, such as about 4.2 mg, for example about 4.3 mg, such as about 4.4 mg, for example about 4.5 mg, for example about 4.6 mg, for example about 4.7 mg, for example about 4.8 mg, such as about 4.9 mg, for example about 5.0 mg of caglilintide. 9. The caglilintide formulation according to any one of embodiments 1 to 8, wherein the buffer is glutamic acid / glutamate at a concentration of 2 to 10 mM, such as 2.5 to 10 mM, for example 2.5 to 5 mM, for example 5 to 10 mM, such as 2 to 9 mM, for example 2 to 8 mM, such as 2.5 to 7.5 mM, for example 2 to 7 mM, such as 2 to 6 mM, for example 4 to 6 mM, such as about 5 mM. 10. The kaglilintide formulation according to any one of embodiments 1 to 8, wherein the buffer solution is lactic acid / lactate at a concentration of about 2 to 35 mM, such as 2 to 30 mM, for example 2 to 25 mM, for example 2 to 20 mM, such as 2 to 15 mM, for example 2 to 10, such as 2.5 to 10 mM, for example 5 to 10 mM, such as 2 to 9 mM, for example 2 to 8 mM, about 2 to 7 mM, for example about 2 to 6 mM, such as about 2.5 to 5 mM, for example about 5 mM. 11. The caglilintide formulation according to any one of embodiments 1 to 8, wherein the buffer is acetic acid / acetate at a concentration of about 2 to 10 mM, such as 2.5 to 10 mM, for example 5 to 10 mM, such as 2 to 9 mM, for example 2 to 8 mM, such as 2 to 7 mM, for example 2 to 6 mM, such as 2.5 to 5.0 mM, for example about 5 mM. 12. Caglilintide in a concentration of 0.1 to 20 mg / ml, for example 0.32 to 18 mg / ml, for example 0.5 to 18 mg / ml, for example about 9.6 mg / ml; 10. The formulation according to any one of embodiments 1 to 9, comprising glutamic acid / glutamate at a concentration of 2 to 10 mM, such as 2.5 to 10 mM, for example 2.5 to 5 mM, such as 5 to 10 mM, for example 2 to 9 mM, such as 2 to 8 mM, for example 2.5 to 7.5 mM, for example 2 to 7 mM, such as 2 to 6 mM, for example 4 to 6 mM, such as about 2.5 to 5.0 mM, for example about 5 mM. 13. Caglilintide in a concentration of 0.1 to 20 mg / ml, for example 0.32 to 18 mg / ml, for example about 9.6 mg / ml; 11. The formulation according to any one of embodiments 1 to 8 or 10, comprising lactic acid / lactate at a concentration of about 2 to 35 mM, such as about 2 to 30 mM, for example 2 to 25 mM, such as 2 to 20 mM, for example 2 to 15 mM, such as 2 to 10 mM, for example 2.5 to 10 mM, such as 5 to 10 mM, for example 2 to 9 mM, such as 2 to 8 mM, for example 2 to 7 mM, such as 2 to 6 mM, for example 2.5 to 5.0 mM, such as about 5 mM. 14. Caglilintide at a concentration of 0.1 to 20 mg / ml, for example about 15 to 20 mg / ml, for example about 18 mg / ml; 12. The formulation of any one of embodiments 1 to 8 or 11, comprising acetic acid / acetate at a concentration of about 2 to 10 mM, such as 2 to 9 mM, for example 2 to 8 mM, such as 2 to 7 mM, for example about 2 to 6 mM, such as about 2.5 to 5.0 mM. 15. A caglilintide formulation according to any one of embodiments 1 to 14, further comprising an isotonicity agent. 16. The caglilintide formulation according to embodiment 15, wherein the tonicity agent is selected from the group consisting of glycerol, mannitol, propylene glycol, sorbitol, sucrose, or trehalose. 17. The caglilintide formulation of embodiment 15 or 16, wherein the tonicity agent is selected from the group consisting of glycerol, mannitol, sorbitol, sucrose, or trehalose. 18. A caglilintide formulation according to any one of embodiments 15 to 17, wherein the concentration of the tonicity agent is such to achieve isotonicity. 19. The caglilintide formulation according to any one of embodiments 15 to 18, wherein the tonicity agent is glycerol. 20. A caglilintide formulation according to any one of embodiments 1 to 19, wherein the concentration of glycerol is 20 to 31 mg / ml, for example about 24 mg / ml. 21. The caglilintide formulation according to any one of embodiments 15 to 18, wherein the tonicity agent is mannitol. 22. A caglilintide formulation according to any one of embodiments 1 to 21, wherein the concentration of mannitol is 40 to 60 mg / ml, for example about 46 mg / ml. 23. A caglilintide formulation according to any one of embodiments 15 to 18, wherein the tonicity agent is propylene glycol. 24. A caglilintide formulation according to any one of embodiments 1 to 23, wherein the concentration of propylene glycol is 17 to 26 mg / ml, for example about 20 mg / ml. 25. The caglilintide formulation of any one of embodiments 15-18, wherein the tonicity agent is sorbitol. 26. A caglilintide formulation according to any one of embodiments 1 to 25, wherein the concentration of sorbitol is 40 to 60 mg / ml, for example about 46 mg / ml. 27. A caglilintide formulation according to any one of embodiments 15-18, wherein the tonicity agent is sucrose. 28. A caglilintide formulation according to any one of embodiments 1 to 27, wherein the concentration of sucrose is 73 to 105 mg / ml, for example about 83 mg / mg. 29. A caglilintide formulation according to any one of embodiments 15 to 18, wherein the tonicity agent is trehalose. 30. A caglilintide formulation according to any one of embodiments 1 to 29, wherein the concentration of trehalose is 73 to 105 mg / ml, for example about 83 mg / ml. 31. The caglilintide formulation according to any one of embodiments 1 to 30, comprising more than 90% w / w water, such as 90-99% w / w water, for example 90-99% w / w water, for example 91-99% w / w water, for example 92-99% w / w water, for example 93-99% w / w water, for example 94-99% w / w water, for example more than 91% w / w water, such as more than 92% w / w water, for example more than 93% w / w water, for example more than 94% w / w water, such as about 95% w / w water, for example more than 95% w / w water, such as about 96% w / w water, for example more than 96% w / w water, for example about 97% w / w water, for example more than 97% w / w water, such as about 98% w / w water, for example more than 99% w / w water. 32. A caglilintide formulation according to any one of embodiments 1-31, wherein the formulation comprises one or more agents for adjusting pH, such as HCl and / or NaOH. 33. The formulation of any one of embodiments 1-32, wherein the caglilintide is in the form of a pharmaceutically acceptable salt. 34. A caglilintide formulation according to any one of embodiments 1-33, wherein fewer impurities are produced during storage. 35. A caglilintide formulation according to any one of embodiments 1 to 34, which provides improved chemical stability of the formulation. 36. A caglilintide formulation according to any one of embodiments 1 to 35, which provides improved physical stability of the formulation. 37. A caglilintide formulation according to any one of embodiments 1 to 36, which provides improved chemical and physical stability of the formulation. 38. A caglilintide formulation according to any one of embodiments 1-37, wherein less HMGP is produced during storage. 39. A caglilintide formulation according to any one of embodiments 1 to 38, for use in an injection device. 40. A caglilintide formulation according to any one of embodiments 1 to 38, for use in medicine. 41. A caglilintide formulation according to any one of embodiments 1 to 38, for parenteral administration. 42. A caglilintide formulation according to any one of embodiments 1 to 38, for subcutaneous administration. 43. An aqueous semaglutide formulation, -Semaglutide, - phenol not exceeding 0.1% (w / w); sodium chloride and / or potassium chloride to achieve isotonicity, a buffer solution, and a pH of -7 to 8. 44. A semaglutide formulation according to any one of embodiments 1 to 43, wherein the buffer is a phosphate buffer. 45. An aqueous semaglutide formulation, -Semaglutide, - Phosphate at a concentration of more than 15 mM and not more than 45 mM, for example 16 to 45 mM, for example 20 to 45 mM, for example 20 to 40 mM, for example 25 to 45 mM, for example 25 to 40 mM, for example 20 to 35 mM, for example 20 to 30 mM, for example about 25 to 35 mM, for example about 30 mM; - 90-99% w / w water for injection; and a pH of -7.0 to 8.0, for example about 7.4. 46. ​​An aqueous semaglutide formulation, Semaglutide in a concentration of 0.1 to 10 mg / ml; - Phosphate at a concentration of more than 15 mM and not more than 45 mM, for example 16 to 45 mM, for example 20 to 45 mM, for example 20 to 40 mM, for example 25 to 45 mM, for example 25 to 40 mM, for example 20 to 35 mM, for example 20 to 30 mM, for example about 25 to 35 mM, for example about 30 mM; and a pH of -7 to 8, for example about 7.4. 