Pharmaceutical formulation

Abstract

Disclosed herein are aqueous pharmaceutical formulations comprising canagliflozin and aqueous formulations comprising semeglutide. The composition of these two pharmaceutical formulations allows them to be presented in, and administered using, the two-compartment medical devices disclosed herein. Individuals having a disease, such as diabetes and / or obesity and / or associated co-diseases, may benefit from co-administration of semeglutide and canagliflozin and / or the two liquid pharmaceutical formulations disclosed herein using the medical devices disclosed herein.

Description

[0001] This application is a divisional application of patent application No. 202180015117.5, filed on February 17, 2021, entitled "Pharmaceutical Preparation". Technical Field

[0002] This invention relates to aqueous pharmaceutical formulations of semaglutide and canagliflozintide that can be administered using suitable drug delivery devices. When administered together, semaglutide and canagliflozintide, as well as the pharmaceutical formulations disclosed herein containing them, can be used to treat individuals suffering from medical conditions such as diabetes and obesity and their associated comorbidities. Background Technology

[0003] Obesity, defined as the abnormal or excessive accumulation of fat in the body, has been recognized by the World Health Organization (WHO) as a rapidly developing disease worldwide. It is a leading risk factor for death and a host of serious conditions such as type 2 diabetes and cardiovascular disease.

[0004] When diet and exercise alone are insufficient 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 result in weight loss in obese individuals. Nevertheless, bariatric surgery is necessary in many cases. While 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, minimally invasive treatments with comparable efficacy to bariatric surgery would significantly improve the management of obesity.

[0005] Smegglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist and the active pharmaceutical ingredient in the commercially available product Ozempic®. Ozempic® is indicated for (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 a history of cardiovascular disease. Smegglutide was first described in WO2006 / 097537.

[0006] Canagliflozin, also known as AM833, is an amylin receptor agonist, first described in WO2012 / 168432. Canagliflozin monotherapy for the treatment of obesity is currently in clinical development.

[0007] Nevertheless, there remains a long-standing need in the field for non-invasive obesity treatments that approach the efficacy of bariatric surgery. Summary of the Invention

[0008] This article discloses aqueous formulations containing... -Cangaliskide; - Buffers, which are: glutamate / glutamate at a concentration of about 2-10 mM; or lactate / lactate at a concentration of about 2-35 mM; or acetate / acetate at a concentration of about 2-10 mM; -90-99% w / w of water; and - pH is 3.5-4.5, preferably about pH 4.0.

[0009] This article discloses an aqueous formulation comprising: - Canagliflozin at concentrations of 0.1-20 mg / ml; - A buffer, which is: glutamate / glutamate at a concentration of approximately 2-10 mM; or lactate / lactate at a concentration of approximately 2-35 mM; or acetate / acetate at a concentration of approximately 2-10 mM; and - pH is 3.5-4.5, for example, about pH 4.0.

[0010] This article discloses an aqueous formulation comprising: -Smigratide; - Concentrations greater than 15 mM and less than or equal to 45 mM, such as 16-45 mM, such as 20-45 mM, such as 20-40 mM, such as 25-45 mM, such as 25-40 mM, such as 20-35 mM, such as 20-30 mM, such as 25-35 mM, such as about 30 mM of phosphate; -90-99% w / w of water; and - pH is 7.0-8.0, for example, about 7.4.

[0011] This article discloses an aqueous formulation comprising: - Smegglutinin at concentrations of 0.1-10 mg / ml; - Concentrations greater than 15 mM and less than or equal to 45 mM, such as 16-45 mM, 20-45 mM, 20-40 mM, 25-45 mM, 25-40 mM, 20-35 mM, 25-35 mM, such as approximately 30 mM phosphate; and - pH is 7-8, for example, about 7.4.

[0012] This article discloses a medical device containing the aforementioned pharmaceutical preparation containing semaglutide in a first chamber and the aforementioned pharmaceutical preparation containing canagliflozin in a second chamber.

[0013] This article discloses a medical device containing a single dose of smegglutide in a first compartment and a single dose of canagliflozin in a second compartment.

[0014] This article discloses a fixed-dose combination of 0.025-5.0 mg canagliflozin and 0.05-5.0 mg smegglutinin for pharmaceutical use. Attached Figure Description

[0015] Figure 1 This is a model illustration of a suitable drug delivery device according to an embodiment of the present invention. Two liquids are separated by a front (distal) plunger until injection, during which time both plungers are pushed toward the needle. When the front plunger reaches the bypass, liquid in the rear (proximal) chamber is allowed to flow into the front (distal) chamber.

[0016] Figure 2 The solubility of semaglutide in the pH range of 3.5–7.5 was described. Concentrations equal to or greater than about 0.6 mM (corresponding to about 2.5 mg / ml) indicate that all added semaglutide was dissolved at pH above about 5.9, i.e., the maximum solubility is greater than 0.6 mM. Concentrations less than about 0.6 mM indicate that no more than the amount of semaglutide analyzed is soluble at pH below about 5.9.

[0017] Figure 3 The study describes the weight loss observed in subjects who were co-administered with canagliflozin and smegglutinin. Detailed Implementation

[0018] This article discloses a combination therapy of semaglutide and canagliflozin for pharmaceutical use. Studies of this combination therapy, employing the GLP-1 receptor agonist semaglutide and the amylin receptor agonist canagliflozin, have shown very strong potential for weight loss, indicating that co-administration in humans can lead to weight loss approaching or comparable to bariatric surgery. This combination therapy may be the answer to the long-standing need in the field for a minimally invasive treatment comparable to bariatric surgery. Furthermore, surprisingly, this combination therapy results in a degree of undesirable side effects, such as gastrointestinal disturbances, comparable to those typically seen when using GLP-1 receptor agonists alone.

[0019] Unfortunately, semaglutide and canagliflozin cannot be formulated into the same pharmaceutical preparation. To ensure chemical and physical stability, semaglutide must be formulated to pH 7-8; for example, approximately pH 7.4. To ensure chemical and physical stability, canagliflozin must be formulated to pH 3.5-4.5; for example, approximately pH 4.0. The two pharmaceutical preparations containing semaglutide and canagliflozin, respectively, must be stored separately until administration.

[0020] However, subcutaneous drug delivery is often associated with discomfort, as many people dislike the feeling of a needle being inserted into their skin. An undisclosed number of people even suffer from needle phobia. If these individuals only needed to inject themselves once with a single needle to receive the required combination of semaglitinide and canagliflozin, they would be far less uncomfortable and more convenient: a single injection leads to better treatment adherence (improved compliance) and ultimately, improved patient outcomes, which two injections do not. Furthermore, administering canagliflozin and semaglitinide in a single injection can affect the efficacy of these active pharmaceutical ingredients, whereas separate administration does not.

[0021] Dual-chamber devices are known in the art, and this is the first attempt to use such a device to sequentially administer (1) Ozempic® or smegglutide formulation currently in clinical development, and (2) canagliflozin formulation currently in clinical development.

[0022] Ozempic® and its clinically developed formulation, semaglutide, are buffered with 8 mM phosphate / phosphate to maintain a stable pH of approximately 7.4. Commercially available Ozempic® contains phenol (5.5 mg / ml) as a preservative.

[0023] The canagliflozin formulation used in the Phase 1 and Phase 2 clinical trials was buffered with 5 mM acetate / acetate to maintain a stable pH of approximately 4.0. The formulations used in the Phase 1 and Phase 2 trials also contained 20 mM m-cresol as a preservative, 23 mg / ml glycerol as a pH adjuster, HCl / NaOH for pH adjustment, and water for injection (WFI).

[0024] The inventors of this invention have discovered that known semaglitide formulations and canagliflozin formulations used in Phase 1 and Phase 2 (monotherapy) clinical trials cannot be stored and administered using preferred dual-chamber medical devices. Firstly, the drug formulations are unstable during storage in a dual-chamber device. Secondly, when the drug formulations are injected through the device, they form particles.

[0025] This article discloses semaglutide and canagliflozin pharmaceutical formulations suitable for storage and administration in medical devices such as dual-chamber devices. This article also discloses a medical device containing a semaglutide pharmaceutical formulation in one chamber and a canagliflozin pharmaceutical formulation in another chamber. This article discloses a protocol for minimally invasive treatment of obesity that brings patients closer to the level of bariatric surgery.

[0026] Canagliflozin Canagliflozin is an amylin receptor agonist, also known as AM833. It is the compound of Example 53 in WO2012 / 168432: N-α-[(S)-4-carboxy-4-(19-carboxy-9-decanoylamino)butyryl]-[Glu14,Arg17,Pro37]-pramlintide. Canagliflozin can be prepared as described on pages 153-155 of WO2012 / 168432.

[0027] In some embodiments, canagliflozin is in the form of a salt. In some embodiments, canagliflozin is in the form of a pharmaceutically acceptable salt.

[0028] Smegglutide Smegglutinin is a GLP-1 receptor agonist, also known as N... 6,26 -{18-[N-(17-carboxyheptadecyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecyl}-[8-(2-amino-2-propionic acid),34-L-arginine]human glucagon-like peptide-1(7-37). Smegglutinin is also described in WHO Drug Information Vol. 24, No. 1, 2010, and can be prepared as described in Example 4 of WO2006 / 097537.

[0029] In some embodiments, smegglutinin may be present in the composition in its fully or partially ionized form; for example, one or more carboxylic acid groups (-COOH) may be deprotonated to carboxylate groups (-COO). - And / or one or more amino groups (-NH2) can be protonated to -NH3. + Group.

[0030] In some embodiments, semaglutide is in the form of a salt. In some embodiments, semaglutide is in the form of a pharmaceutically acceptable salt.

[0031] pharmaceutical preparations The terms “pharmaceutical formulation,” “formulation,” “pharmaceutical composition,” and “composition” are used interchangeably herein to refer to a pharmaceutical preparation suitable for administration to a subject in need. Pharmaceutical formulations and compositions are also referred to as “pharmaceutical products” by those skilled in the art. This document discloses two liquid pharmaceutical formulations suitable for parenteral injection, preferably subcutaneous injection. One pharmaceutical formulation contains canagliflozin as the sole active pharmaceutical ingredient. The other pharmaceutical formulation contains smegglutinin as the sole active pharmaceutical ingredient.

[0032] Pharmaceutical formulations containing canagliflozin This document discloses an aqueous liquid pharmaceutical formulation comprising canagliflozin as the sole active pharmaceutical ingredient. Compared to known formulations, the canagliflozin formulation disclosed herein exhibits improved chemical and / or physical stability; for example, a reduced tendency to form HMWPs during storage. The pharmaceutical formulation containing canagliflozin is suitable for storage in and administration using a suitable medical device such as a dual-compartment device. The composition of the pharmaceutical formulation containing canagliflozin ensures that canagliflozin is physically and chemically stable during storage in the medical device, despite contact with the materials of the storage compartment. The composition of the pharmaceutical formulation containing canagliflozin also ensures that canagliflozin is physically and chemically stable during removal from the medical device where it is stored.

[0033] In some embodiments, pharmaceutical formulations containing canagliflozin are suitable for storage in a dual-compartment device and for administration using the dual-compartment device, wherein the latter also contains a pharmaceutical formulation containing smegglutinin, which is also disclosed herein, in a separate compartment.

[0034] Pharmaceutical formulations containing canagliflozin can come into contact with pharmaceutical formulations containing smegglutinin because both formulations can, for example, exit through the same device and pass through the same needle of a dual-chamber device. Preferably, the composition of the pharmaceutical formulation containing canagliflozin is such that it has no adverse effect on the chemical and / or physical stability of smegglutinin over time, both during expulsion from the device storing it and during injection into the subject.

[0035] In some embodiments, the pharmaceutical formulation comprises 0.1-20 mg / ml canagliflozin, such as 0.32-18 mg / ml, such as 0.5-18 mg / ml, such as about 1.0 mg / ml, such as about 2.0 mg / ml, such as at least 2 mg / ml, such as about 4.0 mg / ml, such as about 4.8 mg / ml, such as about 6.8 mg / ml, such as about 9.6 mg / ml, such as about 18 mg / ml.

[0036] In some embodiments, the formulation comprises 1-19 mg / ml canagliflozin. In some embodiments, the formulation comprises 2-18 mg / ml canagliflozin. In some embodiments, the formulation comprises 3-17 mg / ml canagliflozin. In some embodiments, the formulation comprises 4-16 mg / ml canagliflozin. In some embodiments, the formulation comprises 5-15 mg / ml canagliflozin. In some embodiments, the formulation comprises 6-14 mg / ml canagliflozin. In some embodiments, the formulation comprises 7-13 mg / ml canagliflozin. In some embodiments, the formulation comprises 8-12 mg / ml canagliflozin. In some embodiments, the formulation comprises 9-11 mg / ml canagliflozin. In a preferred embodiment, the formulation comprises 9.6 mg / ml canagliflozin.

[0037] In some embodiments, the formulation comprises not more than 20 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 19 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 18 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 17 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 16 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 15 mg / ml. In some embodiments, the formulation comprises not more than 14 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 13 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 12 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 11 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 10 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 9 mg / ml of canagliflozin. In some embodiments, the formulation comprises not more than 8 mg / ml of canagliflozin. In some embodiments, the formulation contains no more than 7 mg / ml of canagliflozin. In some embodiments, the formulation contains no more than 6 mg / ml of canagliflozin. In some embodiments, the formulation contains no more than 5 mg / ml of canagliflozin.

[0038] In some embodiments, the formulation comprises at least 0.5 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 1 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 2 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 3 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 4 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 5 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 6 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 7 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 8 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 9 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 10 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 11 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 12 mg / ml canagliflozin. In some embodiments, the formulation comprises at least 13 mg / ml of canagliflozin. In some embodiments, the formulation comprises at least 14 mg / ml of canagliflozin. In some embodiments, the formulation comprises at least 15 mg / ml of canagliflozin.

[0039] The formulation may contain one or more pharmaceutically acceptable excipients.

[0040] The formulation of canagliflozin at pH 3.5-4.5, such as approximately pH 4, ensures the chemical and physical stability of this active pharmaceutical ingredient.

[0041] In some embodiments, the pH is measured at room temperature, for example, 15-25°C. In some embodiments, the formulation contains a buffer with a pKa close to the desired pH of the solution.

[0042] In some embodiments, the buffer in the pharmaceutical formulation containing canagliflozin is lactate / lactic acid. In some embodiments, the buffer in the pharmaceutical formulation containing canagliflozin is lactate / lactic acid at a concentration of about 2-35 mM, such as about 2-30 mM, such as 2-25 mM, such as 2-20 mM, such as 2-15 mM, such as 2-10 mM, such as 2.5-10 mM, such as 5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2-7 mM, such as 2-6 mM, such as about 2.5-5 mM, or such as about 5 mM.

[0043] In some embodiments, the buffer in the pharmaceutical formulation containing canagliflozin is glutamate / glutamate. In some embodiments, the buffer in the pharmaceutical formulation containing canagliflozin is glutamate / glutamate at a concentration of 2-10 mM, such as 2.5-10 mM, such as 5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2.5-7.5 mM, such as 2-7 mM, such as 2-6 mM, such as 4-6 mM, such as about 2.5-5 mM, or such as about 5 mM.

[0044] In some embodiments, the buffer in the pharmaceutical formulation containing canagliflozin is acetate / acetate. In some embodiments, the buffer in the pharmaceutical formulation containing canagliflozin is acetate / acetate at a concentration of about 2-10 mM, such as 2.5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2-7 mM, such as 2-6 mM, such as about 2.5-5.0 mM, such as about 5 mM.

[0045] In pharmaceutical formulations containing canagliflozin, the concentration of the buffer must be high enough to ensure sufficient pH stability of approximately 3.5–4.5, for example, approximately pH 4.0, during storage in the medical device. The concentration of the buffer in pharmaceutical formulations containing canagliflozin must also be low enough to prevent the pH from dropping to a level that would cause semagliflozin to precipitate or form particles during discharge from the device and injection into the subject (and thus mixing with pharmaceutical formulations containing semagliflozin).

[0046] Pharmaceutical formulations containing canagliflozin may further include a tensile agent. The purpose of the tensile agent may be to protect living tissue when the formulation is injected into the body. For example, the presence of a tensile agent may make the injection relatively painless or prevent necrosis. The tensile agent may be selected from glycerol, mannitol, propylene glycol, sorbitol, sucrose, or trehalose. In some embodiments, the tensile agent is glycerol. In some embodiments, the tensile agent is mannitol. In some embodiments, the tensile agent is propylene glycol. In some embodiments, the tensile agent is sorbitol. In some embodiments, the tensile agent is sucrose. In some embodiments, the tensile agent is trehalose.

[0047] The concentration of the tonic agent makes the formulation isotonic.

[0048] When the tonic is glycerol, it can be present at a concentration of 20-31 mg / ml, such as about 24 mg / ml.