47. A semaglutide formulation according to embodiment 45 or 46, comprising semaglutide in a concentration of 0.1 to 10 mg / ml, for example 0.5 to 10 mg / ml, for example 0.5 to 5.0 mg / ml, for example 0.5 to 4.8 mg / ml, such as about 0.5 mg / ml, for example about 1 mg / ml, such as about 2 mg / ml, for example about 3.4 mg / ml, for example about 4.8 mg / ml. 48. A semaglutide formulation according to any one of embodiments 45 to 47, which is a pharmaceutical formulation comprising a single dose of semaglutide. 49. A semaglutide formulation according to any one of embodiments 45 to 48, which is a pharmaceutical formulation comprising an effective dose of semaglutide. 50. The dose of semaglutide is about 0.05 to 5 mg, for example about 0.125 to 5.0 mg, for example about 0.25 to 3.0 mg, for example about 0.125 mg, for example about 0.2 to 0.3 mg, for example about 0.25 mg, for example about 0.4 mg, for example about 0.5 mg, for example about 0.4 to 0.6 mg, for example about 0.6 mg, for example about 0.7 mg, for example about 0.8 mg, for example about 8.5 mg, for example about 0.9 mg, for example about 1.0 mg, for example about 1.1 mg, for example about 1.2 mg, 50. The semaglutide formulation of any one of embodiments 45 to 49, for example about 1.3 mg, for example about 1.4 mg, for example about 1.5 mg, for example about 1.6 mg, for example about 1.7 mg, for example about 1.8 mg, for example about 1.9 mg, for example about 2.0 mg, for example about 2.1 mg, for example about 2.2 mg, such as about 2.3 mg, for example about 2.4 mg, for example about 2.5 mg, for example about 2.6 mg, for example about 2.7 mg, for example about 2.8 mg, for example about 2.9 mg, such as about 3.0 mg. 51. A formulation according to any one of embodiments 45 to 50, wherein the semaglutide is in the form of a pharmaceutically acceptable salt. 52. A semaglutide formulation according to any one of embodiments 45 to 51, wherein the phosphate buffer is selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate, and trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and tripotassium phosphate. 53. A semaglutide formulation according to any one of embodiments 45 to 52, wherein the phosphate buffer is disodium hydrogen phosphate dihydrate. 54. A semaglutide formulation according to any one of embodiments 45 to 53, wherein the concentration of the phosphate buffer is more than 15 mM and not more than 45 mM, for example 16 to 45 mM, for example 20 to 45 mM, for example 20 to 40 mM, for example 25 to 45 mM, for example 25 to 40 mM, such as 20 to 35 mM, for example 20 to 30 mM, such as about 25 to 35 mM, for example about 30 mM. 55. A semaglutide formulation according to any one of embodiments 45 to 54, further comprising histidine. 56. A semaglutide formulation according to embodiment 55, wherein the concentration of histidine is less than about 20 mM, such as between 1 and 20 mM, for example between 5 and 15 mM, for example between 8 and 12 mM, such as about 10 mM. 57. A semaglutide formulation according to any one of embodiments 45 to 56, further comprising an isotonicity agent. 58. The semaglutide formulation of embodiment 57, wherein the tonicity agent is selected from the group consisting of propylene glycol, potassium chloride, and / or sodium chloride. 59. The semaglutide formulation of embodiment 57 or 58, wherein the tonicity agent is sodium chloride. 60. The semaglutide formulation of embodiment 57 or 58, wherein the tonicity agent is potassium chloride. 61. A semaglutide formulation according to any one of embodiments 1 to 60, wherein the tonicity agent is sodium chloride and potassium chloride. 62. A semaglutide formulation according to any one of embodiments 57 to 61, wherein the concentration of the tonicity agent is such to achieve isotonicity. 63. A semaglutide pharmaceutical formulation according to any one of embodiments 59, 61 or 62, wherein the concentration of sodium chloride is 4.5 to 8.5 mg / ml, for example 5.0 to 8.5 mg / ml, for example 5.5 to 8.5 mg / ml, for example 6.0 to 8.5 mg / ml, such as 7.0 to 8.25 mg / ml, for example 4.5 to 7.0, such as 5.0 to 7.5 mg / ml, for example 5.0 to 7.0 mg / ml, such as 5.5 to 7 mg / ml, for example 6.4 to 7.9 mg / ml, for example 6.4 to 7.5 mg / ml, such as 6 to 7 mg / ml, for example more than 6.4 mg / ml, such as about 5.4 mg / ml, for example about 6.4 mg / ml, such as about 6.7 mg / ml. 64. A semaglutide pharmaceutical formulation according to any one of embodiments 60 to 62, wherein the concentration of potassium chloride is 5.5 to 11 mg / ml, for example about 8.2 mg / ml. 65. More than 90% w / w water, for example 90-99% w / w water, for example 91-99% w / w water, for example 92-99% w / w water, for example 93-99% w / w water, for example 94-99% w / w water, for example 95-99% w / w water, for example 96-99% w / w water, for example 97-99% w / w water, for example 98-99% w / w water, for example at least 91% w / w water, for example at least 92% w / w water, e.g. 65. A semaglutide formulation according to any one of embodiments 45 to 64, for example comprising at least 93% w / w water, such as at least 94% w / w water, for example about 95% w / w water, such as at least 95% w / w water, for example about 96% w / w water, such as at least 96% w / w water, for example about 97% w / w water, such as at least 97% w / w water, for example about 98% w / w, such as at least 98% w / w water. 66. A semaglutide formulation according to any one of embodiments 45 to 65, wherein the formulation comprises one or more agents for adjusting pH, such as HCl or NaOH. 67. A semaglutide formulation according to any one of embodiments 45 to 66, wherein the formulation does not contain a preservative. 68. A semaglutide formulation according to any one of embodiments 45 to 67, wherein the formulation has a pH of about 7.4. 69. The formulation of any one of embodiments 45-68, wherein the formulation is for parenteral administration. 70. A semaglutide formulation according to any one of embodiments 45 to 68, wherein the formulation is for subcutaneous administration. 71. A semaglutide formulation according to any one of embodiments 45 to 68, for use in an injection device. 72. A semaglutide formulation according to any one of embodiments 45 to 68, wherein fewer impurities are produced during storage. 73. A semaglutide formulation according to any one of embodiments 45-68, wherein fewer HMWPs are produced during storage. 74. A semaglutide formulation according to any one of embodiments 45 to 68, which provides improved chemical stability of the formulation. 75. A semaglutide formulation according to any one of embodiments 45 to 68 for use in medicine. 76. A semaglutide formulation according to any one of embodiments 45 to 68 for use in the treatment and / or prevention of diabetes, obesity, Alzheimer's disease, non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH), and / or cardiovascular disease. 77. The aqueous pharmaceutical formulation according to any one of embodiments 45 to 68, for use in the treatment and / or prevention of Alzheimer's disease. 78. The aqueous pharmaceutical formulation according to any one of embodiments 45 to 68, for use in the treatment and / or prevention of Alzheimer's disease, non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH), and / or cardiovascular disease. 79. A medical device comprising semaglutide in a first chamber and caglilintide in a second chamber, such as a single dose of semaglutide in the first chamber and a single dose of caglilintide in the second chamber. 80. A medical device comprising a first chamber and a second chamber, wherein the first chamber contains a semaglutide formulation according to any one of embodiments 43 to 68, and the second chamber contains a caglilintide formulation according to any one of embodiments 1 to 38. 81. A medical device described in any one of embodiments 79 to 80, further comprising a wall portion extending along a reference axis between the distal end and the proximal end, wherein the first chamber and the second chamber are arranged consecutively along the reference axis within the wall portion such that the first chamber constitutes the distal chamber and the second chamber constitutes the proximal chamber. 82. A medical device according to embodiment 80 or 81, comprising a semaglutide formulation according to any one of embodiments 43 to 68 in the distal chamber and a caglilintide formulation according to any one of embodiments 1 to 38 in the proximal chamber. 83. A medical device according to any one of embodiments 79-82, wherein the caglilintide formulation comprises lactic acid / lactate, acetic acid / acetate, or glutamic acid / glutamate as a buffer (pH 3.5-4.5). 84. A medical device according to any one of embodiments 79 to 83, wherein the caglilintide formulation comprises glutamic acid / glutamate as a buffer. 85. Caglilintide preparations are glycerol, mannitol, propylene glycol, sorbitol, sucrose, or trehalose, - NaOH / HCl to reach a pH of 3.5 to 4.5, e.g., about pH 4.0; - water. 86. Caglilintide preparations are caglilintide in a concentration of 0.1 to 20 mg / ml, for example 0.32 to 18 mg / ml; glutamic acid / glutamate at a concentration of 2 to 10 mM, for example 2.5 to 5 mM, for example about 5 mM; - NaOH / HCl to reach a pH of 3.5 to 4.5, e.g., about pH 4.0; - water. The medical device of any one of embodiments 79 to 85, further comprising: 87. A preparation containing caglilintide is -lactic acid / lactate, glycerol, mannitol, propylene glycol, sorbitol, sucrose, or trehalose, - NaOH / HCl to reach a pH of 3.5 to 4.5, e.g., about pH 4.0; - water. The medical device according to any one of embodiments 79 to 83, further comprising: 88. A preparation containing caglilintide is caglilintide in a concentration of 0.1 to 20 mg / ml, for example 0.32 to 18 mg / ml; 2.5 to 10 mM, for example about 5 mM lactic acid / lactate; - glycerol to obtain isotonicity, such as 24 mg / ml; - NaOH / HCl to reach a pH of 3.5 to 4.5, e.g., about pH 4.0; - water. The medical device of any one of embodiments 79 to 83, further comprising: 89. A medical device according to any one of embodiments 79 to 88, comprising 400 to 600 μl, preferably about 500 to 550 μl, of the semaglutide formulation in the distal chamber and 200 to 300 μl, preferably about 250 to 300 μl, of the caglilintide formulation in the proximal chamber. 90. A medical device according to any one of embodiments 79 to 89, wherein the concentration of caglilintide in the formulation in the proximal chamber is higher than the concentration of semaglutide in the formulation in the distal chamber. 91. A medical device according to any one of embodiments 79 to 90, for use in medicine. 92. A medical device according to any one of embodiments 79 to 90 for use in the treatment and / or prevention of obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH), cardiovascular disease, and Alzheimer's disease. 93. A medical device comprising a formulation comprising 0.1 to 10 mg / ml semaglutide in a first chamber and a formulation comprising 0.1 to 20 mg / ml caglilintide in a second chamber, the medical device being for use in treating a subject with an initial body mass index (BMI) of 30 kg / m2 or greater (obese) or with an initial BMI of 27 kg / m2 or greater (overweight) and at least one weight-related comorbidity. 94. A semaglutide formulation according to any one of embodiments 45 to 68 and a caglilintide formulation according to any one of embodiments 1 to 38 for use in medicine. 95. A semaglutide formulation according to any one of embodiments 45 to 68 and a caglilintide formulation according to any one of embodiments 1 to 38 for use in the treatment and / or prevention of obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH), cardiovascular disease, and / or Alzheimer's disease. A semaglutide formulation according to any one of embodiments 45 to 68 and a caglilintide formulation according to any one of embodiments 1 to 38 for use in treating a subject with an initial body mass index (BMI) of 96.30 kg / m2 or greater (obese) or an initial BMI of 27 kg / m2 or greater (overweight) and at least one weight-related comorbidity. 97. A method for the prevention and / or treatment of obesity, diabetes, non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH), cardiovascular disease, and / or Alzheimer's disease, in which a semaglutide formulation according to any one of embodiments 45 to 68 and a caglilintide formulation according to any one of embodiments 1 to 38 are administered to a subject in need thereof. A method for the prevention and / or treatment of subjects with an initial body mass index (BMI) of 98.30 kg / m2 or more (obese) or with an initial BMI of 27 kg / m2 or more (overweight) and at least one weight-related comorbidity, wherein a semaglutide formulation according to any one of embodiments 45 to 68 and a caglilintide formulation according to any one of embodiments 1 to 38 are administered to a subject in need thereof. An effective fixed dose combination comprising 0.08 to 5.0 mg of caglilintide and 0.125 to 5.0 mg of semaglutide for use in a method for the treatment of subjects with an initial body mass index (BMI) of 99.30 kg / m2 or greater (obese), or subjects with an initial BMI of 27 kg / m2 or greater (overweight) and at least one weight-related comorbidity, wherein the caglilintide and semaglutide formulations are administered parenterally, such as subcutaneously, in a single injection. 100. A caglilintide formulation according to any one of embodiments 1 to 38 and a semaglutide formulation according to any one of embodiments 45 to 68 for use in a method for the treatment of a subject with an initial body mass index (BMI) of 30 kg / m2 or more (obese), or a subject with an initial BMI of 27 kg / m2 or more (overweight) and at least one weight-related comorbidity, wherein the caglilintide and semaglutide formulations are administered parenterally, such as subcutaneously, in a single injection. A formulation comprising 0.1 to 20 mg / ml of caglilintide and 0.1 to 10 mg / ml of semaglutide for use in a method for the treatment of a subject with an initial body mass index (BMI) of 101.30 kg / m2 or greater (obese) or a subject with an initial BMI of 27 kg / m2 or greater (overweight) and at least one weight-related comorbidity, wherein the caglilintide and semaglutide formulations are administered parenterally, such as subcutaneously, in a single injection. 102. The use according to any one of embodiments 91 to 101, wherein the dose of caglilintide administered in said single injection is 0.16 mg to 4.5 mg per week, for example about 0.25 mg, 0.5 mg, 1.0 mg, 1.2 mg, 1.7 mg, 2.4 mg, or 4.5 mg. 103. The use according to any one of embodiments 91 to 102, wherein the dose of semaglutide administered in said single injection is about 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, or 2.4 mg. 104. The use according to any one of embodiments 91 to 103, wherein the ratio of administered caglilintide to semaglutide (in mg) is about 1:1. 105. The use according to any one of embodiments 91 to 103, wherein the ratio of administered caglilintide to semaglutide (in mg) is about 1:2. 106. The use according to any one of embodiments 91 to 104, wherein the administered dose of caglilintide is 0.25 mg and the administered dose of semaglutide is 0.25 mg. 107. The use according to any one of embodiments 91 to 104, wherein the administered dose of caglilintide is 0.5 mg and the administered dose of semaglutide is 0.5 mg. 108. The use according to any one of embodiments 91 to 104, wherein the administered dose of caglilintide is 1.0 mg and the administered dose of semaglutide is 1.0 mg. 109. The use according to any one of embodiments 91 to 104, wherein the administered dose of caglilintide is 1.7 mg and the administered dose of semaglutide is 1.7 mg. 110. The use according to any one of embodiments 91 to 104, wherein the administered dose of caglilintide is 2.4 mg and the administered dose of semaglutide is 2.4 mg. 111. The use according to any one of embodiments 91 to 103 or 105, wherein the administered dose of caglilintide is 1.2 mg and the administered dose of semaglutide is 2.4 mg. 112. The use according to any one of embodiments 91 to 111, wherein the caglilintide and semaglutide preparations are administered in a single injection approximately once a week, for example once every 5 to 9 days, for example once every 6 to 8 days, preferably once every 7 days. 113.-0.25 mg of caglilintide and 0.25 mg of semaglutide were administered once weekly for 4 weeks (weeks 0-3). -0.5 mg of caglilintide and 0.5 mg of semaglutide were administered once weekly for 4 weeks (weeks 4-7), 1.0 mg of caglilintide and 1.0 mg of semaglutide were administered once weekly for 4 weeks (weeks 8-11). 1.7 mg of caglilintide and 1.7 mg of semaglutide were administered once weekly for 4 weeks (weeks 12-15). -The use according to any one of embodiments 91 to 112, wherein 2.4 mg of caglilintide and 2.4 mg of semaglutide are subsequently administered once a week. 114. The use according to any one of embodiments 91-113, wherein the fixed-dose combination of semaglutide and caglilintide results in a weight loss of > 15% within 26 weeks of starting treatment. [Example]