[0049] When the tonic is mannitol, it can be present at a concentration of 40-60 mg / ml, such as about 46 mg / ml.

[0050] When the tonic is propylene glycol, it can be present at a concentration of 17-26 mg / ml, such as about 20 mg / ml.

[0051] When the tonic is sorbitol, it can be present at a concentration of 40-60 mg / ml, such as about 46 mg / ml.

[0052] When the tensile agent is sucrose, it can exist at a concentration of 73-105 mg / ml, such as about 83 mg / ml.

[0053] When the tonic is trehalose, it can be present at a concentration of 73-105 mg / ml, such as about 83 mg / ml.

[0054] The pharmaceutical preparation may further contain one or more reagents for adjusting pH, such as NaOH and / or HCl.

[0055] The pharmaceutical preparation comprises water for injection (WFI). The pharmaceutical preparation may contain more than 90% w / w water, such as 90-99% w / w water, such as 91-99% w / w water, such as 92-99% w / w water, such as 93-99% w / w water, such as 94-99% w / w water; such as more than 91% w / w water, such as more than 92% w / w water, such as more than 93% w / w water, such as more than 94% w / w water, such as about 95% w / w water, such as more than 95% w / w water, such as about 96% w / w water, such as more than 96% w / w water, such as about 97% w / w water, such as more than 97% w / w water, such as about 98% w / w water, such as more than 98% w / w water.

[0056] In some embodiments, the canagliflozin formulation does not contain a preservative. In some embodiments, the pharmaceutical formulation does not contain m-cresol.

[0057] The canagliflozin formulation disclosed in this article is suitable for pharmaceutical applications.

[0058] The canagliflozin formulation disclosed in this article is suitable for parenteral administration, such as subcutaneous administration.

[0059] Pharmaceutical formulations containing smegglutinin This document discloses an aqueous liquid pharmaceutical formulation containing semaglutide as the sole active pharmaceutical ingredient. The pharmaceutical formulation containing 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 containing semaglutide is preferably such that semaglutide is physically and chemically stable during storage in the device, despite contact with the material of the storage chamber. 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 the subject.

[0060] During parenteral administration, pharmaceutical formulations containing semaglutide may come into contact with pharmaceutical formulations containing canagliflozin because both formulations are expelled through the same device outlet / needle of a dual-chamber device. The composition of pharmaceutical formulations containing semaglutide ensures that it has no adverse effect on the chemical and / or physical stability of canagliflozin over time, both during expulsion from the device storing it and during injection into the subject.

[0061] This article discloses a liquid pharmaceutical formulation comprising semaglutide, not more than 0.1% (w / w) of phenol, sodium chloride and / or potassium chloride.

[0062] In some embodiments, pharmaceutical formulations containing semaglutide are suitable for storage in a dual-chamber medical device and for administration using the dual-chamber medical device, wherein the latter also contains the pharmaceutical formulation containing canagliflozin disclosed herein in a separate chamber.

[0063] In some embodiments, the formulation comprises 0.1-10 mg / ml semaglutide. In some embodiments, the formulation comprises 1-9 mg / ml semaglutide. In some embodiments, the formulation comprises 2-8 mg / ml semaglutide. In some embodiments, the formulation comprises 3-7 mg / ml semaglutide. In some embodiments, the formulation comprises 4-6 mg / ml semaglutide.

[0064] In some embodiments, the formulation comprises 0.1-5 mg / ml semaglutide. In some embodiments, the formulation comprises 0.5-5.0 mg / ml semaglutide. In some embodiments, the formulation comprises 4.0-5.5 mg / ml semaglutide. In some embodiments, the formulation comprises 4.5-6.0 mg / ml semaglutide. In some embodiments, the formulation comprises 4.5-5.0 mg / ml semaglutide.

[0065] In a preferred embodiment, the formulation comprises 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 smegglutide.

[0066] In some embodiments, the concentration of semaglutide is 0.5-10 mg / ml or 0.01-3.5 mg / ml of the pharmaceutical preparation. In some embodiments, the concentration of semaglutide is 0.5 mg / ml, or 1 mg / ml, or 1.5 mg / ml, or 2 mg / ml, or 2.5 mg / ml, or 3 mg / ml, or 3.5 mg / ml.

[0067] In some embodiments, the formulation comprises not more than 10 mg / ml of semaglutide. In some embodiments, the formulation comprises not more than 9 mg / ml of semaglutide. In some embodiments, the formulation comprises not more than 8 mg / ml of semaglutide. In some embodiments, the formulation comprises not more than 7 mg / ml of semaglutide. In some embodiments, the formulation comprises not more than 6 mg / ml of semaglutide. In some embodiments, the formulation comprises not more than 5 mg / ml. In some embodiments, the formulation comprises not more than 4 mg / ml of semaglutide. In some embodiments, the formulation comprises not more than 3 mg / ml of semaglutide. In some embodiments, the formulation comprises not more than 2 mg / ml of semaglutide. In some embodiments, the formulation comprises not more than 1 mg / ml of semaglutide.

[0068] In some embodiments, the formulation comprises at least 0.5 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 1 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 2 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 3 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 4 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 5 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 6 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 7 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 8 mg / ml of semaglutide. In some embodiments, the formulation comprises at least 9 mg / ml of semaglutide.

[0069] In a preferred embodiment, the formulation comprises 4.8 mg / ml smegglutide.

[0070] The formulation may contain one or more pharmaceutically acceptable excipients.

[0071] Pharmaceutical formulations containing semaglutide must always have a pH greater than approximately 5.9 to ensure that semaglutide remains soluble in water (see [link to pharmaceutical formulation]). Figure 2 Pharmaceutical formulations containing smegglutinin must maintain a pH greater than approximately 5.9 during storage and administration.

[0072] In some embodiments, the pH of the semaglutide formulation is in the range of 6-9. In some embodiments, the pH of the semaglutide formulation is in the range of 6.5-8.5. In some embodiments, the pH of the semaglutide formulation is in the range of pH 7.0-8.2, such as pH 7.0-8.0, such as pH 7.0-7.8. In some embodiments, the pH of the semaglutide formulation is approximately 7.4. The formulation of semaglutide at pH 7-8, for example, approximately pH 7.4, ensures the chemical and physical stability of this active pharmaceutical ingredient.

[0073] In some embodiments, the pH is measured at room temperature, for example, at 15-25°C. In some embodiments, the pharmaceutical formulation contains a buffer with a pKa close to the desired pH of the solution.

[0074] In some embodiments, the buffer is a phosphate buffer. The phosphate buffer may be selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and / or tripotassium phosphate.

[0075] The concentration of phosphate buffer can be greater than 15 mM and less than or equal to 45 mM, such as 16-45 mM, 20-45 mM, 20-40 mM, 25-45 mM, 25-40 mM, 20-35 mM, 25-35 mM, or about 30 mM.

[0076] In some embodiments, the pharmaceutical formulation comprises a tensile agent. The purpose of the tensile agent may be to protect living tissue when the formulation is injected into the body. For example, the presence of a tensile agent can make injection relatively painless or prevent necrosis. The tensile agent may be selected from propylene glycol, potassium chloride, and / or sodium chloride. In some embodiments, the formulation comprises a tensile agent, such as propylene glycol or sodium chloride. In some embodiments, the tensile agent is propylene glycol and / or sodium chloride. In some embodiments, the tensile agent is not propylene glycol. In some embodiments, the tensile agent is sodium chloride and / or potassium chloride. In some embodiments, the tensile agent is sodium chloride.

[0077] The concentration of the osmotic agent is sufficient to achieve isotonicity in vivo. In a preferred embodiment, the osmotic agent is sodium chloride at a concentration sufficient to achieve isotonicity.

[0078] In some embodiments, the tensile agent is sodium chloride at a concentration of 4.5-8.5 mg / ml, such as 5.0-8.5 mg / ml, such as 6.0-8.5 mg / ml, such as 7.0-8.25 mg / ml, such as 4.5-7.0, such as 5.0-7.5 mg / ml, such as 5.0-7.0 mg / ml, such as 5.5-7 mg / ml, such as 6.4-7.9 mg / ml, such as 6.4-7.5 mg / ml, such as 6-7 mg / ml, such as above 6.4 mg / ml, such as about 5.4 mg / ml, such as about 6.4 mg / ml, such as about 6.7 mg / ml.

[0079] In some embodiments, the tensile agent is a concentration of 5.5-11 mg / ml, such as potassium chloride at about 8.2 mg / ml.

[0080] In some embodiments, the formulation does not contain other tensioning agents.

[0081] In some embodiments, the pharmaceutical preparation comprises histidine. In some embodiments, the concentration of histidine is 0-20 mM, or 0.5-20 mM, or 0.5-15 mM, or 0.5-10 mM. In some embodiments, the concentration of histidine is 1-20 mM, such as 2-20 mM, such as 2-15 mM, such as 2-10 mM, such as 5-20 mM, such as 5-15 mM, such as 5-10 mM, such as 10-20 mM, such as 10-15 mM. In some embodiments, the concentration of histidine is 5-15 mM, such as 8-12 mM, such as about 10 mM.

[0082] The aqueous smegglutide formulation contains water for injection (WFI). The simegrolatide formulation may contain more than 60% w / w water, such as more than 90% w / w water, such as 90-99% w / w water, such as 91-99% w / w water, such as 92-99% w / w water, such as 93-99% w / w water, such as 94-99% w / w water, such as 95-99% w / w water, such as 96-99% w / w water, such as 97-99% w / w water, such as 98-99% w / w water; such as at least 91% w / w water, such as at least 92% w / w water, such as at least 93% w / w water, such as at least 94% w / w water, such as about 95% w / w water, such as at least 95% w / w water, such as about 96% w / w water, such as at least 96% w / w water, such as about 97% w / w water, such as at least 97% w / w water, such as about 98% w / w water. w / w, such as at least 98% w / w water.

[0083] The pharmaceutical preparation may further contain one or more reagents for adjusting pH, such as NaOH and / or HCl.

[0084] In some embodiments, the pharmaceutical formulation disclosed herein does not contain preservatives. In some embodiments, the formulation is substantially preservative-free. In some embodiments, the pharmaceutical formulation does not contain phenol.

[0085] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, such as 0.01-3.5 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) of phenol, c) a tensor, d) a buffer, e) at least 60% water, and f) histidine. In some embodiments, the tensor is sodium chloride.

[0086] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, such as 0.01-3.5 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) of phenol, c) sodium chloride as a tensioning agent, d) a buffer, e) at least 60% water, and f) histidine.

[0087] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, such as 0.01-3.5 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) phenol, c) 2-12 mg / ml sodium chloride, such as 3-12 mg / ml, such as 4-12 mg / ml, such as 5-12 mg / ml, such as 6-12 mg / ml sodium chloride, d) a buffer, e) at least 60% water, and f) histidine.

[0088] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, such as 0.1-10 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) of phenol, c) 5.0-7.0 mg / ml sodium chloride, such as 5.4 or 6.7 mg / ml, d) a buffer, e) at least 60% water, and f) histidine.

[0089] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, such as 0.1-10 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) of phenol, c) sodium chloride, d) phosphate, e) water for injection, f) histidine, and optionally NaOH / HCl to achieve a pH of 7-8, for example, about pH 7.4.

[0090] In some embodiments, the pharmaceutical formulation comprises a) semaglutide, such as 0.1-10 mg / ml semaglutide or 0.5-10 mg / ml semaglutide, optionally b) not more than 0.1% (w / w) of phenol, c) about or more than 6.4 mg / ml of sodium chloride, d) a buffer, e) at least 60% water, and f) histidine.

[0091] In some embodiments, the pharmaceutical formulation consists of or substantially consists of: a) smegglutide, optionally b) no more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and the formulation optionally has a pH of 6-10, such as 7-8.

[0092] In some embodiments, the pharmaceutical formulation consists of or substantially consists of: a) smegglutide, optionally b) phenol not exceeding 0.1% (w / w), c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 97% water, optionally f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and the formulation optionally has a pH of 7-8.

[0093] In some embodiments, the pharmaceutical formulation consists of or substantially consists of: a) smegglutide, optionally b) no more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, f) histidine, optionally g) one or more agents for adjusting pH, such as HCl, NaOH, or acetic acid (salt) such as sodium acetate or acetic acid, and the formulation optionally has a pH of 6-10, such as 7-8.

[0094] In some embodiments, the pharmaceutical formulation consists of or substantially consists of: a) smegglutide, optionally b) no more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, d) a buffer, e) at least 60% water, optionally f) one or more agents for adjusting pH, such as HCl, NaOH or acetic acid (salt), and the formulation optionally has a pH of 6-10, such as 7-8.

[0095] In some embodiments, the pharmaceutical formulation consists of or substantially consists of: a) smegglutide, optionally b) no more than 0.1% (w / w) phenol, c) sodium chloride at a concentration higher than 6.4 mg / ml, 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 acetic acid (salt), and the formulation optionally has a pH of 6-10, such as 7-8.

[0096] In some embodiments, the semaglutide formulation is for parenteral administration. In some embodiments, the semaglutide formulation is for subcutaneous administration.

[0097] In some embodiments, the smegglutide formulation is used in an injection device.

[0098] Suitable medical equipment A medical device can be used to administer a predetermined dose of canagliflozin and a predetermined dose of smegglutinin in a single injection. The medical device can be used to administer a single dose, such as a single effective dose, of canagliflozin and smegglutinin in a single injection. The medical device can be used to administer canagliflozin drug formulations and smegglutinin drug formulations in a single injection. The medical device may be or include a variable-volume drug reservoir or drug delivery device, and may include a first chamber and a second chamber, which are fluidly disconnected in the storage or pre-injection state of the medical device. For example, the medical device may be a dual-chamber device including a tubular wall portion extending along a reference axis, wherein the first chamber and the second chamber are continuously arranged along the reference axis. The dual-chamber device may extend between a distal and a proximal end, and may further include a drug outlet portion disposed at the distal end.

[0099] A first elastomeric plug may be arranged to make sealing contact with a tubular wall between the drug outlet portion and the proximal end to define the first chamber as a distal chamber. A second elastomeric plug may be arranged to make sealing contact with a tubular wall between the first elastomeric plug and the proximal end to define the second chamber as a proximal chamber.

[0100] Based on the expectation of improving user convenience by providing medical devices with small physical dimensions, and considering the appropriate concentrations and expected clinically relevant ratios of the canagliflozin and semagraft formulations, the distal chamber may contain the semagraft formulation, while the proximal chamber may contain the canagliflozin formulation. From a stability perspective, this particular combination may be more advantageous when considering the process of filling both chambers, as the canagliflozin formulation has higher surface reactivity than the semagraft formulation, and it is difficult to avoid introducing a certain amount of air into the distal chamber using conventional filling methods.

[0101] The dual-chamber device may further include means that allow liquid to flow from the proximal chamber through and / or through a first elastomeric plug to the distal chamber. For example, the tubular wall may include a bypass geometry that allows liquid to flow from the proximal chamber through the first elastomeric plug to the distal chamber when the first elastomeric plug is in a specific bypass position relative to the tubular wall. In this case, the first elastomeric plug is positioned proximal to the bypass geometry in the pre-injection state of the dual-chamber device and is adapted to move towards the bypass position for a dose administration event.

[0102] The drug outlet section can be configured to allow liquid drug to be expelled through an injection needle, or as a high-pressure jet through a nozzle. In the former case, the injection needle can be pre-positioned, for example, pre-attached to the drug outlet section, or the drug outlet section can be adapted to receive the injection needle. The drug outlet section can be fluid-tight, for example, through a permeable self-sealing diaphragm.

[0103] The dual-chamber device may further include a drug dispensing device comprising a piston rod actuable to apply a driving force to a second elastomeric plug. The drug dispensing device may also include an energy source, such as a spring member releasable to actuate the piston rod.

[0104] In some embodiments, the dual-chamber device is a syringe device. In some embodiments, the dual-chamber device is a pen syringe device. Examples of different dual-chamber devices are disclosed in WO 2010 / 139793, WO 2012 / 089445 and US 4,394,863.

[0105] Alternatively, the medical device may be a dual-reservoir device, comprising 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 plug arranged to seal against 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 plug arranged to seal against the second tubular wall. The first reference axis may be parallel to the second reference axis.

[0106] The dual reservoir device may also include a needle manifold for allowing fluid to be delivered from a first drug outlet section and a second drug outlet section to a single skin interface element.

[0107] The needle manifold may include multiple fluidly interconnected channels, including a first inlet channel configured to be in fluid communication with a first drug outlet portion, a second inlet channel configured to be in fluid communication with a second drug outlet portion, and an outlet channel in the form of a hypodermic needle.

[0108] The dual reservoir device may also include a drug dispensing device for sequentially or simultaneously advancing a first elastomeric plug within a first tubular wall portion and a second elastomeric plug within a second tubular wall portion.

[0109] Exemplary embodiments of a dual-reservoir device are disclosed in WO 2017 / 114921.

[0110] In some embodiments, the tubular wall portion of any of the above-described devices is made of glass. In some embodiments, the tubular wall portion narrows towards the drug outlet portion. In some embodiments, the drug outlet portion includes a wall portion made of glass.

[0111] Therefore, by using the medical device described above, the canagliflozin and smegglutinin drug formulations are physically separated and prevented from mixing during storage until the user initiates the dosing event, resulting in the expulsion of both drug formulations through a single injection needle. This medical device provides convenience for subjects requiring treatment, thereby improving adherence.

[0112] To avoid any ambiguity, in the context, the terms “distal” and “proximal” refer to the location or direction along which a drug delivery device, medical reservoir, or needle unit is located, where “distal” refers to the drug outlet end and “proximal” refers to the end opposite the drug outlet end. Furthermore, throughout this document, the terms “plug,” “piston,” and “plunger” are used interchangeably to refer to a movable sealing component within the reservoir body.

[0113] Figure 1 This is a longitudinal sectional view of a drug reservoir 1 according to an exemplary embodiment of the present invention. The drug reservoir 1 is depicted in a pre-injection state.

[0114] The drug reservoir 1 has a generally cylindrical reservoir body 2 with a bypass passage 3 and a narrowed distal portion 4. An injection needle 5 is attached to the distal 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 proximal end of the opening 7, thereby defining a front chamber 10 by the reservoir outlet 6, the front portion of the reservoir body 2 including the bypass passage 3, and the front piston 8. A rear piston 9 is disposed within the reservoir body 2 between the front piston 8 and the proximal end of the opening 7, thereby defining a rear chamber 11 by the front piston 8, the middle portion of the reservoir body 2, and the rear piston 9. The rear piston 9 has a cavity 13 adapted to receive an end of a piston rod (not shown). Notably, in other exemplary embodiments, the rear piston does not have a cavity and is therefore similar to the front piston. In these embodiments, the piston rod is adapted to abut against the lateral end face of the rear piston.

[0115] The anterior chamber 10, which forms the distal chamber, contains a neutral or slightly alkaline liquid pharmaceutical preparation 18 containing smegglutinin, while the posterior chamber 11, which forms the proximal chamber, contains an acidic liquid pharmaceutical preparation 19 containing canagliflozin.

[0116] In use, when the piston rod is inserted into the cavity 13 and a sufficiently large distal force is applied to the rear piston 9, the rear piston 9 will begin to move. Due to the incompressibility of the acidic liquid drug formulation, the force will be transmitted to the front piston 8, thus activating the front piston 8 as well. Therefore, the rear chamber 11 shifts within the reservoir body 2, and a certain volume of neutral or slightly alkaline liquid drug formulation 18 is ejected through the injection needle 5 until the front piston 8 reaches the bypass channel 3. At this point, as the piston rod continues to apply driving force to the rear piston 9, the acidic liquid drug formulation 19 is forced into the bypass channel 3 and passes through the front piston 8.

[0117] As the rear piston 9 approaches the front piston 8, the rear chamber 11 eventually collapses, and the acidic liquid pharmaceutical preparation 19 is gradually transferred to the front chamber 10, where it mixes with the residue of the neutral or slightly alkaline liquid pharmaceutical preparation 18.

[0118] As the rear chamber 11 collapses completely, the rear piston 9, under the influence of the piston rod, pushes the front piston 8 further distally within the reservoir body 2, and the mixture is discharged from the front chamber 10 through the injection needle 5. Discharge continues until the front piston 8 reaches the contracted portion of the reservoir body 2 at the reservoir outlet 6.

[0119] 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 can be 400-600 µl, such as about 500-550 µl. The volume of the semaglutide pharmaceutical formulation present in the distal chamber ensures a drawable volume of about 500 µl.

[0120] In some embodiments, the extractable volume of the semagraviride pharmaceutical formulation provides a dose of about 0.125 to about 5.0 mg of semagraviride. In some embodiments, the extractable volume provides a dose of about 0.125 mg of semagraviride. In some embodiments, the extractable volume corresponds to a dose of 0.2-0.3 mg, such as about 0.25 mg of semagraviride. In some embodiments, the extractable volume corresponds to a dose of about 0.3 mg of semagraviride. In some embodiments, the extractable volume corresponds to a dose of about 0.4 mg of semagraviride. In some embodiments, the extractable volume corresponds to a dose of 0.4-0.6 mg, such as about 0.5 mg of semagraviride. In some embodiments, the extractable volume corresponds to a dose of about 0.6 mg of semagraviride. In some embodiments, the extractable volume corresponds to a dose of about 0.7 mg of semagraviride. In some embodiments, the extractable volume corresponds to a dose of about 0.8 mg of semagraviride. In some embodiments, the extractable volume corresponds to a dose of about 0.85 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 0.9 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of 0.9-1.1 mg, such as about 1.0 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.1 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.2 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.3 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.4 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.5 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of about 1.6 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of 1.6-1.8 mg, such as about 1.7 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 1.8 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 1.9 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 2.0 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 2.1 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 2.2 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 2.3 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of 2.3-2.5 mg, such as approximately 2.4 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 2.5 mg of semaglutide.In some embodiments, the extractable volume corresponds to a dose of approximately 2.6 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 2.7 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 2.8 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 2.9 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.0 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.1 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.2 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.3 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.4 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.5 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.6 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.7 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.8 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 3.9 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.0 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.1 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.2 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.3 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.4 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.5 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.6 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.7 mg semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.8 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 4.9 mg of semaglutide. In some embodiments, the extractable volume corresponds to a dose of approximately 5.0 mg of semaglutide.

[0121] In a preferred embodiment, the drug formulation containing canagliflozin is stored in the proximal compartment of the dual-compartment device (farthest from the needle). The volume of the canagliflozin drug formulation present in the proximal compartment can be 200-300 µl, such as 250-300 µl. The volume of the canagliflozin drug formulation present in the proximal compartment ensures a drawable volume of approximately 250 µl.

[0122] In some embodiments, the extractable volume corresponds to a dose of about 0.08 to about 5.0 mg of canagliflozin, such as a dose of about 0.125 mg to about 5.0 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.08 mg of canagliflozin. In some embodiments, the extractable volume provides a dose of about 0.125 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.25 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.3 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.4 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.5 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.6 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.7 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.8 mg of canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.85 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 0.9 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.0 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.1 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.2 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.3 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.4 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.5 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.6 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.7 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of about 1.8 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 1.9 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.0 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.1 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.2 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.3 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.4 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.5 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.6 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.7 mg canagliflozin.In some embodiments, the extractable volume corresponds to a dose of approximately 2.8 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 2.9 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.0 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.1 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.2 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.3 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.4 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.5 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.6 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.7 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.8 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 3.9 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.0 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.1 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.2 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.3 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.4 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.5 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.6 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.7 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.8 mg canagliflozin. In some embodiments, the extractable volume corresponds to a dose of approximately 4.9 mg canagliflozin. In some implementations, the extractable volume corresponds to a dose of approximately 5.0 mg canagliflozin.

[0123] In some embodiments, the concentration of canagliflozin in the canagliflozin formulation present in one chamber of the device is greater than the concentration of smegglutinin in the smegglutinin formulation present in another chamber of the device.

[0124] Medical applications The formulations disclosed in this article are used in pharmaceuticals.

[0125] The aqueous pharmaceutical formulations containing canagliflozin and the aqueous pharmaceutical formulations containing smegglutinin disclosed herein are used in pharmaceuticals.

[0126] This article discloses a combination of canagliflozin and smegglutinin for pharmaceutical use.

[0127] This article discloses a method for the prevention or treatment of medical conditions or diseases such as diabetes or obesity, in which a combination of canagliflozin and smegglutinin is administered to subjects in need.

[0128] This article discloses methods for the prevention or treatment of medical conditions or diseases, wherein the liquid pharmaceutical preparations disclosed herein are administered to subjects in need.

[0129] As used herein, the term "treatment" refers to medical treatment of any human or other vertebrate subject in need. The subject is expected to have undergone a physical examination by a licensed veterinarian who has provided a preliminary or definitive diagnosis indicating that the use of the specific 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 condition. Therefore, the treatment may be preventative (avoidant), palliative, symptomatic, and / or curative.

[0130] Combinations of canagliflozin and smegglutinin and / or the canagliflozin and smegglutinin formulations disclosed herein may be used for: (i) Prevention and / or treatment of all forms of diabetes and related symptoms, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes, MODY (mature-onset diabetes in young adults), gestational diabetes, and / or for reducing HbA1c. (ii) Delay or prevent the progression of diabetes, such as the progression of type 2 diabetes, delay the progression of impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, and / or delay the progression of insulin-free type 2 diabetes to insulin-requiring type 2 diabetes. (iii) For example, by reducing food intake, losing weight, suppressing appetite, inducing satiety to prevent and / or treat eating disorders such as obesity; treat or prevent bulimia, irritable eating disorder, bulimia nervosa and / or obesity induced by antipsychotic drugs or steroid administration; reduce gastric motility; and / or delay gastric emptying; (iv) Prevention and / or treatment of cardiovascular diseases, such as delaying or reducing the development of major adverse cardiovascular events (MACE) selected from cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, hospitalization due to unstable angina, and hospitalization due to heart failure; (v) Prevention and / or treatment of non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH); (vi) Prevention and / or treatment of cognitive impairments, such as Alzheimer's disease.

[0131] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In yet another specific aspect, the indication is (iii). In yet another specific aspect, the indication is (iv). In yet another specific aspect, the indication is (v). In yet another specific aspect, the indication is (vi). In some embodiments, the indication is type 2 diabetes and / or obesity.

[0132] Typically, all subjects suffering from obesity are also considered overweight. This document discloses methods for treating or preventing obesity. This document discloses the use of the formulations disclosed herein for treating or preventing obesity. In some embodiments, the subjects suffering from obesity are persons, such as adults or pediatric patients (including infants, children, and adolescents).

[0133] 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 Human subjects suffering from obesity may have a BMI ≥30; such subjects may also be referred to as obese. In some embodiments, human subjects suffering from obesity may have a BMI ≥35 or a BMI in the range of ≥30 to <40. In some embodiments, the obesity is severe obesity or morbid obesity, wherein the human subject may have a BMI ≥40.

[0134] This document discloses methods for treating or preventing overweight optionally in the presence of at least one weight-related comorbidity. This document also discloses the use of the disclosed formulations optionally for treating or preventing overweight in the presence of at least one weight-related comorbidity.

[0135] In some implementations, the overweight subject is a person, such as an adult or a pediatric patient (including infants, children, and adolescents). In some implementations, the overweight human subject may have a BMI ≥25, such as a BMI ≥27. In some implementations, the overweight human subject has a BMI in the range of 25 to <30 or in the range of 27 to <30.

[0136] An elevated BMI increases an individual's risk of developing multiple diseases or any of their comorbidities. Weight-related comorbidities can be one or a combination of the diseases mentioned above. In some implementations, weight-related comorbidities are selected from hypertension, diabetes (such as type 2 diabetes), dyslipidemia, high cholesterol, and obstructive sleep apnea.

[0137] This document discloses methods for weight loss. Individuals who will undergo weight loss may have a BMI ≥25, such as a BMI ≥27 or a BMI ≥30. In some implementations, individuals who will undergo weight loss may have a BMI ≥35 or a BMI ≥40. The term "weight loss" may include the treatment or prevention of obesity and / or overweight.

[0138] In some embodiments, the semaglutide and canagliflozin pharmaceutical formulations disclosed herein can be administered at an initial body mass index (BMI) of 30 kg / m². 2 Or higher (obesity) or 27 kg / m 2 In adult patients who are overweight or higher, in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, or dyslipidemia), it is used as an adjunct to a low-calorie diet and increased physical activity for long-term weight management.

[0139] In some implementations, administration of the smegglutide and canagliflozin drug formulations disclosed herein can result in >15% weight loss, such as >20% weight loss, such as >25% weight loss, such as >30% weight loss, such as approximately 15-40% weight loss, such as approximately 20-35% weight loss, such as approximately 25-30% weight loss within 26 weeks of treatment initiation.

[0140] In some implementations, the fixed-dose combination of smegglutide and canagliflozin disclosed herein can result in >15% weight loss, such as >20% weight loss, such as >25% weight loss, such as >30% weight loss, such as about 15-40% weight loss, such as about 20-35% weight loss, such as about 25-30% weight loss within 26 weeks of treatment initiation.

[0141] dose As mentioned above, suitable medical devices can be used to administer smegglutinin and canagliflozin to individuals in need.

[0142] In some implementations, an effective amount of smegglutinin can be administered together with an effective amount of canagliflozin to individuals in need.

[0143] In some embodiments, the dose is administered approximately once a week. In some embodiments, the interval between two fixed doses may be approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, or approximately 10 days. In a preferred embodiment, a fixed maintenance dose is administered approximately every 7 days (once a week).

[0144] In some embodiments, the dose is administered to individuals having any of the indications listed above. In some preferred embodiments, the dose is administered to individuals suffering from obesity (body mass index [BMI] ≥ 30 kg / m²). 2 Individuals who are overweight (BMI ≥ 27 kg / m²). In some preferred embodiments, the dose is administered to overweight individuals (BMI ≥ 27 kg / m²). 2 –<30 kg / m 2 Individuals who also have at least one weight-related comorbidity.

[0145] In some implementations, weekly treatment resulted in statistically significant, dose-dependent weight loss.

[0146] After treatment has begun, it may be beneficial to administer escalating doses of canagliflozin and / or smegglutinin to individuals in need. Once an individual has adapted to the treatment, it may be beneficial to administer maintenance doses of canagliflozin and smegglutinin to individuals in need.

[0147] In some implementations, treatment is performed weekly with a dose escalation period of 16 weeks.

[0148] In some implementations, treatment is performed once a week and the dosage is increased approximately once a week.

[0149] In some implementations, treatment is performed once a week and the dosage is increased approximately every other week.

[0150] In some implementations, treatment is performed once a week and the dosage is increased approximately every three weeks.

[0151] In some implementations, treatment is performed once a week and the dosage is increased approximately every four weeks.

[0152] In some implementations, incremental doses of canagliflozin are administered together with incremental doses of smegglutinin.

[0153] In some implementations, incremental doses of canagliflozin are administered together with a fixed dose of smegglutinin.

[0154] In some implementations, escalating doses of canagliflozin are administered together with 2.4 mg smegglutinin.

[0155] The dosage of canagliflozin can be 0.025-5.0 mg.

[0156] The dosage of canagliflozin can be 0.08-5.0 mg.

[0157] In some implementations, the dose of canagliflozin administered is 0.08 mg.

[0158] In some implementations, the dose of canagliflozin administered is 0.125 mg.

[0159] In some implementations, the dose of canagliflozin administered is 0.16 mg.

[0160] In some implementations, the dose of canagliflozin administered is 0.25 mg.

[0161] In some implementations, the dose of canagliflozin administered is 0.5 mg.

[0162] In some implementations, the dose of canagliflozin administered is at least 0.6 mg.

[0163] In some implementations, the dose of canagliflozin administered is 0.85 mg.

[0164] In some implementations, the dose of canagliflozin administered is 1.0 mg.

[0165] In some implementations, the dose of canagliflozin administered is 1.1 mg.

[0166] In some implementations, the dose of canagliflozin administered is 1.2 mg.

[0167] In some implementations, the maintenance dose of canagliflozin is 1.2 mg.

[0168] In some implementations, the dose of canagliflozin administered is 1.3 mg.

[0169] In some implementations, the dose of canagliflozin administered is 1.4 mg.

[0170] In some implementations, the dose of canagliflozin administered is 1.5 mg.

[0171] In some implementations, the dose of canagliflozin administered is 1.6 mg.

[0172] In some implementations, the dose of canagliflozin administered is 1.7 mg.

[0173] In some implementations, the dose of canagliflozin administered is 1.8 mg.

[0174] In some implementations, the dose of canagliflozin administered is 1.9 mg.

[0175] In some implementations, the dose of canagliflozin administered is 2.0 mg.

[0176] In some implementations, the dose of canagliflozin administered is 2.1 mg.

[0177] In some implementations, the dose of canagliflozin administered is 2.2 mg.

[0178] In some implementations, the dose of canagliflozin administered is 2.3 mg.

[0179] In some implementations, the dose of canagliflozin administered is 2.4 mg.

[0180] In some implementations, the maintenance dose of canagliflozin is 2.4 mg.

[0181] In some implementations, the dose of canagliflozin administered is 2.5 mg.

[0182] In some implementations, the dose of canagliflozin administered is 2.6 mg.

[0183] In some implementations, the dose of canagliflozin administered is 2.7 mg.

[0184] In some implementations, the dose of canagliflozin administered is 2.8 mg.

[0185] In some implementations, the dose of canagliflozin administered is 2.9 mg.