[0250] All semaglutide drug product (DP) compositions were prepared by dissolving buffer (disodium hydrogen phosphate dihydrate), tonicity agent (propylene glycol or NaCl), and histidine (where relevant) in water, adjusting the pH to approximately 7.4 using sodium hydroxide and / or hydrochloric acid. Semaglutide drug substance (DS) was dissolved therein, adjusting the pH to 7.4 where necessary using sodium hydroxide and / or hydrochloric acid, and sterilising the composition by filtering through a 0.22 μm sterile filter.

[0251] All compositions of caglilintide drug product (DP) were prepared by dissolving buffer and isotonicity agent in water, adjusting the pH to approximately 7.4 using sodium hydroxide and / or hydrochloric acid, dissolving caglilintide drug substance (DS) therein, adjusting the pH to 4.0 using sodium hydroxide and / or hydrochloric acid as needed, and finally sterilizing the compositions by filtering them through a 0.22 μm sterile filter.

[0252] Where a chlorobutyl rubber plunger is mentioned, the non-recessed type was used, i.e., the shape was similar to the distal plunger 8 shown in Figure 1, regardless of whether it acted as the distal or proximal plunger.

[0253] Example 1: Investigation of the rate of formation of high molecular weight protein (HMWP) species in caglilintide formulations using different buffer substances or tonicity agents Experiments were conducted to determine the optimal buffer substance for caglilintide pharmaceutical formulations at pH 4.0, as well as the optimal tonicity agent or agent, with respect to the rate of formation of the high molecular weight protein (HMWP) impurity. Generally, the level of HMWP in a pharmaceutical peptide or protein formulation is an important parameter to consider as part of the assessment of the formulation's stability, and the rate of formation of this impurity during storage should be minimized.

[0254] These buffers have pK values ​​close to the optimal pH of 4.0 for the caglilintide formulation. a The buffer substances investigated because of their value were acetate, benzoate, glutamate, and lactate. The tonicity agents investigated were glycerol, mannitol, propylene glycol, sorbitol, sucrose, and trehalose.

[0255] For buffer investigations, a total of 38 formulations of caglilintide were prepared with the following general composition: -Caglilintide at one concentration as specified in Table 1-1. -One buffer substance in one concentration as specified in Table 1-1. -Tonicity agent: glycerol (24mg / ml). -Hydrochloric acid (HCl) to obtain a pH of 4.0 as needed. -Sodium hydroxide (NaOH) to obtain a pH of 4.0 as needed. -Water for injection (WFI) as solvent.

[0256] For the tonicity agent investigation, a total of six caglilintide formulations were prepared with the following compositions: -Caglilintide (9.6mg / ml) Buffer: glutamate (added as 5 mM, 0.74 mg / ml L-glutamic acid) -One of the following tonicity agents: o Glycerol (24mg / ml) Mannitol (46 mg / ml) o Propylene glycol (20mg / ml) Sorbitol (46mg / ml) o Sucrose (83mg / ml) o Trehalose (83mg / ml) -Hydrochloric acid (HCl) to achieve a pH of 4.0, if necessary -Sodium hydroxide (NaOH) to achieve a pH of 4.0, if needed -Water for injection (WFI) as solvent. [Table 1]

[0257] Each sterile filtered formulation was filled into multiple glass syringes, each syringe containing approximately 280 μl of the caglilintide formulation enclosed by two chlorobutyl rubber plungers, resulting in a configuration of liquid formulation and primary packaging material corresponding to the proximal chamber of a dual-chamber pre-filled syringe, as described in the section entitled "Preferred Medical Device" and shown in FIG. 1.

[0258] Each syringe was stored at 37±2° C. for 12 weeks, and samples were analyzed for HMWP content at time zero and after 6, 8, and 12 weeks of storage.

[0259] Analysis of HMWP was performed by size-exclusion high-performance liquid chromatography (SE-HPLC), which separates HMWP species from the major peptide form. Analysis was performed using a WATERS HMWP, 7.8 x 300 mm column. Samples formulated at 9.6 mg / ml or 18 mg / ml caglilintide concentrations were diluted to 1 mg / ml in 0.09 M phosphate solution at pH 3.6 prior to injection. Samples formulated at 0.6 mg / ml caglilintide concentration were injected directly. The injection volume was 10 μl, and 500 mM sodium chloride, 10 mM sodium dihydrogen phosphate monohydrate, and 5 mM phosphoric acid with 50% (v / v) 2-propanol were used as the isocratic eluent. The flow rate was 0.5 ml / min, and UV detection was obtained at 215 nm wavelength. The HMWP content (in percent of the total peptide content) is calculated by dividing the HMWP peak area by the total area of ​​the HMWP and major peaks and multiplying by 100%.

[0260] The rate of HMWP formation for each of the formulations investigated was calculated as the slope of the linear regression function of HMWP content (in percent) as a function of time (in weeks).

[0261] The results of the buffer substance survey are presented in Tables 1 and 2. [Table 2]

[0262] From the results shown in Table 1-2, the following can be observed: At each investigated combination of buffer concentration and caglilintide concentration, glutamate resulted in the lowest rate of HMWP formation when compared to the other buffer substances. At each investigated combination of buffer concentration and caglilintide concentration where -benzoate was investigated, benzoate resulted in the highest rate of HMWP formation compared to the other buffer substances. All four buffers were investigated, and at each investigated combination of buffer concentration and caglilintide concentration, formulations containing acetate or lactate as buffering substances were observed to have HMWP formation rates closer to those of formulations containing glutamate compared to those of formulations containing benzoate. - In each of the combinations with all buffers investigated and with concentrations of caglilintide up to 9.6 mg / ml, formulations containing lactate exhibited a lower rate of HMWP formation compared to the corresponding formulations containing acetate. At each combination of buffer concentrations ranging from -5 to 10 mM and a caglilintide concentration of 18 mg / ml, the acetate-containing formulation exhibited a lower HMWP formation rate compared to the lactate-containing formulation, whereas at a combination of a buffer concentration of 2.5 mM and a caglilintide concentration of 18 mg / ml, the lactate-containing formulation exhibited a lower HMWP formation rate compared to the acetate-containing formulation.

[0263] Surprisingly, the data show that selecting glutamate over either acetate, benzoate, or lactate as the buffering substance in caglilintide formulations consistently results in the lowest rate of HMWP formation, i.e., it results in the most stable caglilintide formulation based on this parameter.

[0264] Furthermore, when the caglilintide concentration is 9.6 mg / ml and the buffer is either glutamic acid or lactic acid, the data show that increasing the buffer concentration from 2.5 mM to 5 mM results in a lower HMWP formation rate, however, a further increase to 10 mM does not result in a further decrease in the HMWP formation rate.

[0265] Moreover, surprisingly, the data show that selecting benzoate over either acetate, glutamate, or lactate as a buffering agent in caglilintide formulations consistently results in the highest rate of HMWP formation, i.e., it results in the least stable caglilintide formulation based on this parameter.

[0266] Furthermore, the data show that at a caglilintide concentration of 9.6 mg / ml, choosing lactate as a buffering substance in the concentration range of 2.5-5 mM results in a decreased rate of HMWP formation compared to choosing acetate as a buffering substance in the same concentration range, i.e., it results in a more stable caglilintide formulation based on this parameter.

[0267] The results of studies using different tonicity agents in a 9.6 mg / ml formulation of caglilintide buffered with 5 mM glutamic acid are presented in Tables 1-3. [Table 3]

[0268] The results in Table 1-3 show that glycerol and propylene glycol produce the lowest HMWP formation rate, but the rate is at a similar level for all six tonicity agents investigated.Therefore, based on this parameter, it can be concluded that all six tonicity agents can be used without compromising the stability of kaglilintide formulations.

[0269] Example 2: Investigation of the physical stability of caglilintide formulations containing different buffer substances Injectable liquid pharmaceutical formulations should remain physically stable throughout the product's shelf life, preferably with the ability to withstand periods under stressful conditions, such as higher temperatures and greater physical stress, compared to recommended long-term storage conditions (typically static storage at 2-8° C.). This allows patients to carry their medication with them, for example, when traveling, thereby increasing both patient safety and patient adherence to medication.

[0270] Experiments were conducted to determine the optimal buffer substance for a caglilintide pharmaceutical formulation at pH 4.0 with respect to the physical stability of the formulation, measured as the evolution over time of the following parameters: - the amount of subvisible particles present in the formulation - Presence of amyloid fibrils in the formulation

[0271] The amount of subvisible particles is an important safety parameter to consider in injectable pharmaceutical products, and any occurrence of this parameter in peptide or protein pharmaceuticals such as caglilintide should be minimized. Caglilintide is an analog of the amylin hormone, which is known to be capable of forming amyloid fibrils. The formation of such fibrils should be avoided in parenteral peptide or protein pharmaceuticals to minimize the risk of immunogenic reactions in patients.

[0272] These buffers have pK values ​​close to the target pH of 4.0 for caglirintide. a The buffer substances investigated because of their value were acetate, benzoate, glutamate, and lactate.

[0273] Four formulations of caglilintide were prepared with the following compositions, differing only in buffer: -Caglilintide: 9.6mg / ml. one of the following buffer substances at a concentration of 5 mM: Acetate (added as sodium acetate trihydrate) o Benzoate (added as benzoic acid) o-Glutamate (added as l-glutamic acid) Lactate (added as 50% w / w sodium lactate solution) -Glycerol: 24mg / ml -Hydrochloric acid (HCl) to achieve a pH of 4.0, if necessary -Sodium hydroxide (NaOH) to achieve a pH of 4.0, if needed -Water for injection (WFI) as solvent.

[0274] Each sterile-filtered formulation was filled into multiple glass syringes, each syringe containing approximately 280 μl of the caglilintide formulation enclosed by two chlorobutyl rubber plungers, resulting in a configuration of liquid formulation and primary packaging material corresponding to the proximal chamber of a dual-chamber pre-filled syringe, as described in the section entitled "Preferred Medical Device" and shown in Figure 1. The plungers were inserted so that approximately 100 μl of air was present along with the caglilintide product enclosed by the two plungers.

[0275] All syringes were stored under stress storage conditions, defined in this study as follows: -Temperature: 37±2℃ Physical Stress: During the storage period, all syringes were rotated end-to-end, i.e., 180° back and forth, allowing the product to move back and forth between the two plungers, as specified in Table 2-1. The rotations were performed at room temperature at a rate of approximately 1 second per complete rotation (up and down). The frequency and number of rotations outlined in Table 2-1 corresponds to an average of 100 complete rotations per day, 5 days a week. - Duration: Maximum 28 days (see Table 2-2) [Table 4]

[0276] At the time points indicated in Table 2-2, samples of each of the four caglilintide formulations were analyzed for the following: -Subvisible particle content analyzed by Microflow Imaging (MFI) - the presence of amyloid peptide fibrils, as analyzed by thioflavin-T (ThT) fluorescence assay

[0277] For the analysis of the content of subvisible particles, the MFI method was adopted: for further details on the principles of the MFI technique, see, for example, Sharma, DK et al. AAPS J. (2010), 12:455-464. The following procedure was adopted for each sample. The experiments were carried out at ambient temperature. - The contents of the three syringes were pooled into a sample container. - The liquid from each syringe was removed by first removing the rear (proximal) plunger by vacuum aspiration and then pipetting the liquid into a sample container. - Samples were transferred to a 96 deep well plate, which was inserted into the sample handling unit (Bot1) of a Protein Simple MFI™ 5200 instrument equipped with a standard Protein Simple MFI™ 100 μm flow cell. Samples were analyzed using standard MFI system settings, meaning that the liquid was pipetted into a reservoir connected to a flow cell, the liquid was illuminated by an LED light source (470 nm), and a digital camera through magnification optics recorded bright-field images of the flow cell contents throughout the experiment. Data collection was achieved using Protein Simple MVSS software. Recorded image streams from the entire experiment were processed by validated Novo Nordisk proprietary software, MFI Data Validator, to obtain the number of individual particles with sizes >2 μm, >5 μm, >10 μm, and >25 μm (normalized to counts per ml of analyzed liquid). Particle size is defined as the equivalent circular diameter (ECD).

[0278] The analysis for the presence of peptide fibrils was based on the fluorescent properties of the ThT probe, which exhibits low fluorescence in the unbound / native peptide-bound state but high fluorescence when bound to peptide fibrils, as well as a red shift in the wavelength of maximum fluorescence upon fibril binding. The following procedure was employed for each sample. -Experiments were carried out at 25°C. The contents of two or three syringes were pooled in a sample container if necessary to obtain a total of at least 500 μl. - The liquid from each syringe was removed by first removing the rear (proximal) plunger by vacuum aspiration and then pipetting the liquid into a sample container. Approximately 500 μl of sample was then mixed with approximately 9 μl of ThT stock solution in a separate sample vessel to give a final ThT concentration of 20 μM. - The samples were allowed to incubate for 25 minutes in the dark at ambient temperature. - 200 μl of sample was transferred to wells in a 96-well microtiter plate. -Samples were measured on a BMG CLARIOstar fluorescence plate reader equipped with monochromators for both excitation and emission using 440 nm and 470-550 nm, respectively. Data collection was achieved using CLARIOstar Control software. - The emission maximum in this assay was observed to occur at a wavelength of approximately 485 nm, and therefore the results of each analysis were reported as ThT fluorescence at 485 nm, expressed in relative fluorescence units (RFU). [Table 5]

[0279] The results of the subvisible particle content at each sampling point analyzed by MFI are shown in Table 2-3. [Table 6]

[0280] From Table 2-3, it can be seen that after 14 and 18 days, particle counts at all size intervals are lowest for the glutamate-buffered kaglilintide formulation. Furthermore, up to 14 days, particle counts for the glutamate-buffered kaglilintide formulation remain at a low level, only slightly above the time zero level, and counts do not appear to accelerate up to the 18 day time point. In comparison, a clear increase in particle count is already observed at 11 days for benzoate or 14 days for acetate and lactate.

[0281] It was also clear that the formulations containing benzoate as the buffer agent experienced the most rapid increase in particle count; after 14 days, particle counts were significantly higher for benzoate than for any of the other buffers after 18 days. Sampling for analysis of subvisible particle content was discontinued for the benzoate-buffered formulations after 14 days, in part because subvisible particle levels had already increased so rapidly at that time point (see Tables 2-3), and in part because visible particles were detected upon visual inspection of samples from the 18-day time point at approximately 10,000 lux, and no visible particles were observed for any of the other buffers throughout the duration of this experiment (up to 28 days, including the portion of the study involving ThT fluorescence analysis).

[0282] After 18 days, the particle counts for acetate and lactate were similar for particle sizes >5 and >10 μm, but for particle sizes >2 and >25 μm, the particle counts were higher for acetate compared to lactate.

[0283] Based on the number of subvisible particles, it can therefore be concluded that: The -5 mM glutamate buffered caglilintide formulation surprisingly retains its physical stability for a longer period under stress storage conditions compared to acetate, benzoate, or lactate. By a clear margin, the 5 mM benzoate buffered caglilintide formulation surprisingly exhibits the lowest degree of physical stability compared to the other buffers by having both the earliest onset and highest level of subvisible and visible particle formation. - Acetate and lactate formulations of caglilintide exhibit comparable physical stability, with the lactate salt providing slightly more favorable stability compared to the acetate salt.

[0284] The results of the presence of amyloid fibrils at each sampling point as measured by the ThT fluorescence assay are shown in Tables 2-4. [Table 7]

[0285] From Tables 2-4, it can be seen that after 28 days under stressed storage conditions, the glutamate-containing formulation retains fluorescence levels equal to or slightly above the time zero level. When buffered with lactate, a slightly larger increase is observed after 25 days, reaching approximately two-fold higher levels at 28 days compared to time zero. A much larger increase in fluorescence is observed with the acetate-buffered formulation, with a rapid increase after 21 days, reaching levels more than four-fold higher than those observed at time zero after 28 days. The fastest and largest increase in fluorescence was observed with benzoate as the buffer, with a slight increase already observed after 11 days, followed by a larger increase after 14 days, reaching levels approximately four-fold higher than those at time zero. After another large increase in fluorescence measured at 21 days, the experiment was stopped for the benzoate-buffered formulation, at which point visible particles were observed in the samples when visually inspected at approximately 1,000 lux.

[0286] An increase in the ThT fluorescence level, combined with an increase in the number of observed subvisible particles detected by the MFI method, indicates that the peptide or protein under investigation is forming amyloid fibrils. Based on the ThT fluorescence results, it can therefore be concluded that: -Glutamate-buffered caglilintide formulations surprisingly remained free or nearly free of amyloid fibrils for longer periods under stressed storage conditions compared to acetate, benzoate, or lactate, and appeared to form no or few fibrils over the study period (up to 28 days). -Lactate-buffered kaglilintide formulations remained free or nearly free of amyloid fibrils for longer periods under stressed storage conditions compared to acetate or benzoate, and the level of fibrils ultimately formed over the study period (observed after 25 days) appeared to be lower than those containing acetate or benzoate when comparing the same time points. By a clear margin, the benzoate-buffered caglilintide formulation surprisingly exhibits the highest propensity to form amyloid fibrils during stress storage conditions compared to glutamate, lactate, and acetate, both in terms of having the earliest onset of formation and in terms of showing the greatest levels of fibrils. The tendency of acetate buffered formulations to fibrillate during stress storage conditions is evident from their fluorescence levels, which are intermediate between those of glutamate and benzoate buffered formulations, both in terms of development time and level of fibrils formed.