[0186] In some implementations, the dose of canagliflozin administered is 3.0 mg.

[0187] In some implementations, the dose of canagliflozin administered is 3.1 mg.

[0188] In some implementations, the dose of canagliflozin administered is 3.2 mg.

[0189] In some implementations, the dose of canagliflozin administered is 3.3 mg.

[0190] In some implementations, the dose of canagliflozin administered is 3.4 mg.

[0191] In some implementations, the dose of canagliflozin administered is 3.5 mg.

[0192] In some implementations, the dose of canagliflozin administered is 3.6 mg.

[0193] In some implementations, the dose of canagliflozin administered is 3.7 mg.

[0194] In some implementations, the dose of canagliflozin administered is 3.8 mg.

[0195] In some implementations, the dose of canagliflozin administered is 3.9 mg.

[0196] In some implementations, the dose of canagliflozin administered is 4.0 mg.

[0197] In some implementations, the dose of canagliflozin administered is 4.1 mg.

[0198] In some implementations, the dose of canagliflozin administered is 4.2 mg.

[0199] In some implementations, the dose of canagliflozin administered is 4.3 mg.

[0200] In some implementations, the dose of canagliflozin administered is 4.4 mg.

[0201] In some implementations, the dose of canagliflozin administered is 4.5 mg.

[0202] In some implementations, the maintenance dose of canagliflozin is 4.5 mg.

[0203] In some implementations, the dose of canagliflozin administered is 4.6 mg.

[0204] In some implementations, the dose of canagliflozin administered is 4.7 mg.

[0205] In some implementations, the dose of canagliflozin administered is 4.8 mg.

[0206] In some implementations, the dose of canagliflozin administered is 4.9 mg.

[0207] In some implementations, the dose of canagliflozin administered is 5.0 mg.

[0208] The dosage of semaglutide can be approximately 0.05-5 mg, such as at least 0.5 mg of semaglutide.

[0209] The dosage of smegglutide can be approximately 0.25–3.0 mg.

[0210] In some implementations, the dose of smegglutinin administered is 0.25 mg.

[0211] In some implementations, the dose of smegglutinin administered is 0.5 mg.

[0212] In some implementations, the dose of smegglutinin administered is at least 0.6 mg.

[0213] In some implementations, the dose of smegglutinin administered is 0.85 mg.

[0214] In some implementations, the dose of smegglutinin administered is 1.0 mg.

[0215] In some implementations, the dose of smegglutinin administered is 1.2 mg.

[0216] In some implementations, the dose of smegglutinin administered is 1.5 mg.

[0217] In some implementations, the dose of smegglutinin administered is 1.7 mg.

[0218] In some implementations, the dose of smegglutinin administered is 2.4 mg.

[0219] In some implementations, the dose of smegglutinin administered is 3.0 mg.

[0220] In some implementations, the ratio of canagliflozin to smegglutinin is 1:2.

[0221] In some implementations, the dose of canagliflozin is 0.125 mg and the dose of smegglutinin is 0.25 mg.

[0222] In some implementations, the dose of canagliflozin is 0.25 mg and the dose of smegglutinin is 0.5 mg.

[0223] In some implementations, the dose of canagliflozin is 0.5 mg and the dose of smegglutinin is 1.0 mg.

[0224] In some implementations, the dose of canagliflozin is 0.85 mg and the dose of smegglutinin is 1.7 mg.

[0225] In some implementations, the dose of canagliflozin is 1.2 mg and the dose of smegglutinin is 2.4 mg.

[0226] In some implementations, the maintenance dose of canagliflozin is 1.2 mg and the maintenance dose of smegglutinin is 2.4 mg.

[0227] In some implementations, the ratio of canagliflozin to smegglutinin is 1:1.

[0228] In some implementations, the dose of canagliflozin is 0.25 mg and the dose of smegglutinin is 0.25 mg.

[0229] In some implementations, the dose of canagliflozin is 0.5 mg and the dose of smegglutinin is 0.5 mg.

[0230] In some implementations, the dose of canagliflozin is 1.0 mg and the dose of smegglutinin is 1.0 mg.

[0231] In some implementations, the dose of canagliflozin is 1.7 mg and the dose of smegglutinin is 1.7 mg.

[0232] In some implementations, the dose of canagliflozin is 0.16 mg and the dose of smegglutinin is 2.4 mg.

[0233] In some implementations, the dose of canagliflozin is 0.3 mg and the dose of smegglutinin is 2.4 mg.

[0234] In some implementations, the dose of canagliflozin is 0.6 mg and the dose of smegglutinin is 2.4 mg.

[0235] In some implementations, the dose of canagliflozin is 1.2 mg and the dose of smegglutinin is 2.4 mg.

[0236] In some implementations, the maintenance dose of canagliflozin is 1.2 mg and the maintenance dose of smegglutinin is 2.4 mg.

[0237] In some implementations, the dose of canagliflozin is 2.4 mg and the dose of smegglutinin is 2.4 mg.

[0238] In some implementations, the maintenance dose of canagliflozin is 2.4 mg and the maintenance dose of smegglutinin is 2.4 mg.

[0239] In some implementations, the dose of canagliflozin is 4.5 mg and the dose of smegglutinin is 2.4 mg.

[0240] In some implementations, the maintenance dose of canagliflozin is 4.5 mg and the maintenance dose of smegglutinin is 2.4 mg.

[0241] In some implementations, canagliflozin is administered as an initial dose of 0.16 mg once weekly, followed by weekly increments of 0.3 mg, 0.6 mg, 1.2 mg, and 2.4 mg until a target / maintenance dose of 2.4 mg once weekly is reached.

[0242] In some implementations, canagliflozin is administered as an initial dose of 0.3 mg once weekly, followed by weekly increments of 0.6 mg, 1.2 mg, and 2.4 mg until a target / maintenance dose of 2.4 mg once weekly is reached.

[0243] In some implementations, canagliflozin is administered as an initial dose of 0.3 mg once weekly, followed by escalation to subsequent doses 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.

[0244] In some implementations, 0.25 mg canagliflozin is administered once weekly, with subsequent doses increasing to 0.5 mg every four weeks, followed by a target / maintenance dose of 1.0 mg once weekly.

[0245] In some implementations, 0.25 mg canagliflozin is administered once weekly, and then increased to a follow-up dose of 0.5 mg every four weeks, before being increased to a target / maintenance dose of 1.2 mg once weekly.

[0246] In some implementations, 0.25 mg canagliflozin is administered once weekly, and the dose is increased every four weeks to subsequent doses of 0.5 mg, 1.0 mg, and 1.7 mg until a target / maintenance dose of 2.4 mg once weekly is reached.

[0247] In some implementations, 0.25 mg of smegglutide is administered once weekly, with subsequent dosing levels increasing to 0.5 mg, 1.0 mg, and 1.7 mg every four weeks until a target / maintenance dose of 2.4 mg once weekly is reached.

[0248] In some implementations, 0.25 mg canagliflozin and 0.25 mg smegglutide are administered once weekly for four weeks (weeks 0-3), and every four weeks the dose is increased to subsequent dosing levels of 0.5 mg canagliflozin and 0.5 mg smegglutide (weeks 4-7), 1.0 mg canagliflozin and 1.0 mg smegglutide (weeks 8-11), and 1.7 mg canagliflozin and 1.7 mg smegglutide (weeks 12-15) until the target / maintenance dose of 2.4 mg canagliflozin and 2.4 mg smegglutide once weekly (week 16 and thereafter) is reached.

[0249] In this article, specific values ​​given for numbers or ranges can be interpreted as specific values ​​or approximate values ​​(e.g., when certain quantities are available by weight, a specific value plus or minus 10%, 15%, or 20%; for example, when measuring pH, plus or minus 0.4).

[0250] Implementation Plan The following are non-limiting embodiments of the present invention: 1. An aqueous canagliflozin formulation comprising: -Cangaliskide; - Buffers, which are: glutamate / glutamate at a concentration of about 2-10 mM; or lactate / lactate at a concentration of about 2-35 mM; or acetate / acetate at a concentration of about 2-10 mM; -90-99% w / w of water; and - pH is 3.5-4.5, for example, about pH 4.0.

[0251] 2. An aqueous canagliflozin formulation comprising: - Canagliflozin at concentrations of 0.1-20 mg / ml; - A buffer, which is: glutamate / glutamate at a concentration of approximately 2-10 mM; or lactate / lactate at a concentration of approximately 2-35 mM; or acetate / acetate at a concentration of approximately 2-10 mM; and - pH is 3.5-4.5, such as pH 4.0.

[0252] 3. The formulation according to any one of the foregoing embodiments is a pharmaceutical formulation comprising canagliflozin at a concentration of 0.1-20 mg / ml, such as about 1.0 mg / ml, such as about 2.0 mg / ml, such as at least 2 mg / ml, such as about 4.0 mg / ml, such as about 4.8 mg / ml, such as about 6.8 mg / ml, such as about 9.6 mg / ml, such as about 18 mg / ml.

[0253] 4. The formulation according to any one of the foregoing embodiments is a pharmaceutical formulation comprising a single dose of canagliflozin.

[0254] 5. The formulation according to any one of the foregoing embodiments is a pharmaceutical formulation containing an effective dose of canagliflozin.

[0255] 6. An aqueous canagliflozin formulation comprising: - A single dose of canagliflozin; - A buffer, which is: glutamate / glutamate at a concentration of approximately 2-10 mM; or lactate / lactate at a concentration of approximately 2-35 mM; or acetate / acetate at a concentration of approximately 2-10 mM; and - pH is 3.5-4.5, for example, about pH 4.0.

[0256] 7. Aqueous canagliflozin formulation, which contains -A single effective dose of canagliflozin; - A buffer, which is: glutamate / glutamate at a concentration of approximately 2-10 mM; or lactate / lactate at a concentration of approximately 2-35 mM; or acetate / acetate at a concentration of approximately 2-10 mM; and - pH is 3.5-4.5, for example, about pH 4.0.

[0257] 8. The formulation according to any one of embodiments 4-7, wherein the dose of canagliflozin is 0.025-5.0 mg, such as 0.08-5.0 mg, such as about 0.125 mg, such as about 0.16 mg, such as about 0.25 mg, such as about 0.5 mg, such as at least about 0.6 mg, such as about 0.85 mg, such as about 1.0 mg, such as about 1.1 mg, such as about 1.2 mg, such as about 1.3 mg, such as about 1.4 mg, such as about 1.5 mg, such as about 1.6 mg, such as about 1.7 mg, such as about 1.8 mg, such as about 1.9 mg, such as about 2.0 mg, such as about 2.1 mg, such as about 2.2 mg, such as about 2.3 mg, such as about 2.4 mg, such as about 2.5 mg, such as about 2.6 mg, such as about 2.7 mg, such as about 2.8 mg, such as about 2.9 mg, such as about 3.0 mg, such as about 3.1 mg. mg, such as 3.2 mg, such as 3.3 mg, such as 3.4 mg, such as 3.5 mg, such as 3.6 mg, such as 3.7 mg, such as 3.8 mg, such as 3.9 mg, such as 4.0 mg, such as 4.1 mg, such as 4.2 mg, such as 4.3 mg, such as 4.4 mg, such as 4.5 mg, such as 4.6 mg, such as 4.7 mg, such as 4.8 mg, such as 4.9 mg, such as 5.0 mg canagliflozin.

[0258] 9. The canagliflozin formulation according to any one of the foregoing embodiments, wherein the buffer is a glutamate / glutamate concentration of 2-10 mM, such as 2.5-10 mM, such as 2.5-5 mM, such as 5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2.5-7.5 mM, such as 2-7 mM, such as 2-6 mM, such as 4-6 mM, such as about 5 mM.

[0259] 10. The canagliflozin formulation according to any one of embodiments 1-8, wherein the buffer is a lactate / lactate solution at a concentration of about 2-35 mM, such as about 2-30 mM, such as 2-25 mM, such as 2-20 mM, such as 2-15 mM, such as 2-10 mM, such as 2.5-10 mM, such as 5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2-7 mM, such as 2-6 mM, such as about 2.5-5 mM, such as about 5 mM.

[0260] 11. The canagliflozin formulation according to any one of embodiments 1-8, wherein the buffer is an acetate / acetate at a concentration of about 2-10 mM, such as 2.5-10 mM, such as 5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2-7 mM, such as 2-6 mM, such as 2.5-5.0 mM, such as about 5 mM.

[0261] 12. The formulation according to any one of embodiments 1-9, comprising - Concentrations of 0.1-20 mg / ml, such as 0.32-18 mg / ml, such as 0.5-18 mg / ml, such as canagliflozin at approximately 9.6 mg / ml; - Concentrations of 2-10 mM, such as 2.5-10 mM, such as 2.5-5 mM, such as 5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2.5-7.5 mM, such as 2-7 mM, such as 2-6 mM, such as 4-6 mM, such as about 2.5-5.0 mM, such as about 5 mM of glutamate / glutamate.

[0262] 13. The formulation according to any one of embodiments 1-8 or 10, comprising - Concentrations of 0.1-20 mg / ml, such as 0.32-18 mg / ml, such as canagliflozin at approximately 9.6 mg / ml; and - Concentrations of approximately 2-35 mM, such as approximately 2-30 mM, such as 2-25 mM, such as 2-20 mM, such as 2-15 mM, such as 2-10 mM, such as 2.5-10 mM, such as 5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2-7 mM, such as 2-6 mM, such as 2.5-5.0 mM, such as approximately 5 mM of lactate / lactate.

[0263] 14. The formulation according to any one of embodiments 1-8 or 11, comprising - Concentrations of 0.1-20 mg / ml, such as approximately 15-20 mg / ml, such as approximately 18 mg / ml canagliflozin. - Concentrations of approximately 2-10 mM, such as 2-9 mM, 2-8 mM, 2-7 mM, 2-6 mM, or approximately 2.5-5.0 mM of acetic acid / acetate.

[0264] 15. The canagliflozin formulation according to any one of the foregoing embodiments further comprises a tensioning agent.

[0265] 16. The canagliflozin formulation according to embodiment 15, wherein the tonic agent is selected from glycerol, mannitol, propylene glycol, sorbitol, sucrose, or trehalose.

[0266] 17. The canagliflozin formulation according to any one of embodiments 15-16, wherein the tonic agent is selected from glycerol, mannitol, sorbitol, sucrose or trehalose.

[0267] 18. The canagliflozin formulation according to any one of embodiments 15-17, wherein the concentration of the tonic agent is such that isotonicity is achieved.

[0268] 19. The canagliflozin formulation according to any one of embodiments 15-18, wherein the tonic agent is glycerol.

[0269] 20. The canagliflozin formulation according to the foregoing embodiments, wherein the concentration of glycerol is 20-31 mg / ml, such as about 24 mg / ml.

[0270] 21. The canagliflozin formulation according to any one of embodiments 15-18, wherein the tonic agent is mannitol.

[0271] 22. The canagliflozin formulation according to the aforementioned implementation scheme, wherein the concentration of mannitol is 40-60 mg / ml, such as about 46 mg / ml.

[0272] 23. The canagliflozin formulation according to any one of embodiments 15-18, wherein the tonic agent is propylene glycol.

[0273] 24. The canagliflozin formulation according to the aforementioned implementation scheme, wherein the concentration of propylene glycol is 17-26 mg / ml, such as about 20 mg / ml.

[0274] 25. The canagliflozin formulation according to any one of embodiments 15-18, wherein the tonic agent is sorbitol.

[0275] 26. The canagliflozin formulation according to the aforementioned implementation scheme, wherein the concentration of sorbitol is 40-60 mg / ml, such as about 46 mg / ml.

[0276] 27. The canagliflozin formulation according to any one of embodiments 15-18, wherein the tonic agent is sucrose.

[0277] 28. The canagliflozin formulation according to the aforementioned implementation scheme, wherein the concentration of sucrose is 73-105 mg / ml, such as about 83 mg / ml.

[0278] 29. The canagliflozin formulation according to any one of embodiments 15-18, wherein the tonic agent is trehalose.

[0279] 30. The canagliflozin preparation according to the aforementioned implementation scheme, wherein the concentration of trehalose is 73-105 mg / ml, such as about 83 mg / ml.

[0280] 31. The canagliflozin formulation according to any one of the foregoing embodiments, comprising more than 90% w / w water, such as 90-99% w / w water, such as 90-99% w / w water, such as 91-99% w / w water, such as 92-99% w / w water, such as 93-99% w / w water, such as 94-99% w / w water; such as more than 91% w / w water, such as more than 92% w / w water, such as more than 93% w / w water, such as more than 94% w / w water, such as about 95% w / w water, such as more than 95% w / w water, such as about 96% w / w water, such as more than 96% w / w water, such as about 97% w / w water, such as more than 97% w / w water, such as about 98% w / w water, such as more than 99% w / w water.