[0287] In conclusion, 5 mM glutamate surprisingly exhibits clear advantages over 5 mM lactate, 5 mM acetate, and especially 5 mM benzoate as buffers for obtaining the most physically stable formulation of caglirintide under stress storage conditions. Furthermore, both 5 mM lactate and 5 mM acetate exhibit clear advantages over 5 mM benzoate as buffers for obtaining the most physically stable formulation of caglirintide under stress storage conditions.

[0288] Example 3: Physical stability during injection - Effect of buffer concentration in caglilintide on the formation of subvisible particles during mixing in a dual-chamber syringe The buffer concentration in the caglilintide formulation, e.g., glutamate or lactate concentration, should be sufficiently high to ensure stability of the caglilintide drug product during and outside of shelf-life, but should not impair the physical stability of semaglutide upon co-ejection with semaglutide from a dual-chamber syringe, e.g., by inducing the formation of visible and / or subvisible particles, which could potentially result in immunogenic responses and / or unpredictable pharmacokinetic profiles in patients.

[0289] Experiments were carried out to determine the maximally feasible concentration of glutamate or lactate buffer in a semaglutide formulation at pH 4.0, given that mixing with semaglutide should not lead to the formation of visible and / or subvisible particles.

[0290] A total of eight different formulations of caglilintide at pH 4.0 containing various concentrations of glutamate or lactate were prepared with the following compositions: -Caglilintide: 9.6mg / ml Glutamate (added as l-glutamic acid) or lactate (added as a 50% w / w solution of sodium l-lactate) in one of the following concentrations: o2.5mM o5mM o10mM o40mM -Glycerol: 24mg / ml -Hydrochloric acid (HCl) to achieve a pH of 4.0, if necessary -Sodium hydroxide (NaOH) to achieve a pH of 4.0, if needed -Water for injection (WFI) as solvent.

[0291] Two formulations of semaglutide at pH 7.4, with and without histidine included as an excipient, were prepared with the following compositions: -Semaglutide: 4.8mg / ml -Phosphate: 30 mM (added as 5.34 mg / ml disodium hydrogen phosphate dihydrate) - Histidine: 0 or 10 mM (added as 1.55 mg / ml l-histidine) -Sodium chloride: 6.4mg / ml -Hydrochloric acid (HCl) to achieve a pH of 7.4, if necessary -Sodium hydroxide (NaOH) to achieve a pH of 7.4, if needed -Water for injection (WFI) as solvent.

[0292] Each sterile-filtered caglilintide and semaglutide formulation was loaded into a dual-chamber glass syringe (see Figure 1) so that each syringe contained approximately 515-525 μl of the semaglutide formulation in the distal chamber towards the needle and approximately 280 μl of one of the caglilintide formulations in the proximal chamber enclosed by two chlorobutyl rubber plungers. Thus, a total of 12 different combinations of semaglutide and caglilintide formulations in dual-chamber syringes were obtained: Histidine-free semaglutide (four different concentrations) in combination with each of the glutamate-containing semaglutide formulations Semaglutide containing 10mM histidine (four different concentrations) combined with each of the glutamate-containing semaglutide formulations Semaglutide containing 10mM histidine (4 different concentrations) in combination with each of the lactate-containing semaglutide formulations

[0293] In the following, an experiment carried out with one such combination will be referred to as an "emission experiment."

[0294] For each expulsion experiment, the syringe was emptied by expelling the entire contents of the liquid formulation through the needle and into the flow cell of the MFI device. The following procedure was used separately for each expulsion experiment: The experiments were carried out at ambient temperature. The needle tip of the dual chamber syringe was directly connected via silicone tubing to the flow cell of the Protein Simple MFI™ 4200 instrument (Protein Simple MFI™ 100 μm flow cell). - A force was applied to the rear (proximal) plunger separating the caglilintide formulation from the external environment to obtain an approximately constant liquid flow of approximately 0.17 ml / min through the flow cell of the MFI device. As the liquid exiting the syringe needle passed through the flow cell, it was illuminated by an LED light source (470 nm), and a digital camera through magnifying optics recorded bright-field images of the flow cell contents throughout the experiment. Recording began as soon as possible after all air in the detection zone of the flow cell was displaced by the liquid from the syringe, and ended as close as possible to the point at which all liquid contents from the syringe had been expelled and passed through the detection zone of the flow cell. Data collection was accomplished using Protein Simple MVSS software. - The recorded image stream from the entire experiment was processed by the validated Novo Nordisk proprietary software MFI Data Validator to obtain the number of individual particles >10 μm in size and >25 μm in size (ECD) (normalized to counts per ml of analyzed liquid).

[0295] The results, presented as a range of particle numbers per ml, for each of the semaglutide and caglilintide combinations investigated are provided in Table 3-1. [Table 8]

[0296] To allow comparison with the background particle levels of the formulations without mixing, the particle counts of the separate formulations expelled from the syringe in the same manner as the expulsion experiment described above are shown in Table 3-2 (normalized to counts per ml). [Table 9]

[0297] MFI particle data show that at glutamate concentrations of 2.5 and 5 mM, the observed particle levels were comparable to background levels, i.e., no particle formation was observed as a result of mixing with semaglutide. Increasing the glutamate concentration to 10 mM resulted in an increase in the number of particles of both particle sizes (>10 μm and >25 μm). Increasing the glutamate concentration further to 40 mM resulted in the formation of visible particles during the excretion experiment, at which point the level of subvisible particles was too high for meaningful analysis with the MFI instrument.

[0298] For lactate, the MFI particle counts for both particle sizes (>10 μm and >25 μm) remained at low and comparable levels at both concentrations of 2.5, 5, and 10 mM, whereas an increase to 40 mM resulted in visible particle formation during the excretion experiments.

[0299] Comparing semaglutide formulations with 0 or 10 mM histidine, the two formulations, along with increasing concentrations of glutamate, show comparable particle levels when mixed with each of the four semaglutide formulations.

[0300] Therefore, the results of this experiment show the following: The concentration of glutamate in a caglilintide formulation at pH 4.0 should not exceed 10 mM, as concentrations above this level may cause excessive formation of subvisible particles during simultaneous injection with a dual-chamber syringe of a semaglutide formulation containing 30 mM phosphate and either 0 or 10 mM histidine at pH 7.4, and even visible particles at 40 mM glutamate. In contrast, the concentration of glutamate in a caglilintide formulation at pH 4.0 should be ≦10 mM, for example 5 mM or 2.5 mM, as this level of glutamate does not cause excessive formation of subvisible particles during injection using the same combination. The lactate concentration in a pH 4.0 formulation of semaglutide combined with a pH 7.4 formulation of semaglutide containing 30 mM phosphate and 10 mM histidine during injection with a dual-chamber syringe can be up to at least 10 mM, including 2.5 mM or 5 mM, to avoid the formation of subvisible particles. However, the lactate concentration should not approach 40 mM, as visible particles will form at this concentration. - The results of this physical stability study show that a 4.8 mg / ml semaglutide formulation containing 30 mM phosphate can optionally contain 10 mM histidine as an excipient, and the physical stability of semaglutide and caglilintide co-injected with a dual-chamber syringe is comparable between semaglutide formulations containing 0 or 10 mM histidine.

[0301] Example 4: Physical stability during injection - Effect of caglilintide on the formation of subvisible particles during mixing in a dual-chamber syringe In Example 3, it was found that when the concentration of the buffer (e.g., glutamate) used in the caglilintide formulation was increased above a certain threshold, subvisible or even visible particles were formed during simultaneous ejection from a dual-chamber syringe with a formulation containing semaglutide. The caglilintide peptide itself also contributes to the buffer capacity of the caglilintide formulation, i.e., increasing the caglilintide concentration leads to an increase in the buffer concentration.

[0302] Experiments were carried out using a dual-chamber syringe to determine whether the presence of the caglilintide peptide in a caglilintide formulation (pH 4.0) poses a higher or lower risk of subvisible particle formation during co-ejection from the dual-chamber syringe with a semaglutide formulation (pH 7.4).

[0303] A total of three different caglilintide formulations at pH 4.0 containing various concentrations of caglilintide were prepared using the following compositions: -Caglilintide: 0, 0.5, or 9.6 mg / ml - Glutamate: 5 mM (added as 0.74 mg / ml l-glutamic acid) -Glycerol: 24mg / ml -Hydrochloric acid (HCl) to achieve a pH of 4.0, if necessary -Sodium hydroxide (NaOH) to achieve a pH of 4.0, if needed -Water for injection (WFI) as solvent.

[0304] Two semaglutide formulations at pH 7.4 were prepared with the following compositions: -Semaglutide: 0.5 or 4.8 mg / ml -Phosphate: 30 mM (added as 5.34 mg / ml disodium hydrogen phosphate dihydrate) -Histidine: 10 mM (added as 1.55 mg / ml l-histidine) -Sodium chloride: 6.4mg / ml -Hydrochloric acid (HCl) to achieve a pH of 7.4, if necessary -Sodium hydroxide (NaOH) to achieve a pH of 7.4, if needed -Water for injection (WFI) as solvent.

[0305] Each sterile-filtered caglilintide and semaglutide formulation was loaded into a dual-chamber glass syringe (see Figure 1) so that each syringe contained approximately 520-530 μl of the semaglutide formulation in the distal chamber toward the needle and approximately 270-280 μl of one of the caglilintide formulations in the proximal chamber enclosed by two chlorobutyl rubber plungers. Thus, a total of four different combinations of semaglutide and caglilintide formulations in the dual-chamber syringes were obtained (defined as test combinations): Semaglutide 0.5mg / ml in combination with caglilintide 0mg / ml Semaglutide 0.5mg / ml in combination with caglilintide 0.5mg / ml Semaglutide 4.8mg / ml in combination with caglilintide 0mg / ml Semaglutide 4.8mg / ml in combination with caglilintide 9.6mg / ml

[0306] In addition, a semaglutide vehicle was prepared for semaglutide formulations containing 0 mg / ml semaglutide, i.e., for the 0.5 mg / ml and 4.8 mg / ml semaglutide formulations, with the same composition and pH as above, but without adding semaglutide to the formulation. This vehicle was used to obtain information on the expected background particle levels across the following three combinations (defined as background combinations): Semaglutide 4.8mg / ml in the distal chamber combined with semaglutide vehicle in the proximal chamber Semaglutide vehicle in the distal chamber combined with caglilintide 0.5mg / ml in the proximal chamber Semaglutide vehicle in the distal chamber combined with caglilintide 9.6 mg / ml in the proximal chamber

[0307] For each of the test and background combinations listed above, an "exclusion experiment" was performed as detailed in Example 3, and the MFI instrument and software were used to obtain the number of individual particles >10 μm in size and >25 μm in size (ECD) (normalized to counts per ml of liquid analyzed).

[0308] The results, presented as ranges of particle counts per ml, for each of the four investigated test combinations with semaglutide and caglilintide formulations are provided in Table 4-1. [Table 10]

[0309] The particle counts for background combinations expelled from the syringe in the same manner as the combinations described above are shown in Table 4-2 (normalized to counts per ml). [Table 11]

[0310] The data in Table 4-1 for the test combinations show that subvisible particle levels for the combination of 0 mg / ml caglilintide and 4.8 mg / ml semaglutide are clearly elevated compared to the background levels shown in Table 4-2, and in some instances, visible particles were even observed to form during excretion. For the combination of 0 mg / ml caglilintide and 0.5 mg / ml semaglutide, particle levels >10 μm are elevated in some experiments compared to background levels (see Table 4-2). For the remaining two test combinations, in which caglilintide was present at either 0.5 mg / ml or 9.6 mg / ml, no subvisible particle formation was observed above that expected from background levels.

[0311] This experiment surprisingly shows that caglilintide needs to be present at a certain concentration above 0 mg / ml to consistently avoid the formation of subvisible particles, and even visible particles in combination with semaglutide 4.8 mg / ml, when co-injecting the tested semaglutide formulation and the tested caglilintide formulation from a dual-chamber syringe.The presence of caglilintide is unexpected because the caglilintide peptide contributes to the buffering capacity in the caglilintide formulation at pH 4.0, and the results of Example 3 show that increasing the buffering capacity in the caglilintide formulation increases the risk of particle formation during mixing of the same caglilintide and semaglutide formulations tested in this example.

[0312] Example 5: Physical stability during injection of semaglutide formulations with different phosphate concentrations The phosphate buffer concentration in the semaglutide formulation should ensure the stability of the semaglutide drug product during and after storage, and the physical stability of semaglutide during simultaneous discharge of semaglutide from the dual-chamber device, for example by ensuring that visible and / or subvisible particles are not formed. Such particle formation could potentially result in immunogenic responses and / or unpredictable pharmacokinetic profiles in patients. Example 3 showed that the effect of the buffer concentration in the semaglutide formulation is important for ensuring the physical stability of semaglutide during simultaneous discharge of semaglutide from the dual-chamber device.

[0313] Experiments were carried out to determine the minimum feasible concentration of phosphate buffer in semaglutide formulations at pH 7.4, given that mixing with semaglutide should not lead to the formation of visible and / or subvisible particles.

[0314] A total of four semaglutide formulations at pH 7.4 were prepared with various concentrations of phosphate using the following compositions: -Semaglutide: 4.8mg / ml - one of the following combinations of phosphate (buffer) with either propylene glycol or sodium chloride as a tonicity agent (the concentration of the tonicity agent was adjusted based on the concentration of phosphate to obtain an approximately isotonic formulation): 8 mM phosphate (added as 1.42 mg / ml disodium hydrogen phosphate dihydrate) and 18.5 mg / ml propylene glycol o 15 mM phosphate (added as 2.67 mg / ml disodium hydrogen phosphate dihydrate) and 17.5 mg / ml propylene glycol 20 mM phosphate (added as 3.56 mg / ml disodium hydrogen phosphate dihydrate) and 17.0 mg / ml propylene glycol 20 mM phosphate (added as 3.56 mg / ml disodium hydrogen phosphate dihydrate) and 7.60 mg / ml sodium chloride -Hydrochloric acid (HCl) to achieve a pH of 7.4, if necessary -Sodium hydroxide (NaOH) to achieve a pH of 7.4, if needed -Water for injection (WFI) as solvent.

[0315] One caglilintide formulation at pH 4.0 was prepared with the following composition: -Caglilintide: 9.6mg / ml - Glutamate: 5 mM (added as 0.74 mg / ml l-glutamic acid) -Glycerol: 24mg / ml -Hydrochloric acid (HCl) to achieve a pH of 4.0, if necessary -Sodium hydroxide (NaOH) to achieve a pH of 4.0, if needed -Water for injection (WFI) as solvent.

[0316] Each sterile filtered caglilintide and semaglutide formulation was loaded into a dual-chamber glass syringe (see Figure 1) so that each syringe contained an extractable volume of at least 550 μl of one of the semaglutide formulations in the distal chamber toward the needle, and an extractable volume of at least 250 μl of the caglilintide formulation in the proximal chamber enclosed by two chlorobutyl rubber plungers. Thus, a total of four different combinations of semaglutide and caglilintide formulations in dual-chamber syringes were obtained. For each combination, the "discharge experiment" detailed in Example 3 was performed, and the MFI device and software were used to obtain the number of individual particles with a size of >10 μm and a size of >25 μm (ECD) (normalized to the number of counts per ml of analyzed liquid).

[0317] The results, expressed as a range of particles per ml for each of the phosphate concentrations investigated, are provided in Table 5-1. [Table 12]

[0318] To allow comparison with the background particle levels of the formulations without mixing, the particle counts of the separate formulations expelled from the syringe in the same manner as the expulsion experiment described above are shown in Table 5-2 (normalized to counts per ml). [Table 13]

[0319] The MFI particle data in Table 5-1 show that a phosphate concentration of 8 mM in the semaglutide formulation results in clearly elevated particle counts for both particle sizes (>10 μm and >25 μm) when mixed with semaglutide containing 5 mM glutamate as a buffer.

[0320] The data also reveal that increasing the phosphate concentration to 15 mM removes most, but not all, of the subvisible particles formed during the excretion experiments. A further increase to 20 mM phosphate resulted in a further reduction in the number of subvisible particles measured during the excretion experiments, with similar levels observed whether propylene glycol or sodium chloride was used as the tonicity agent. The particle levels observed at 20 mM phosphate correspond to background levels in this experiment (Table 5-2) and therefore represent a lack of subvisible particle formation as a result of mixing of the semaglutide and caglilintide formulations in the dual-chamber syringe.

[0321] Therefore, the results of this experiment indicate that the phosphate concentration in a semaglutide formulation at pH 7.4 should be greater than 15 mM, for example 20 mM or greater, to avoid the formation of subvisible particles during injection with a dual-chamber syringe in combination with a semaglutide formulation containing 5 mM glutamate at pH 4.0.