[0281] 32. The canagliflozin formulation according to any one of the foregoing embodiments, wherein the formulation comprises one or more reagents for adjusting pH, such as HCl and / or NaOH.

[0282] 33. The formulation according to any one of the foregoing embodiments, wherein the canagliflozin is in the form of a pharmaceutically acceptable salt.

[0283] 34. The canagliflozin formulation according to any one of the foregoing embodiments, wherein fewer impurities are generated during storage.

[0284] 35. The canagliflozin formulation according to any one of the foregoing embodiments, wherein the formulation achieves improved chemical stability.

[0285] 36. The canagliflozin formulation according to any one of the foregoing embodiments, wherein the formulation achieves improved physical stability.

[0286] 37. The canagliflozin formulation according to any one of the foregoing embodiments, wherein the formulation achieves improved chemical and physical stability.

[0287] 38. The canagliflozin formulation according to any one of the foregoing embodiments, wherein less HMWP is generated during storage.

[0288] 39. The canagliflozin formulation according to any one of the foregoing embodiments, used in an injection device.

[0289] 40. The canagliflozin formulation according to any one of embodiments 1-38, for use in medicine.

[0290] 41. The canagliflozin formulation according to any one of embodiments 1-38, for parenteral administration.

[0291] 42. The canagliflozin formulation according to any one of embodiments 1-38, for subcutaneous administration.

[0292] 43. An aqueous smegglutide formulation, comprising: -Smigratide; - Phenol not exceeding 0.1% (w / w); - Sodium chloride and / or potassium chloride to achieve isotonicity; -buffer; and - pH is 7-8.

[0293] 44. The smegglutide formulation according to the foregoing embodiments, wherein the buffer is a phosphate buffer.

[0294] 45. An aqueous smegglutide formulation, comprising: -Smigratide; - Concentrations greater than 15 mM and less than or equal to 45 mM, such as 16-45 mM, such as 20-45 mM, such as 20-40 mM, such as 25-45 mM, such as 25-40 mM, such as 20-35 mM, such as 20-30 mM, such as 25-35 mM, such as about 30 mM of phosphate; -90-99% w / w water for injection; and - pH is 7.0-8.0, for example, about 7.4.

[0295] 46. ​​An aqueous smegglutide formulation, comprising: - Smegglutinin at concentrations of 0.1-10 mg / ml; - Concentrations greater than 15 mM and less than or equal to 45 mM, such as 16-45 mM, 20-45 mM, 20-40 mM, 25-45 mM, 25-40 mM, 20-35 mM, 20-30 mM, 25-35 mM, such as approximately 30 mM phosphate; and - pH is 7-8, for example, about 7.4.

[0296] 47. The semaglutide formulation according to any one of embodiments 45-46, comprising semaglutide at a concentration of 0.1-10 mg / ml, such as 0.5-10 mg / ml, such as 0.5-5.0 mg / ml, such as 0.5-4.8 mg / ml, such as about 0.5 mg / ml, such as about 1 mg / ml, such as about 2 mg / ml, such as about 3.4 mg / ml, such as about 4.8 mg / ml.

[0297] 48. The semaglutide formulation according to any one of embodiments 45-47, wherein it is a pharmaceutical formulation comprising a single dose of semaglutide.

[0298] 49. The semaglutide formulation according to any one of embodiments 45-48, wherein it is a pharmaceutical formulation comprising an effective dose of semaglutide.

[0299] 50. The semaglutide formulation according to any one of embodiments 45-49, wherein the said dose of semaglutide is about 0.05-5 mg, such as about 0.125-5.0 mg, such as about 0.25-3.0 mg, such as about 0.125 mg, such as about 0.2-0.3 mg, such as about 0.25 mg, such as about 0.4 mg, such as about 0.5 mg, such as about 0.4-0.6 mg, such as about 0.6 mg, such as about 0.7 mg, such as about 0.8 mg, such as about 8.5 mg, such as about 0.9 mg, such as about 1.0 mg, such as about 1.1 mg, such as about 1.2 mg, such as about 1.3 mg, such as about 1.4 mg, such as about 1.5 mg, such as about 1.6 mg, such as about 1.7 mg, such as about 1.8 mg, such as about 1.9 mg, such as about 2.0 mg, such as about 2.1 mg, such as about 2.2 mg. mg, such as 2.3 mg, such as 2.4 mg, such as 2.5 mg, such as 2.6 mg, such as 2.7 mg, such as 2.8 mg, such as 2.9 mg, such as 3.0 mg.

[0300] 51. The formulation according to any one of embodiments 45-50, wherein the smegglutide is in the form of a pharmaceutically acceptable salt.

[0301] 52. The smegglutide formulation according to any one of embodiments 45-51, wherein the phosphate buffer is selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, and trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and tripotassium phosphate.

[0302] 53. The smegglutide formulation according to any one of embodiments 45-52, wherein the phosphate buffer is disodium hydrogen phosphate dihydrate.

[0303] 54. The smegglutide formulation according to any one of embodiments 45-53, wherein the concentration of the phosphate buffer is greater than 15 mM and less than or equal to 45 mM, such as 16-45 mM, such as 20-45 mM, such as 20-40 mM, such as 25-45 mM, such as 25-40 mM, such as 20-35 mM, such as 20-30 mM, such as 25-35 mM, such as about 30 mM.

[0304] 55. The smegglutide formulation according to any one of embodiments 45-54, further comprising histidine.

[0305] 56. The smegglutide formulation according to embodiment 55, wherein the concentration of histidine is less than about 20 mM, such as 1-20 mM, such as 5-15 mM, such as 8-12 mM, such as about 10 mM.

[0306] 57. The smegglutide formulation according to any one of embodiments 45-56, further comprising a tensioning agent.

[0307] 58. The smegglutide formulation according to embodiment 57, wherein the tonic agent is selected from propylene glycol, potassium chloride and / or sodium chloride.

[0308] 59. The smegglutide formulation according to any one of embodiments 57-58, wherein the toning agent is sodium chloride.

[0309] 60. The smegglutide formulation according to any one of embodiments 57-58, wherein the tensile agent is potassium chloride.

[0310] 61. The smegglutide formulation according to the aforementioned implementation scheme, wherein the tensioning agent is sodium chloride and potassium chloride.

[0311] 62. The smegglutide formulation according to any one of embodiments 57-61, wherein the concentration of the tonic agent is such that isotonicity is achieved.

[0312] 63. The semaglutide pharmaceutical preparation according to any one of embodiments 59, 61 or 62, wherein the concentration of sodium chloride is 4.5-8.5 mg / ml, such as 5.0-8.5 mg / ml, such as 5.5-8.5 mg / ml, such as 6.0-8.5 mg / ml, such as 7.0-8.25 mg / ml, such as 4.5-7.0 mg / ml, such as 5.0-7.5 mg / ml, such as 5.0-7.0 mg / ml, such as 5.5-7 mg / ml, such as 6.4-7.9 mg / ml, such as 6.4-7.5 mg / ml, such as 6-7 mg / ml, such as above 6.4 mg / ml, such as about 5.4 mg / ml, such as about 6.4 mg / ml, such as about 6.7 mg / ml.

[0313] 64. The smegglutide pharmaceutical preparation according to any one of embodiments 60-62, wherein the concentration of potassium chloride is 5.5-11 mg / ml, such as about 8.2 mg / ml.

[0314] 65. The semaglutide formulation according to any one of embodiments 45-64, comprising more than 90% w / w water, such as 90-99% w / w water, such as 91-99% w / w water, such as 92-99% w / w water, such as 93-99% w / w water, such as 94-99% w / w water, such as 95-99% w / w water, such as 96-99% w / w water, such as 97-99% w / w water, such as 98-99% w / w water; such as at least 91% w / w water, such as at least 92% w / w water, such as at least 93% w / w water, such as at least 94% w / w water, such as about 95% w / w water, such as at least 95% w / w water, such as about 96% w / w water, such as at least 96% w / w water, such as about 97% w / w water, such as at least 97% w / w water, such as about 98% w / w water. w / w, such as at least 98% w / w water.

[0315] 66. The smegglutide formulation according to any one of embodiments 45-65, wherein the formulation comprises one or more reagents for adjusting pH, such as HCl or NaOH.

[0316] 67. The smegglutide formulation according to any one of embodiments 45-66, wherein the formulation does not contain a preservative.

[0317] 68. The smegglutide formulation according to any one of embodiments 45-67, wherein the pH of the formulation is about 7.4.

[0318] 69. The formulation according to any one of embodiments 45-68, wherein the formulation is for parenteral administration.

[0319] 70. The smegglutide formulation according to any one of embodiments 45-68, wherein the formulation is for subcutaneous administration.

[0320] 71. The smegglutide formulation according to any one of embodiments 45-68, used in an injection device.

[0321] 72. The smegglutide formulation according to any one of embodiments 45-68, wherein fewer impurities are generated during storage.

[0322] 73. The smegglutide formulation according to any one of embodiments 45-68, wherein less HMWP is generated during storage.

[0323] 74. The smegglutide formulation according to any one of embodiments 45-68, wherein the formulation achieves improved chemical stability.

[0324] 75. The smegglutide formulation according to any one of embodiments 45-68, for use in medicine.

[0325] 76. The smegglutide formulation according to any one of embodiments 45-68, for 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.

[0326] 77. An aqueous pharmaceutical preparation according to any one of embodiments 45-68, used for the treatment and / or prevention of Alzheimer's disease.

[0327] 78. An aqueous pharmaceutical preparation according to any one of embodiments 45-68, for 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.

[0328] 79. A medical device comprising semaglutide in a first compartment and canagliflozin in a second compartment, for example, comprising a single dose of semaglutide in the first compartment and a single dose of canagliflozin in the second compartment.

[0329] 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 43-68, and the second chamber contains a canagliflozin formulation according to any one of embodiments 1-38.

[0330] 81. The medical device according to any one of embodiments 79-80, further comprising a wall portion extending along a reference axis between a distal and a proximal end, wherein the first chamber and the second chamber are continuously arranged within the wall portion along the reference axis such that the first chamber constitutes a distal chamber and the second chamber constitutes a proximal chamber.

[0331] 82. The medical device according to any one of embodiments 80-81, wherein the distal compartment contains a semaglutide formulation according to any one of embodiments 43-68, and the proximal compartment contains a canagliflozin formulation according to any one of embodiments 1-38.

[0332] 83. The medical device according to any one of embodiments 79-82, wherein the canagliflozin formulation comprises lactate / lactate, acetate / acetate or glutamate / glutamate as a buffer (pH 3.5-4.5).

[0333] 84. The medical device according to any one of embodiments 79-83, wherein the canagliflozin formulation comprises glutamate / glutamate as a buffer.

[0334] 85. The medical device according to embodiment 84, wherein the canagliflozin formulation further comprises - Glycerin, mannitol, propylene glycol, sorbitol, sucrose or trehalose, -NaOH / HCl to achieve a pH of 3.5-4.5, for example, approximately pH 4.0. -water.

[0335] 86. The medical device according to any one of embodiments 79-85, wherein the canagliflozin formulation comprises: - Concentrations of 0.1-20 mg / ml, such as canagliflozin at 0.32-18 mg / ml; - Concentrations of 2-10 mM, such as 2.5-5 mM, or approximately 5 mM of glutamate / glutamate. -NaOH / HCl to achieve a pH of 3.5-4.5, for example, approximately pH 4.0; -water.

[0336] 87. The medical device according to any one of embodiments 79-83, wherein the formulation comprising canagliflozin further comprises - Lactic acid / lactate, - Glycerin, mannitol, propylene glycol, sorbitol, sucrose or trehalose, -NaOH / HCl to achieve a pH of 3.5-4.5, for example, approximately pH 4.0. -water.

[0337] 88. The medical device according to any one of embodiments 79-83, wherein the formulation comprising canagliflozin comprises: - Concentrations of 0.1-20 mg / ml, such as canagliflozin at 0.32-18 mg / ml. -2.5-10 mM, such as approximately 5 mM lactate / lactate. - Glycerin to achieve isotonicity, such as 24 mg / ml, -NaOH / HCl to achieve a pH of 3.5-4.5, for example, approximately pH 4.0. -water.

[0338] 89. The medical device according to any one of embodiments 79-88, comprising 400-600 µl, preferably about 500-550 µl, of the smegglutide formulation in its distal compartment and 200-300 µl, preferably about 250-300 µl, of the canagliflozin formulation in its proximal compartment.

[0339] 90. The medical device according to any one of embodiments 79-89, wherein the concentration of canagliflozin in the formulation in the proximal compartment is greater than the concentration of smegglutinin in the formulation in the distal compartment.

[0340] 91. The medical device according to any one of embodiments 79-90, which is used in medicine.

[0341] 92. The medical device according to any one of embodiments 79-90, for 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.

[0342] 93. A medical device comprising a formulation containing 0.1-10 mg / ml semaglutide in a first compartment and a formulation containing 0.1-20 mg / ml canagliflozin in a second compartment, for the treatment of patients with an initial body mass index (BMI) of 30 kg / m². 2 Subjects with a BMI of 27 kg / m² or higher (obese) or an initial BMI of 27 kg / m² 2 Subjects who are overweight or higher and have at least one weight-related comorbidity.

[0343] 94. The semaglutide formulation according to any one of embodiments 45-68 and the canagliflozin formulation according to any one of embodiments 1-38, for use in medicine.

[0344] 95. The semaglutide formulation according to any one of embodiments 45-68 and the canagliflozin formulation according to any one of embodiments 1-38, for 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.

[0345] 96. The semaglutide formulation according to any one of embodiments 45-68 and the canagliflozin formulation according to any one of embodiments 1-38, for the treatment of patients with an initial body mass index (BMI) of 30 kg / m². 2 Subjects with a BMI of 27 kg / m² or higher (obese) or an initial BMI of 27 kg / m² 2 Subjects who are overweight or higher and have at least one weight-related comorbidity.

[0346] 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, wherein the semaglutide formulation according to any one of embodiments 45-68 and the canagliflozin formulation according to any one of embodiments 1-38 are administered to subjects in need.

[0347] 98. For prevention and / or treatment of an initial body mass index (BMI) of 30 kg / m² 2 Subjects with a BMI of 27 kg / m² or higher (obese) or an initial BMI of 27 kg / m² 2 A method for subjects who are overweight or have at least one weight-related comorbidity, wherein the semaglutide formulation according to any one of embodiments 45-68 and the canagliflozin formulation according to any one of embodiments 1-38 are administered to the subjects in need.

[0348] An effective fixed-dose combination of 99.0.08-5.0 mg canagliflozin and 0.125-5.0 mg smegglutinin is used to treat patients with an initial body mass index (BMI) of 30 kg / m². 2 Subjects with a BMI of 27 kg / m² or higher (obese) or an initial BMI of 27 kg / m² 2 In a method for subjects who are overweight or have at least one weight-related comorbidity, the canagliflozin and smegglutinin formulations are administered parenterally in a single injection, for example, subcutaneously.

[0349] 100. The canagliflozin formulation according to any one of embodiments 1-38 and the smegglutinin formulation according to any one of embodiments 45-68, for the treatment of patients with an initial body mass index (BMI) of 30 kg / m². 2 Subjects with a BMI of 27 kg / m² or higher (obese) or an initial BMI of 27 kg / m² 2 In a method for subjects who are overweight or have at least one weight-related comorbidity, the canagliflozin and smegglutinin formulations are administered parenterally in a single injection, for example, subcutaneously.

[0350] 101. Preparations containing 0.1-20 mg / ml canagliflozin and preparations containing 0.1-10 mg smegglutinin, for the treatment of patients with an initial body mass index (BMI) of 30 kg / m². 2 Subjects with a BMI of 27 kg / m² or higher (obese) or an initial BMI of 27 kg / m² 2 In a method for subjects who are overweight or have at least one weight-related comorbidity, the canagliflozin and smegglutinin formulations are administered parenterally in a single injection, for example, subcutaneously.

[0351] 102. The use according to any one of embodiments 91-101, wherein the dose of canagliflozin administered in the single injection is from 0.16 mg to 4.5 mg per week, such as about 0.25 mg, 0.5 mg, 1.0 mg, 1.2 mg, 1.7 mg, 2.4 mg or 4.5 mg.

[0352] 103. The use according to any one of embodiments 91-102, wherein the dose of smegglutide administered in the single injection is about 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg or 2.4 mg.

[0353] 104. The use according to any one of embodiments 91-103, wherein the ratio of canagliflozin to smegglutinin (in mg) is about 1:1.

[0354] 105. The use according to any one of embodiments 91-103, wherein the ratio of canagliflozin to smegglutinin (in mg) is about 1:2.

[0355] 106. The use according to any one of embodiments 91-104, wherein the dose of canagliflozin administered is 0.25 mg and the dose of smegglutinin administered is 0.25 mg.

[0356] 107. The use according to any one of embodiments 91-104, wherein the dose of canagliflozin administered is 0.5 mg and the dose of smegglutinin administered is 0.5 mg.

[0357] 108. The use according to any one of embodiments 91-104, wherein the dose of canagliflozin administered is 1.0 mg and the dose of smegglutinin administered is 1.0 mg.

[0358] 109. The use according to any one of embodiments 91-104, wherein the dose of canagliflozin administered is 1.7 mg and the dose of smegglutinin administered is 1.7 mg.

[0359] 110. The use according to any one of embodiments 91-104, wherein the dose of canagliflozin administered is 2.4 mg, and the dose of smegglutinin administered is 2.4 mg.

[0360] 111. The use according to any one of embodiments 91-103 or 105, wherein the dose of canagliflozin administered is 1.2 mg and the dose of smegglutinin administered is 2.4 mg.

[0361] 112. The use according to any one of embodiments 91-111, wherein the canagliflozin and smegglutinin formulations are administered in a single injection, approximately once a week, for example every 5-9 days, for example every 6-8 days, preferably every 7 days.

[0362] 113. The use according to any one of embodiments 91-112, wherein: - Administer 0.25 mg canagliflozin and 0.25 mg smegglutinin once weekly for four weeks (weeks 0-3); and - Administer 0.5 mg canagliflozin and 0.5 mg smegglutinin once weekly for four weeks (weeks 4-7); and - Administer 1.0 mg canagliflozin and 1.0 mg smegglutinin once weekly for four weeks (weeks 8-11); and - Administer 1.7 mg canagliflozin and 1.7 mg smegglutinin once weekly for four weeks (weeks 12-15); and - Thereafter administer 2.4 mg canagliflozin and 2.4 mg smegglutinin once a week.

[0363] 114. The use according to any one of embodiments 91-113, wherein the fixed-dose combination of smegglutide and canagliflozin results in a weight loss of >15% within 26 weeks of the start of treatment.

[0364] This application also includes the following items: 1. An aqueous canagliflozin formulation comprising: -Cangaliskide; - Buffers, which are: glutamate / glutamate at a concentration of about 2-10 mM; or lactate / lactate at a concentration of about 2-35 mM; or acetate / acetate at a concentration of about 2-10 mM; -90-99% w / w of water; and - pH is 3.5-4.5, for example, about pH 4.0.

[0365] 2. An aqueous canagliflozin formulation comprising: - Canagliflozin at concentrations of 0.1-20 mg / ml; - A buffer, which is: glutamate / glutamate at a concentration of approximately 2-10 mM; or lactate / lactate at a concentration of approximately 2-35 mM; or acetate / acetate at a concentration of approximately 2-10 mM; and - pH is 3.5-4.5, for example, about pH 4.0.

[0366] 3. The canagliflozin formulation according to any one of items 1-2, wherein the buffer is a glutamate / glutamate concentration of 2-10 mM, such as 2.5-10 mM, such as 2.5-5 mM, such as 5-10 mM, such as 2-9 mM, such as 2-8 mM, such as 2.5-7.5 mM, such as 2-7 mM, such as 2-6 mM, such as 4-6 mM, such as about 5 mM.

[0367] 4. The canagliflozin formulation according to any one of items 1-3, further comprising a tonic agent such as glycerol, mannitol, propylene glycol, sorbitol, sucrose, or trehalose.

[0368] 5. The canagliflozin formulation according to any one of items 1-4, for use in an injection device.

[0369] 6. The canagliflozin formulation according to any one of items 1-5, for use in medicine.

[0370] 7. An aqueous smegglutide formulation, comprising: -Smigratide; - Concentrations greater than 15 mM and less than or equal to 45 mM, such as 16-45 mM, such as 20-45 mM, such as 20-40 mM, such as 25-45 mM, such as 25-40 mM, such as 20-35 mM, such as 20-30 mM, such as 25-35 mM, such as about 30 mM of phosphate; -90-99% w / w of water; and - pH is 7.0-8.0, for example, about 7.4.

[0371] 8. Aqueous smegglutide formulation, comprising: - Smegglutinin at concentrations of 0.1-10 mg / ml; - Concentrations greater than 15 mM and less than or equal to 45 mM, such as 16-45 mM, 20-45 mM, 20-40 mM, 25-45 mM, 25-40 mM, 20-35 mM, 20-30 mM, 25-35 mM, such as approximately 30 mM phosphate; and - pH is 7-8, for example, about 7.4.

[0372] 9. The smegglutide formulation according to any one of items 7-8, further comprising histidine.

[0373] 10. The smegglutide formulation according to any one of items 7-9, further comprising a tensioning agent such as propylene glycol, potassium chloride and / or sodium chloride.

[0374] 11. The smegglutide formulation according to any one of items 7-10, for use in an injection device.

[0375] 12. The semaglutide formulation according to any one of items 7-10, optionally in combination with the canagliflozin formulation according to any one of items 1-4, for use in medicine.

[0376] 13. A medical device comprising smegglutinin in a first compartment and canagliflozin in a second compartment.

[0377] 14. A medical device comprising a first chamber and a second chamber, wherein the first chamber contains a semaglutide formulation according to any one of items 7-10, and the second chamber contains a canagliflozin formulation according to any one of items 1-4.

[0378] 15. The medical device according to item 14, wherein the first chamber is a distal chamber and the second chamber is a proximal chamber.

[0379] 16. A fixed-dose combination of 0.025-5.0 mg canagliflozin and 0.05-5.0 mg smegglutinide for pharmaceutical use, wherein the canagliflozin and smegglutinide are administered parenterally in a single injection, such as subcutaneously.

[0380] Example All compositions of the semaglutide pharmaceutical product (DP) are prepared as follows: a buffer (disodium hydrogen phosphate dihydrate), a tensile agent (propylene glycol or NaCl), and histidine (if applicable) are dissolved in water, and the pH is adjusted to approximately 7.4 using sodium hydroxide and / or hydrochloric acid. The semaglutide active pharmaceutical ingredient (DS) is dissolved therein, and the pH is adjusted to 7.4 using sodium hydroxide and / or hydrochloric acid if necessary. The composition is then sterilized by filtration through a 0.22 µm sterile filter.

[0381] All compositions of the canagliflozin pharmaceutical product (DP) are prepared as follows: a buffer and a tensile agent are dissolved in water, and the pH is adjusted to approximately 7.4 using sodium hydroxide and / or hydrochloric acid. The canagliflozin active pharmaceutical ingredient (DS) is dissolved therein, and the pH is adjusted to 4.0 using sodium hydroxide and / or hydrochloric acid if necessary. The composition is then sterilized by filtration through a 0.22 µm sterile filter.

[0382] When referring to chloroprene rubber plungers, a cavity-free type was used, i.e., a geometry similar to... Figure 1 The distal plunger 8 shown is similar, whether it is used as a distal plunger or a proximal plunger.

[0383] Example 1: Study on the formation rate of high molecular weight protein (HMWP) types in canagliflozin formulations with different buffers or tensile agents Experiments were conducted to determine the optimal one or more buffers, and the optimal one or more tensioning agents, for a canagliflozin drug product formulation at pH 4.0 in terms of the rate of formation of high molecular weight protein (HMWP) impurities. Generally, the level of HMWP in a pharmaceutical peptide or protein formulation is an important parameter to be considered as part of evaluating formulation stability, and the rate of formation of this impurity during storage should be minimized.

[0384] The buffers studied were acetate, benzoate, glutamate, and lactate, because these buffers have high pK... a The pH value is close to the optimal pH of 4.0 for canagliflozin formulation. The tonics studied were glycerol, mannitol, propylene glycol, sorbitol, sucrose, and trehalose.

[0385] For buffering substance research, a total of 38 canagliflozin formulations were prepared using the following general composition: - A concentration of canagliflozin, as specified in Table 1-1.

[0386] - A buffer substance of a certain concentration, as specified in Table 1-1.

[0387] - Tensioning agent: Glycerin (24 mg / ml).

[0388] - Hydrochloric acid (HCl), necessary to achieve pH 4.0.

[0389] - Sodium hydroxide (NaOH), necessary to achieve pH 4.0.

[0390] - Water for injection (WFI) is used as the solvent.

[0391] For the study of tonic agents, a total of six (6) canagliflozin formulations were prepared using the following compositions: - Canagliflozin (9.6 mg / ml) - Buffer: Glutamate (5 mM, added as 0.74 mg / ml L-glutamate) -One of the following tensioning agents: 0.5mg glycerol (24 mg / ml) o Mannitol (46 mg / ml) Propylene glycol (20 mg / ml) sorbitol (46 mg / ml) o-Sucrose (83 mg / ml) trehalose (83 mg / ml) - Hydrochloric acid (HCl), necessary to achieve pH 4.0. - Sodium hydroxide (NaOH), necessary to obtain pH 4.0 - Water for injection (WFI) is used as the solvent.

[0392] Table 1-1: Overview of canagliflozin formulations included in buffer material studies.

[0393] (X): The specified combination of canagliflozin concentration and buffer substance and concentration was included in this study.

[0394] (–): The concentration of canagliflozin and the specified combination of buffer substances and concentrations were not studied.

[0395] 1 It is added in the form of sodium acetate trihydrate.

[0396] 2 Added in the form of benzoic acid 3 Add in the form of L-glutamic acid 4 Add in the form of 50% w / w L-sodium lactate solution.

[0397] Each filtered and sterilized formulation was filled into multiple glass syringes, such that each syringe contained approximately 280 µl of canagliflozin formulation, sealed by two chlorobutyl rubber plungers, to obtain a configuration of liquid formulation and primary packaging material corresponding to the configuration described in the section entitled “Suitable Medical Devices” and as follows. Figure 1 The proximal chamber of the dual-chamber pre-filled syringe is shown.

[0398] Each syringe was stored at 37±2℃ for 12 weeks, and the HMWP content of the samples was analyzed at zero time and after 6, 8 and 12 weeks of storage.

[0399] HMWP analysis was performed using size exclusion high-performance liquid chromatography (SE-HPLC), where HMWP species were separated from the major peptide form. A WATERS HMWP 7.8 x 300 mm column was used. Samples prepared at concentrations of 9.6 mg / ml or 18 mg / ml canagliflozin were diluted to a concentration of 1 mg / ml in 0.09 M phosphate solution (pH 3.6) prior to injection. Samples prepared at a concentration of 0.6 mg / ml canagliflozin were injected unchanged. The injection volume was 10 µl, and isocratic elution was performed using 500 mM sodium chloride, 10 mM sodium dihydrogen phosphate monohydrate, 5 mM phosphate, and 50% (v / v) 2-propanol. The flow rate was 0.5 ml / min, and UV detection was achieved at 215 nm. The HMWP content (as a percentage of total peptide content) was calculated by dividing the HMWP peak area by the total area of ​​the HMWP and main peaks, and then multiplying by 100%.

[0400] For each formulation studied, the HMWP formation rate was calculated as the slope of a linear regression function of HMWP content (in percentage) as a function of time (in weeks).

[0401] The results of the buffering material study are presented in Table 1-2.

[0402] Table 1-2: HMWP formation rate (percentage / week) at 37 °C for each buffer substance and at each buffer concentration and canagliflozin concentration.

[0403] (–): Combinations have not been studied.

[0404] The following can be observed from the results shown in Table 1-2: - In each study combination of buffer concentration and canagliflozin concentration, glutamate resulted in the lowest HMWP formation rate compared to other buffers.

[0405] - In the study of benzoates, in each combination of buffer concentration and canagliflozin concentration, benzoates resulted in the highest HMWP formation rate compared to other buffers.

[0406] - In studying all four buffers, in each study combination of buffer concentration and canagliflozin concentration, it was observed that the HMWP formation rate of formulations using acetate or lactate as buffers was closer to that of formulations containing glutamate than that of formulations containing benzoate.

[0407] - In the study of all buffers, in each combination of canagliflozin concentrations up to 9.6 mg / ml, the lactate-containing formulations showed a lower HMWP formation rate compared to the corresponding acetate-containing formulations.

[0408] - In each combination of buffer concentration in the range of 5-10 mM and canagliflozin concentration of 18 mg / ml, the acetate-containing formulation exhibited a lower HMWP formation rate compared to the lactate-containing formulation, while in the combination of buffer concentration of 2.5 mM and canagliflozin concentration of 18 mg / ml, the lactate-containing formulation exhibited a lower HMWP formation rate compared to the acetate-containing formulation.

[0409] Surprisingly, the data showed that choosing glutamate as the buffer in canagliflozin formulations, compared to acetate, benzoate, or lactate, consistently resulted in the lowest HMWP formation rate, meaning that based on this parameter, it produces the most stable canagliflozin formulations.

[0410] Furthermore, when the canagliflozin concentration was 9.6 mg / ml and the buffer was glutamate or lactate, data showed that increasing the buffer concentration from 2.5 mM to 5 mM resulted in a lower HMWP formation rate; however, further increasing it to 10 mM did not lead to a further decrease in the HMWP formation rate.

[0411] Furthermore, the data surprisingly showed that, compared to acetate, glutamate, or lactate, choosing benzoate as a buffer in canagliflozin formulations consistently resulted in the highest HMWP formation rate, meaning that based on this parameter, it produces the most unstable canagliflozin formulations.

[0412] Furthermore, data showed that at a canagliflozin concentration of 9.6 mg / ml, selecting lactate in the concentration range of 2.5-5 mM as a buffer resulted in a lower HMWP formation rate than when acetate in the same concentration range was selected as a buffer. This means that based on this parameter, it produces a more stable canagliflozin formulation.

[0413] The results of studies using different tensile agents in a 9.6 mg / ml canagliflozin formulation buffered with 5 mM glutamate are presented in Tables 1-3.

[0414] Table 1-3: HMWP formation rate (percentage / week) at 37 °C for each tensioning agent.

[0415] The results in Tables 1-3 indicate that glycerol and propylene glycol result in the lowest HMWP formation rates; however, the rates are at comparable levels for all six tensor agents studied. Therefore, it can be concluded that all six tensor agents can be used without compromising the stability of canagliflozin formulations based on this parameter.

[0416] Example 2: Study on the physical stability of canagliflozin formulations containing different buffering substances Liquid injectable drug formulations should remain physically stable throughout the product's shelf life, preferably exhibiting tolerance to stress conditions such as higher temperatures and greater physical stress for a period of time compared to recommended long-term storage conditions (typically static storage at 2-8°C). This will allow patients to carry the medication with them, for example, while traveling, thereby improving patient safety and medication adherence.

[0417] Experiments were conducted to determine one or more buffering agents that are optimal for the physical stability of the canagliflozin drug product formulation at pH 4.0, which was measured as the following parameters over time: - The amount of subvisible particles present in the formulation -Amyloid fibrils are present in the formulation. The amount of subvisible particles is an important safety parameter to consider in injectable drug products, and any development of this parameter should be minimized for peptide or protein drug products, such as canagliflozin. Canagliflozin is an analogue of the amyloid hormone known to form amyloid fibrils. The formation of such fibrils should be avoided in parenteral peptide or protein drug products to minimize the risk of immunogenic reactions in patients.

[0418] The buffers studied were acetate, benzoate, glutamate, and lactate, because these buffers have high pK... a The value is close to the target pH of canagliflozin, 4.0.

[0419] Four (4) canagliflozin formulations were prepared using the following composition, differing only in the buffering substance: - Canagliflozin: 9.6 mg / ml. - One of the following buffer substances with a concentration of 5 mM: o Acetate (added in the form of sodium acetate trihydrate) o Benzoate (added in the form of benzoic acid) o-Glutamate (added in the form of L-glutamic acid) o-Lactate (added as a 50% w / w L-sodium lactate solution) - Glycerin: 24 mg / ml - Hydrochloric acid (HCl), necessary to achieve pH 4.0. - Sodium hydroxide (NaOH), necessary to obtain pH 4.0 - Water for injection (WFI) is used as the solvent.

[0420] Each filtered and sterilized formulation was filled into multiple glass syringes, such that each syringe contained approximately 280 µl of canagliflozin formulation, surrounded by two chlorobutyl rubber plungers, to obtain a configuration of liquid formulation and primary packaging material corresponding to that described in the section entitled “Suitable Medical Devices” and as follows. Figure 1 The proximal chamber of the dual-chamber pre-filled syringe is shown. Inserting the plunger results in approximately 100 µl of air being present, while the canagliflozin product is surrounded by both plungers.

[0421] All syringes were stored under stress storage conditions, which were defined in this experiment as: Temperature: 37 ± 2 ℃ - Physical stress: During storage, all syringes were inverted (180° back and forth) to allow the product to move back and forth between the two plungers, as specified in Table 2-1. Rotation was performed at room temperature at a rate of approximately 1 second per complete inversion (up and down). The rotation frequency and number of rotations outlined in Table 2-1 correspond to an average of 100 complete inversions per day, 5 days per week.