[0322] Example 6: PK profiles following administration of caglintide and semaglutide via pre-filled dual-chamber syringes A study was conducted in LYD pigs to evaluate the PK of a combination of caglilintide and semaglutide after a single subcutaneous administration via a prefilled dual-chamber syringe (see Figure 1) or via separate injections of each drug. The administered volumes were approximately 500 microliters of semaglutide formulation and approximately 250 microliters of caglilintide formulation. Dose ranges of 0.25 mg to 2.4 mg of semaglutide and 0.25 mg to 4.5 mg of caglilintide were explored.

[0323] Female crossbred domestic pigs (Danish Landrace, Yorkshire and Duroc-LYD pigs) weighing approximately 80-100 kg were used to explore the PK profile.

[0324] The low dose was administered subcutaneously with a single dose of semaglutide / caglilintide, either as monotherapy or in combination using a prefilled dual-chamber syringe or as separate injections at different injection sites using a NovoPen 4 penfill (Novo Nordisk A / S). Prior to administering the high dose of semaglutide / caglilintide, LYD pigs were dose-titrated with liraglutide for 10 days to avoid initial gastrointestinal discomfort from the sudden high dose of semaglutide. On day 11, animals were administered semaglutide / caglilintide as described above.

[0325] A full plasma concentration-time profile was obtained from each animal from pre-dose through 18 days post-dose.

[0326] Plasma was analyzed using luminescence-activated oxygen channel immunoassay (LOCI) and liquid chromatography-mass spectrometry (LCMS) for semaglutide and caglilintide, respectively. Non-compartmental pharmacokinetic analysis was performed using individual plasma concentration-time profiles. [Table 14]

[0327] Moderate differences in semaglutide PK parameters, Cmax, and tmax were observed with different administration methods. max was increased by up to 65% and AUC increased by up to 45% after administration of 2.4 / 2.4 semaglutide / caglilintide using a prefilled dual-chamber syringe, in contrast to when semaglutide was administered via two different devices.

[0328] These non-clinical data may indicate improved efficacy when semaglutide and caglilintide are administered in a single injection using a dual-chamber syringe, as opposed to when they are administered separately using individual syringes such as the NovoPen 4 penfill.

[0329] Example 7: Phase 1 combination study of AM833 (caglilintide) and semaglutide Test Design A 20-week, multiple-ascending dose phase 1 study investigated the safety, tolerability, pharmacokinetics, and weight loss potential of AM833 (caglilintide) administered in combination with 2.4 mg semaglutide. Six different caglilintide doses (0.16 mg, 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, and 4.5 mg per week) were administered as separate subcutaneous injections in six separate cohorts, along with semaglutide (2.4 mg per week). Subjects were randomized 3:1 to receive caglilintide + 2.4 mg semaglutide or placebo + 2.4 mg semaglutide. A 16-week dose-escalation period was followed by 4 weeks at the target dose. Patients were 27.0 to 39.9 kg / m 2 Eighty adults with an initial BMI (including both borderlines) completed the study.

[0330] The study investigated the number of treatment-emergent adverse events (primary endpoint). AM833 was well tolerated, with the most common adverse events being injection site reactions and gastrointestinal disorders, including nausea and vomiting, the majority of which were non-severe and mild or moderate in severity. Surprisingly, the level of gastrointestinal disorders observed with the AM833 and semaglutide combination in the study was comparable to that typically seen with glucagon-like peptide-1 (GLP-1) monotherapy.

[0331] result From a mean baseline weight of 95.7 kg, weight loss occurred in all treatment groups over the 20-week treatment period, with substantial weight loss observed in subjects receiving the three highest doses of caglilintide (1.2 mg, 2.4 mg, and 4.5 mg) plus 2.4 mg semaglutide compared with placebo plus 2.4 mg semaglutide (Figure 5).

[0332] After 20 weeks of treatment, there was a statistically significant treatment difference in the mean change in body weight from baseline to end of treatment for the three highest doses of caglilintide combined with semaglutide (1.2 mg, 2.4 mg, and 4.5 mg) compared with placebo plus semaglutide. The estimated mean change in body weight from baseline to end of treatment was 15.6% for 1.2 mg caglilintide, 17.0% for 2.4 mg caglilintide, and 15.6% for 4.5 mg caglilintide, all combined with 2.4 mg semaglutide. A weight loss of 9.8% was observed for placebo plus semaglutide. The treatment difference was not statistically significant for the three lowest doses of caglilintide combined with semaglutide (0.16 mg, 0.3 mg, and 0.6 mg) compared with placebo combined with 2.4 mg semaglutide. In all treatment groups, there was evidence of weight regain after discontinuation of study drug at week 20.

Claims

1. A fixed dose combination of 0.025 to 5.0 mg caglilintide and 0.05 to 5.0 mg semaglutide for use in medicine.

2. 2. The combination of claim 1, wherein caglilintide and semaglutide are administered parenterally, for example subcutaneously, in a single injection.

3. 3. A combination according to claim 1 or 2, for use in medicine in the treatment of subjects suffering from obesity or subjects who are overweight and suffer from at least one weight-related comorbidity.

4. 4. The combination according to claim 1 or 3, wherein the use in medicine is the treatment or prevention of overweight, optionally in the presence of at least one weight-related comorbidity, and wherein the subject suffering from overweight is a human, such as an adult human or a pediatric human (including infants, children and adolescents), and wherein the subject suffering from overweight may have a BMI of ≧25, such as a BMI of ≧27.

5. Use in medicines (i) the prevention and / or treatment of diabetes; (ii) delaying or preventing the progression of diabetic disease, e.g., type 2 diabetes; (iii) prevention and / or treatment of cardiovascular disease, for example, delaying or reducing the occurrence of major adverse cardiovascular events (MACE) selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, hospitalization for unstable angina, and hospitalization for heart failure; or (v) Prevention and / or treatment of non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH). The combination according to claim 1 or 2,

6. 30 kg / m ２ Subjects with an initial body mass index (BMI) of ≥ 27 kg / m (obese) ２ A fixed dose combination of 0.025 to 5.0 mg of caglilintide and 0.05 to 5.0 mg of semaglutide for use in a method of treating a subject with an initial BMI above (overweight) and at least one weight-related comorbidity, wherein the caglilintide and semaglutide formulations are administered parenterally, for example subcutaneously, in a single injection.

7. 7. The combination according to any one of claims 2 to 6, wherein the dose of caglilintide administered in a single injection is between 0.16 mg and 4.5 mg per week, for example about 0.25 mg, 0.5 mg, 1.0 mg, 1.2 mg, 1.7 mg, 2.4 mg, or 4.5 mg.

8. 8. The combination of any one of claims 1 to 7, wherein the dose of semaglutide administered in a single injection is about 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, or 2.4 mg.

9. 9. A combination according to any one of claims 1 to 8, wherein the administered dose of caglilintide is 0.25 mg and the administered dose of semaglutide is 0.25 mg.

10. 9. A combination according to any one of claims 1 to 8, wherein the administered dose of caglilintide is 0.5 mg and the administered dose of semaglutide is 0.5 mg.

11. 9. A combination according to any one of claims 1 to 8, wherein the administered dose of caglilintide is 1.0 mg and the administered dose of semaglutide is 1.0 mg.

12. 9. A combination according to any one of claims 1 to 8, wherein the administered dose of caglilintide is 1.7 mg and the administered dose of semaglutide is 1.7 mg.

13. 9. A combination according to any one of claims 1 to 8, wherein the administered dose of caglilintide is 2.4 mg and the administered dose of semaglutide is 2.4 mg.

14. 9. A combination according to any one of claims 1 to 8, wherein the administered dose of caglilintide is 1.2 mg and the administered dose of semaglutide is 2.4 mg.

15. 9. The combination of any one of claims 1 to 8, wherein the ratio (in mg) of caglilintide to semaglutide administered is about 1:1 or about 1:

2.

16. 16. A combination according to any one of claims 1 to 15, wherein the caglilintide and semaglutide formulations are administered in a single injection approximately once a week, such as once every 5 to 9 days, for example once every 6 to 8 days, preferably once every 7 days.

17. 0.25 mg caglilintide and 0.25 mg semaglutide administered once weekly for 4 weeks (weeks 0-3), 0.5 mg caglilintide and 0.5 mg semaglutide administered once weekly for 4 weeks (weeks 4-7), 1.0 mg caglilintide and 1.0 mg semaglutide administered once weekly for 4 weeks (weeks 8-11), 1.7 mg caglilintide and 1.7 mg semaglutide administered once weekly for 4 weeks (weeks 12-15); and - 2.4 mg caglilintide and 2.4 mg semaglutide administered once weekly thereafter; A combination according to any one of claims 1 to 16.

18. Use of a combination according to any one of claims 1 to 17 for the preparation of a medicament.

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