[0422] - Duration: Maximum 28 days (see Table 2-2) Table 2-1. Frequency and number of complete inversions during the study period

[0423] (–): Not reversed.

[0424] A) The samples were inverted after being sampled according to Table 2-2 for analysis.

[0425] At the time points shown in Table 2-2, samples from each of the four canagliflozin formulations were analyzed. - The content of subvisible particles was analyzed using microfluidic imaging (MFI). The presence of amyloid peptide fibrils was analyzed using thioflavin-T (ThT) fluorescence assay. For the analysis of subvisible particle content, the micro-fiber spectroscopy (MFI) method was used; for more detailed information on the principles of MFI, see, for example, Sharma, DK et al., AAPS J. (2010), 12: 455-464. The following procedure was used for each sample: - Conduct experiments at ambient temperature.

[0426] - Combine the contents of the three syringes into the sample container.

[0427] - First, the rear (proximal) plunger is removed by vacuum aspiration, and then the liquid is pipetted into the sample container, thereby removing the liquid from each syringe.

[0428] Transfer the sample to a 96-well plate and insert the plate into the sample processing unit (Bot1) of the Protein Simple MFI™ 5200 instrument (apparatus) equipped with a standard Protein Simple MFI™ 100μm flow cell.

[0429] - Samples were analyzed using a standard MFI system setup, which means that liquid was pipetted into a reservoir connected to the flow cell, the liquid was illuminated with an LED light source (470 nm), and a digital camera recorded the contents of the flow cell as bright-field images via magnifying optics throughout the experiment. Data acquisition was performed using Protein Simple MVSS software. The image stream recorded throughout the run was processed by the validated Novo Nordisk MFI Data Validator software to obtain the number of individual particles (normalized to counts per ml of liquid analyzed) with sizes >2 µm, >5 µm, >10 µm, and >25 µm. Particle size was defined as equivalent circle diameter (BCD).

[0430] The analysis for the presence of peptide fibrils was based on the fluorescence properties of the ThT probe. The ThT probe exhibits low fluorescence in its unbound / native peptide-bound state, but high fluorescence when bound to peptide fibrils, with a redshift in the wavelength of maximum fluorescence upon fibril binding. The following procedure was used for each sample: - The experiment was conducted at 25°C.

[0431] - Combine the contents of the 2 or 3 syringes required to obtain a total of at least 500 µl into the sample container.

[0432] - First, the rear (proximal) plunger is removed by vacuum aspiration, and then the liquid is pipetted into the sample container, thereby removing the liquid from each syringe.

[0433] - Subsequently, 500 µl of sample was mixed with approximately 9 µl of ThT stock solution in a separate sample container to obtain a final ThT concentration of 20 μM.

[0434] - Incubate the sample in the dark at ambient temperature for 25 min.

[0435] - Transfer 200 µl of sample into the wells of a 96-well microtiter plate.

[0436] - Samples were measured on a BMG CLARIOstar fluorescence plate reader equipped with a monochromator, with excitation and emission performed at 440 nm and 470-550 nm, respectively.

[0437] - Data acquisition was completed using CLARIOstar Control software.

[0438] - The emission maximum was observed at a wavelength of approximately 485 nm in this assay; therefore, the results of each analysis are reported as ThT fluorescence at 485 nm, expressed in relative fluorescence units (RFU).

[0439] Table 2-2: Sampling Scheme

[0440] (X): Sampling was performed. (–): No sampling was performed. A) For the benzoate-buffered canagliflozin formulation, sampling was stopped earlier than for other formulations because a rapid increase in particle content and ThT fluorescence was observed.

[0441] The results of the subvisible particle content at each sampling point analyzed by MFI are shown in Table 2-3.

[0442] Table 2-3. Subvisible particle counts per ml of analyzed liquid as a function of time in canagliflozin formulations containing different buffers under stress storage conditions. Results were divided into large groups of particles >2 µm, >5 µm, >10 µm, and >25 µm (equivalent circle diameter, ECD) and rounded to the nearest integer.

[0443] (–): Not tested because the experiment was stopped after 14 days for benzoate.

[0444] As shown in Tables 2-3, the glutamate-buffered canagliflozin formulation exhibited the lowest particle counts across all size ranges after 14 and 18 days. Furthermore, up to and including the 14-day time point, the particle count for the glutamate-buffered canagliflozin formulation remained at a low level, only slightly above the zero-time level; the counts only appeared to accelerate at the 18-day time point. In contrast, significant increases in particle counts were observed for benzoate at the 11-day time point, and for acetate and lactate at the 14-day time point.

[0445] Equally evident was the rapid increase in particle counts with benzoate-buffered formulations; the particle count with benzoate after 14 days was significantly higher than that with any other buffer after 18 days. Sampling for subvisible particle content analysis was discontinued for benzoate-buffered formulations after 14 days, partly because the subvisible particle level had increased very rapidly at that time point (see Tables 2-3), and partly because visible particles were detected when visually examining samples at the 18-day time point at approximately 10,000 lux; no visible particles were observed with any other buffer throughout the entire duration of the experiment (up to 28 days when including study portions containing ThT fluorescence analysis).

[0446] After 18 days, for particle sizes >5 and >10 µm, the particle counts of acetate and lactate were roughly equivalent, while for >2 and >25 µm, the particle count of acetate was higher than that of lactate.

[0447] Based on the subvisible particle count, the following conclusions can be drawn: - Compared to acetate, benzoate or lactate, canagliflozin formulations buffered with 5 mM glutamate surprisingly maintain their physical stability for a longer period under stress storage conditions.

[0448] - Significantly, compared to other buffers, the canagliflozin formulation buffered with 5 mM benzoate surprisingly exhibited the lowest degree of physical stability, based on the fastest onset and highest level of sub-visible and visible particle formation. Canagliflozin formulations containing acetate and lactate exhibit considerable physical stability, with lactate providing slightly more favorable stability compared to acetate.

[0449] The results of the presence of amyloid fibrils at each sampling point, measured using ThT fluorescence assay, are shown in Table 2-4.

[0450] Table 2-4. ThT fluorescence at 485 nm (in RFU) as a function of time in canagliflozin formulations containing different buffers under stress storage conditions.

[0451] (–): Not tested because the experiment was stopped after 21 days for benzoate.

[0452] As shown in Table 2-4, after 28 days of stress storage, the canagliflozin formulation containing glutamate maintained fluorescence levels equivalent to or slightly higher than those at time zero. With lactate buffer, a slightly larger increase was observed after 25 days, reaching approximately twice the level observed at time zero by day 28. For the acetate buffer, a much larger increase in fluorescence was observed, with a rapid increase observed after day 21, reaching a level more than four times that observed at time zero by day 28. The fastest and largest increase in fluorescence was observed with benzoate as a buffer; a small increase was observed after day 11, followed by a significant increase after day 14, reaching approximately four times the level observed at time zero. The experiment was stopped with the benzoate buffer after another significant increase in fluorescence was measured at day 21; visible particles were observed in the samples at this time point when visually examined at approximately 1,000 lux.

[0453] The increased ThT fluorescence level, combined with the increased observation of subvisible particles detected by the MFI method, indicates that the studied peptide or protein is forming amyloid fibrils. Based on the ThT fluorescence results, the following conclusions can be drawn: Compared to acetate, benzoate, or lactate, canagliflozin formulations buffered with glutamate surprisingly remained free of or nearly free of amyloid fibrils for longer periods under stress storage conditions, and appeared to have little or no fibril formation during the study period (up to 28 days).

[0454] - Compared to acetate or benzoate, lactate-buffered canagliflozin formulations remained free of or nearly free of amyloid fibrils for a longer period under stress storage conditions, and the level of fibrils that were eventually formed during the study period (observed after 25 days) appeared to be lower than that of acetate or benzoate when comparing the same time points.

[0455] - Significantly, compared with glutamate, lactate and acetate, canagliflozin formulations buffered with benzoate surprisingly showed the highest tendency to form amyloid fibrils under stress storage conditions, both in terms of having the fastest formation initiation and in exhibiting the highest levels of fibrils.

[0456] - In terms of fluorescence levels, the tendency of acetate-buffered formulations to form fibrils under stress storage conditions appears to be lower than that of glutamate-buffered and benzoate-buffered formulations, both in terms of onset time and the level of fibrils formed.

[0457] In summary, regarding obtaining the most physically stable canagliflozin formulation under stress storage conditions, 5 mM glutamate surprisingly showed a significant advantage over 5 mM lactate, 5 mM acetate, and especially 5 mM benzoate as a buffer. Furthermore, regarding obtaining the most physically stable canagliflozin formulation under stress storage conditions, both 5 mM lactate and 5 mM acetate showed significant advantages over 5 mM benzoate as a buffer.

[0458] Example 3: Physical stability during injection – The effect of buffer concentration in canagliflozin on the formation of subvisible particles during mixing in a dual-chamber syringe The concentration of buffers in canagliflozin formulations, such as glutamate or lactate, should be sufficiently high to ensure the stability of the canagliflozin drug product during and outside of storage, but should not impair the physical stability of semagraft when co-ejected from a dual-chamber syringe with it, for example, by inducing the formation of visible and / or subvisible particles. Such particle formation may potentially lead to immunogenic responses and / or unpredictable pharmacokinetic profiles in patients.

[0459] Experiments were conducted to determine the maximum feasible concentration of glutamate or lactate buffer in canagliflozin formulations at pH 4.0, taking into account that mixing with smegglutide should not result in the formation of visible and / or subvisible particles.

[0460] A total of eight (8) different canagliflozin formulations with pH 4.0 were prepared using the following compositions, containing different concentrations of glutamate or lactate: - Canagliflozin: 9.6 mg / ml - Glutamate (added in the form of L-glutamic acid) or lactate (added in the form of 50% w / w sodium L-lactic acid solution) at one of the following concentrations: o2.5 mM o5 mM o10 mM o40 mM - Glycerin: 24 mg / ml - Hydrochloric acid (HCl), necessary to achieve pH 4.0. - Sodium hydroxide (NaOH), necessary to obtain pH 4.0 - Water for injection (WFI) is used as the solvent.

[0461] Two (2) smegglutide formulations at pH 7.4 were prepared using the following composition, with or without histidine as an excipient: - Smegglutinin: 4.8 mg / 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: 6.4 mg / ml - Hydrochloric acid (HCl), necessary to achieve pH 7.4. - Sodium hydroxide (NaOH), necessary to achieve pH 7.4. - Water for injection (WFI) is used as the solvent.

[0462] Fill each of the filtered and sterilized canagliflozin and smegglutinin formulations into a double-chamber glass syringe (see [link]). Figure 1 In this dual-chamber syringe, each syringe contains approximately 515-525 µl of semaglutide formulation in the distal chamber facing the needle, and approximately 280 µl of canagliflozin formulation in the proximal chamber surrounded by two chlorobutyl rubber plungers. Thus, a total of 12 different combinations of semaglutide and canagliflozin formulations are obtained in the dual-chamber syringe. - Histidine-free smegglutide, paired with each of the four different concentrations of canagliflozin formulations containing glutamate. - Smegglutide containing 10 mM histidine, paired with each of the four different concentrations of canagliflozin formulations containing glutamate. - Smegglutinin containing 10 mM histidine, paired with each canagliflozin formulation containing lactate (four different concentrations). In the following text, an experiment conducted on such a combination is referred to as an "exclusion experiment".

[0463] In each ejection test, the syringe was emptied by expelling the entire contents of the liquid formulation through the needle into the flow cell of the MFI instrument. The procedure for each ejection test was as follows: - Conduct experiments at ambient temperature.

[0464] - Connect the tip of the dual-chamber syringe directly to the flow cell of the Protein Simple MFI™ 4200 instrument (Protein Simple MFI™ 100 μm flow cell) via a silicone tube.

[0465] - Applying force to the rear (proximal) plunger that isolates the canagliflozin formulation from the external environment results in a roughly constant liquid flow of approximately 0.17 ml / min through the flow cell of the MFI instrument.

[0466] - As the liquid expelled from the syringe needle passes through the flow cell, the liquid is illuminated by an LED light source (470 nm), and a digital camera records the contents of the flow cell as a bright-field image via magnifying optics throughout the experiment. Recording begins as soon as possible after all air in the flow cell's detection zone has been displaced by the liquid from the syringe, and ends as close as possible to the point where all liquid contents in the syringe have been expelled and passed through the flow cell's detection zone. Data acquisition is performed using Protein Simple MVSS software.

[0467] - The image stream recorded throughout the run was processed by the validated Novo Nordisk MFI DataValidator software to obtain the number of individual particles with a size >10 µm and a size >25 µm (ECD) (normalized to a count per ml of liquid analyzed).

[0468] Table 3-1 provides the results for each of the studied smegglutinin and canagliflozin combinations, given in the range of particle counts per ml.

[0469] Table 3-1. Measured number of particles / ml for each discharge experiment using MFI.

[0470] A) Visible particle formation was observed during the discharge process, resulting in a very high subvisible particle count that is associated with uncertainty.

[0471] B) N / A: MFI was not used in the study. Visible particle formation was observed during the discharge process, therefore completing an MFI analysis for subvisible particle counting was considered meaningless; see also footnote B above.

[0472] To enable comparison with the background particle levels of unmixed formulations, the particle counts of individual formulations expelled from the syringe in the same manner as the expulsion experiments described above are shown in Table 3-2 (normalized to counts per ml).

[0473] Table 3-2: Background particle levels in each formulation (canagliflozin and smegglutinin not mixed)

[0474] MFI particle data showed that at glutamate concentrations of 2.5 and 5 mM, the observed particle levels were comparable to background levels, meaning no particle formation due to mixing with smegglutinin was observed. Increasing the glutamate concentration to 10 mM resulted in an increase in particle counts for both particle sizes (>10 µm and >25 µm). Further increasing the glutamate concentration to 40 mM resulted in the formation of visible particles during the discharge experiment, at which point the level of subvisible particles became too high to be meaningfully analyzed using the MFI instrument.

[0475] For lactate, at concentrations of 2.5, 5, and 10 mM, the MFI particle counts for both particle sizes (>10 µm and >25 µm) remained at low and comparable levels, while increasing to 40 mM resulted in the formation of visible particles during discharge experiments.

[0476] When semaglitide formulations containing 0 or 10 mM histidine were mixed with each of four canaglitide formulations having gradually increasing glutamate concentrations, the two formulations exhibited comparable particle levels.

[0477] Therefore, the results of this experiment show that The glutamate concentration in canagliflozin formulations at pH 4.0 should not exceed 10 mM, as concentrations exceeding this level can lead to excessive formation of subvisible particles. Furthermore, even 40 mM glutamate, when co-injected with a pH 7.4 smegglutide formulation containing 30 mM phosphate and 0 or 10 mM histidine using a dual-chamber syringe, can result in visible particle formation. In contrast, the glutamate concentration in canagliflozin formulations at pH 4.0 should be ≤10 mM, such as 5 mM or 2.5 mM, as this level of glutamate does not lead to excessive formation of subvisible particles when injected using the same combination.

[0478] - During co-injection with a semaglutide formulation at pH 7.4 containing 30 mM phosphate and 10 mM histidine using a dual-chamber syringe, the lactate concentration in the canagliflozin formulation at pH 4.0 can be as high as at least 10 mM, including 2.5 mM or 5 mM, as this will not lead to the formation of subvisible particles. However, the lactate concentration should not approach 40 mM, as visible particles will form at this concentration.

[0479] The results of this physical stability study indicate that the 4.8 mg / ml semaglutide formulation containing 30 mM phosphate may optionally contain 10 mM histidine as an excipient; the physical stability of semaglutide and canagliflozin co-injected with a dual-chamber syringe is comparable between semaglutide formulations containing 0 or 10 mM histidine.

[0480] Example 4: Physical stability during injection – Effect of canagliflozin on the formation of subvisible particles during mixing in a dual-chamber syringe In Example 3, it was found that if the concentration of the buffer (e.g., glutamate) used in the canagliflozin formulation is increased above a certain threshold, sub-visible or even visible particles will form during co-ejection from a dual-chamber syringe along with the semagliflozin-containing formulation. Canagliflozin itself also contributes to the buffer capacity of the canagliflozin formulation; that is, increasing the canagliflozin concentration results in an increased buffer concentration.

[0481] Experiments were conducted using a dual-chamber syringe to determine whether the presence of canagliflozin in the canagliflozin formulation (pH 4.0) resulted in a higher or lower risk of subvisible particle formation during co-ejection from the dual-chamber syringe together with smegglutinin formulation (pH 7.4).

[0482] Three (3) different canagliflozin formulations with pH 4.0 and containing different concentrations of canagliflozin were prepared using the following composition: - Canagliflozin: 0, 0.5, or 9.6 mg / ml - Glutamate: 5 mM (added as 0.74 mg / ml L-glutamate) - Glycerin: 24 mg / ml - Hydrochloric acid (HCl), necessary to achieve pH 4.0. - Sodium hydroxide (NaOH), necessary to obtain pH 4.0 - Water for injection (WFI) is used as the solvent.

[0483] Two (2) semaglutide formulations with pH 7.4 were prepared using the following composition: - Smegglutinin: 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: 6.4 mg / ml - Hydrochloric acid (HCl), necessary to achieve pH 7.4. - Sodium hydroxide (NaOH), necessary to achieve pH 7.4. - Water for injection (WFI) is used as the solvent.

[0484] Fill each of the filtered and sterilized canagliflozin and smegglutinin formulations into a double-chamber glass syringe (see [link]). Figure 1In this dual-chamber syringe, each syringe contains approximately 520-530 µl of semaglutide formulation in the distal chamber facing the needle, and approximately 270-280 µl of canagliflozin formulation in the proximal chamber surrounded by two chlorobutyl rubber plungers. Thus, a total of four different combinations of semaglutide and canagliflozin formulations were obtained in the dual-chamber syringe (defined as test combinations): - Smegglutinin 0.5 mg / ml, paired with canagliflozin 0 mg / ml - Smegglutinin 0.5 mg / ml, paired with canagliflozin 0.5 mg / ml - Smegglutinin 4.8 mg / ml, paired with canagliflozin 0 mg / ml - Smegglutinin 4.8 mg / ml, paired with canagliflozin 9.6 mg / ml Additionally, a semaglutide formulation containing 0 mg / ml semaglutide was prepared, i.e., with the same composition and pH as described above for the 0.5 mg / ml and 4.8 mg / ml semaglutide formulations, but without adding semaglutide to the semaglutide vehicle in this formulation. This vehicle is used to obtain information about the expected background particle level through the following three combinations (defined as the background combination): - Smegglutinin 4.8 mg / ml in the distal chamber, combined with the smegglutinin mediator in the proximal chamber. - A combination of smegglutinin mediator in the distal chamber and canagliflozin 0.5 mg / ml in the proximal chamber. - Smegglutinin mediator in the distal chamber, combined with canagliflozin 9.6 mg / ml in the proximal chamber. For each of the test and background combinations listed above, the “discharge experiment” described in detail in Example 3 was performed, and the number of individual particles with a size >10 µm and a size >25 µm (ECD) was obtained using the MFI device and software (normalized to counts per ml of liquid analyzed).

[0485] Table 4-1 provides the results for each of the four test combinations of the studied smegglutinin and canagliflozin formulations, given in the range of particle counts per ml.

[0486] Table 4-1. Measured particle count / ml for each effluent experiment of the test combination, using MFI.

[0487] A) In some cases, visible particle formation is observed during the discharge process, resulting in a very high subvisible particle count that is associated with uncertainty.

[0488] The particle counts of the background combination expelled from the syringe in the same manner as the combinations described above are shown in Table 4-2 (normalized to counts per ml).

[0489] Table 4-2. Measured particle count / ml for each effluent experiment for the background combination, using MFI.

[0490] The data for the test combinations in Table 4-1 show that, compared to the background levels shown in Table 4-2, the subvisible particle levels were significantly increased with the combination of canagliflozin 0 mg / ml and smegglutinin 4.8 mg / ml; in some cases, even visible particle formation was observed during excretion. For the combination of canagliflozin 0 mg / ml and smegglutinin 0.5 mg / ml, particle levels >10 µm were increased in some experiments compared to background levels (see Table 4-2). For the other two test combinations—where canagliflozin was present at concentrations of 0.5 mg / ml or 9.6 mg / ml—no subvisible particle formation exceeding levels expected from the background levels was observed.

[0491] This experiment surprisingly demonstrates that canagliflozin needs to be present at a specific concentration above 0 mg / ml to consistently avoid subvisible particle formation when the test canagliflozin formulation and the test smegglutinide formulation are co-dispensed from a dual-chamber syringe, and even to avoid visible particle formation when combined with smegglutinide at 4.8 mg / ml. Unexpectedly, the presence of canagliflozin prevented particle formation due to smegglutinide precipitation because canagliflozin contributes to the buffering capacity of the canagliflozin formulation at pH 4.0; the results from Example 3 indicate that increasing the buffering capacity in the canagliflozin formulation increases the risk of particle formation during mixing of the same canagliflozin and smegglutinide formulations tested in this example.

[0492] Example 5: Physical stability of smegglutide formulation during injection with different phosphate concentrations The phosphate buffer concentration in the semaglutide formulation should ensure the stability of the semaglutide drug product during and outside of storage, as well as the physical stability of semaglutide when co-discharged from a dual-compartment device with canagliflozin, for example, by ensuring no visible and / or subvisible particle formation. Such particle formation can potentially lead to immunogenic responses and / or unpredictable pharmacokinetic profiles in patients. In Example 3, the effect of the buffer concentration in the canagliflozin formulation was demonstrated to be critical for ensuring physical stability when co-discharged from a dual-compartment device with semaglutide.

[0493] Experiments were conducted to determine the minimum feasible concentration of phosphate buffer in the smegglutide formulation at pH 7.4, taking into account that mixing with canagliflozin should not result in the formation of visible and / or subvisible particles.

[0494] Four (4) smegglutinin formulations at pH 7.4 were prepared using the following compositions and different concentrations of phosphate: - Smegglutinin: 4.8 mg / ml - One of the following combinations of phosphate (buffer) and propylene glycol or sodium chloride as a tensor (the concentration of the tensor is adjusted according to the concentration of the phosphate to obtain a near-isotonic formulation): 0.8 mM phosphate (added as 1.42 mg / ml disodium hydrogen phosphate dihydrate) and 18.5 mg / ml propylene glycol 0.15 mM phosphate (added as 2.67 mg / ml disodium hydrogen phosphate dihydrate) and 17.5 mg / ml propylene glycol 0.20 mM phosphate (added as 3.56 mg / ml disodium hydrogen phosphate dihydrate) and 17.0 mg / ml propylene glycol 0.20 mM phosphate (added as 3.56 mg / ml disodium hydrogen phosphate dihydrate) and 7.60 mg / ml sodium chloride - Hydrochloric acid (HCl), necessary to achieve pH 7.4. - Sodium hydroxide (NaOH), necessary to achieve pH 7.4. - Water for injection (WFI) is used as the solvent.

[0495] A canagliflozin formulation with pH 4.0 was prepared using the following composition: - Canagliflozin: 9.6 mg / ml - Glutamate: 5 mM (added as 0.74 mg / ml L-glutamate) - Glycerin: 24 mg / ml - Hydrochloric acid (HCl), necessary to achieve pH 4.0. - Sodium hydroxide (NaOH), necessary to obtain pH 4.0 - Water for injection (WFI) is used as the solvent.

[0496] Fill each of the filtered and sterilized canagliflozin and smegglutinin formulations into a double-chamber glass syringe (see [link]). Figure 1In this dual-chamber syringe, each syringe contains one of the semaglutide formulations with a retrievable volume of at least 500 µl in the distal chamber facing the needle, and a canagliflozin formulation with a retrievable volume of at least 250 µl in the proximal chamber surrounded by two chlorobutyl rubber plungers. Thus, a total of four different combinations of semaglutide and canagliflozin formulations were obtained in the dual-chamber syringe. For each combination, a “discharge experiment” as described in detail in Example 3 was performed, and the number of individual particles with a size >10 µm and a size >25 µm (ECD) was obtained (normalized to a count per ml of analyzed liquid) using the MFI device and software.

[0497] Table 5-1 provides the results for each phosphate concentration studied, given in the range of particle counts per ml.

[0498] Table 5-1. Measured number of particles / ml for each discharge experiment using MFI.

[0499] A) Using propylene glycol as a tensioning agent B) Sodium chloride as a tensile agent To enable comparison with the background particle levels of unmixed formulations, the particle counts of individual formulations expelled from the syringe in the same manner as the expulsion experiments described above are shown in Table 5-2 (normalized to counts per ml).

[0500] Table 5-2: Background particle levels in each formulation (canagliflozin and smegglutinin not mixed)

[0501] The MFI particle data in Table 5-1 show that when mixed with canagliflozin containing 5 mM glutamate as a buffer, the 8 mM phosphate concentration in the smegglutinin formulation results in a significantly increased particle count for both particle sizes (>10 µm and >25 µm).

[0502] The data also clearly show that increasing the phosphate concentration to 15 mM removes most, but not all, of the subvisible particles formed during the expulsion experiments. Further increasing to 20 mM phosphate resulted in a further reduction in the subvisible particle count measured during the expulsion experiments, with similar levels observed regardless of whether propylene glycol or sodium chloride was used as the tensile agent. The particle levels observed for 20 mM phosphate correspond to the background levels in this experiment (Table 5-2), thus implying that no subvisible particle formation was caused by the mixing of smegglutinin and canagliflozin formulations in the dual-chamber syringe.

[0503] Therefore, the results of this experiment indicate that the phosphate concentration in the semaglutide formulation at pH 7.4 should be higher than 15 mM, for example 20 mM or higher, in order to avoid the formation of subvisible particles during combined injection with the canagliflozin formulation at pH 4.0 containing 5 mM glutamate using a dual-chamber syringe.

[0504] Example 6: PK curves after administration of canagliflozin and smegglutinin via a pre-filled dual-chamber syringe Studies were conducted in LYD pigs to evaluate the combined use of canagliflozin and smegglutinin via a pre-filled dual-chamber syringe (see [link]). Figure 1 PK can be administered via a single subcutaneous injection of each drug. Dosage volumes are approximately 500 μL for semaglutide and approximately 250 μL for canagliflozin. Dosage ranges of 0.25 mg to 2.4 mg for semaglutide and 0.25 mg to 4.5 mg for canagliflozin were explored.

[0505] PK curves were explored using female crossbred domestic pigs (Danish Landrace, Yorkshire and Duroc – LYD pigs) weighing approximately 80–100 kg. Low doses were administered subcutaneously as monotherapy with a single dose of semaglutide / canagliflozin, or in combination with single injections at different sites using a pre-filled dual-chamber syringe or a NovoPen 4 penfill (Novo Nordisk A / S). Prior to administration of high-dose semaglutide / canagliflozin, LYD pigs were dose-escalated with liraglutide for 10 days to avoid initial gastrointestinal discomfort caused by acute high-dose semaglutide. On day 11, the animals were administered semaglutide / canagliflozin as described above.

[0506] Complete plasma concentration-time curves were obtained from each animal from before administration to 18 days after administration.

[0507] Smegglutinin and canagliflozin in plasma were analyzed using luminescent oxygen channel immunoassay (LOCI) and liquid chromatography-mass spectrometry (LCMS), respectively. Non-compartmental pharmacokinetic analysis was performed using individual plasma concentration-time curves.

[0508] Table 6: Comparison of PK parameters of semaglutide after co-administration of semaglutide / canagliflozin 2.4 mg / 4.5 mg with single injection versus using a pre-filled dual-chamber syringe (mean ± SD)

[0509] Moderate differences in the PK parameters Cmax and tmax of semagraft were observed for different administration methods. For canagliflozin, after administration of 2.4 / 2.4 semagraft / canagliflozin using a pre-filled dual-chamber syringe, the Cmax of canagliflozin was significantly lower than that after administration of semagraft via two different devices. max It increased by up to 65% and AUC increased by up to 45%.

[0510] These non-clinical data demonstrate the improved efficacy when semaglutide and canagliflozin are administered in a single injection using a dual-chamber syringe, compared to administration separately using a single syringe such as the NovoPen 4 penfill.

[0511] Example 7: Phase 1 combined trial of AM833 (canagliflozin) and smegglutinin Experimental Design A 20-week, multi-escalation phase 1 trial investigated the safety, tolerability, pharmacokinetics, and weight loss potential of AM833 (canagliflozin) in combination with 2.4 mg semagliflozin. In this trial, six different doses of canagliflozin (0.16 mg, 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, and 4.5 mg weekly) were administered subcutaneously along with semagliflozin (2.4 mg weekly) to six separate cohorts. Participants were randomized 3:1 to receive canagliflozin + 2.4 mg semagliflozin or placebo + 2.4 mg semagliflozin. A 16-week dose escalation period was used, followed by a 4-week target dose period. Eighty participants had an initial BMI between 27.0 and 39.9 kg / m². 2 Adults aged (inclusive) completed the trial.

[0512] This trial investigated the number of adverse events (the primary endpoint) that occurred during treatment. AM833 was well tolerated, and the most common adverse events were injection site reactions and gastrointestinal disturbances, including nausea and vomiting, most of which were mild or moderate in severity. Surprisingly, the level of gastrointestinal disturbances observed in this trial for the combination of AM833 and smegglutinin was comparable to the levels typically observed for glucagon-like peptide-1 (GLP-1) in monotherapy.

[0513] result Relative to a mean baseline weight of 95.7 kg, all treatment groups experienced weight loss during the 20-week treatment period. Significant weight loss was observed in subjects receiving the three highest doses of canagliflozin (1.2 mg, 2.4 mg, and 4.5 mg) plus 2.4 mg semaglutide compared to placebo plus 2.4 mg semaglutide. Figure 3 ).

[0514] After 20 weeks of treatment, statistically significant differences were observed in mean weight change from baseline to the end of treatment for the three highest doses of canagliflozin (1.2 mg, 2.4 mg, and 4.5 mg) in combination with semagraft, compared to placebo plus semagraft. The estimated mean weight change from baseline to the end of treatment was as follows: 15.6% for canagliflozin 1.2 mg, 17.0% for canagliflozin 2.4 mg, and 15.6% for canagliflozin 4.5 mg; all in combination with 2.4 mg semagraft. A 9.8% weight loss was observed in placebo plus semagraft. The treatment difference was not statistically significant for the three lowest doses of canagliflozin (0.16 mg, 0.3 mg, and 0.6 mg) in combination with semagraft compared to placebo plus 2.4 mg semagraft. Evidence of weight rebound was observed in all treatment groups after discontinuation of the investigational product at week 20.

Claims

1. An aqueous canagliflozin formulation comprising: -Cangaliskide; - A buffer, which is: glutamate / glutamate at a concentration of approximately 2-9 mM; or lactate / lactate at a concentration of approximately 2-25 mM; or acetate / acetate at a concentration of approximately 2-9 mM; and - pH is 3.5-4.5, for example, about pH 4.

0.

2. The aqueous canagliflozin formulation according to claim 1, wherein it is a pharmaceutical formulation containing canagliflozin at a concentration of 0.1-18 mg / ml; preferably, it is a pharmaceutical formulation containing canagliflozin at a concentration of 1-18 mg / ml; more preferably, it is a pharmaceutical formulation containing canagliflozin at a concentration of at least 1 mg / ml; and most preferably, it is a pharmaceutical formulation containing canagliflozin at a concentration of about 1.0 mg / ml, about 2.0 mg / ml, about 4.0 mg / ml, about 4.8 mg / ml, about 6.8 mg / ml, about 9.6 mg / ml, or about 18 mg / ml.

3. The aqueous canagliflozin formulation according to any one of the preceding claims, wherein... The buffer is a glutamate / glutamate concentration of 2.5-9 mM, or 2-6 mM, such as 2.5-5 mM, more preferably about 5 mM; or The buffer is a lactic acid / lactate solution with a concentration of 2-25 mM, preferably 2-15 mM, more preferably 2.5-10 mM, even more preferably 2-10 mM, even more preferably 2-8 mM, and even more preferably about 5 mM; or The buffer is an acetic acid / acetate solution with a concentration of 2-8 mM, preferably 2-7 mM, more preferably 2-5 mM, more preferably 2.5-5 mM, and even more preferably about 5 mM.

4. The aqueous canagliflozin formulation according to any one of the preceding claims, further comprising a tensile agent selected from glycerol, mannitol, propylene glycol, sorbitol, sucrose, or trehalose.

5. Aqueous smegglutide formulation, comprising: -Smigratide; - Phosphate with a concentration greater than 20 mM and less than or equal to 45 mM; and - pH is 7.0-8.0, preferably about pH 7.

4.

6. The aqueous smegglutide formulation according to claim 5, comprising a phosphate at a concentration of 20-40 mM, preferably 20-35 mM, wherein the phosphate is preferably selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium phosphate.

7. The aqueous smegglutide formulation according to any one of claims 5-6, further comprising histidine.

8. The aqueous smegglutide formulation according to any one of claims 5-7 further comprises a tensile agent selected from propylene glycol, potassium chloride and / or sodium chloride.

9. The aqueous smegglutide formulation according to any one of claims 5-8, wherein it does not contain preservatives.

10. A medical device comprising a first chamber and a second chamber, wherein the first chamber contains an aqueous semaglutide formulation according to any one of claims 5-9, and the second chamber contains an aqueous canagliflozin formulation according to any one of claims 1-4.

11. Use of the aqueous smegglutide formulation according to any one of claims 5-9 and the aqueous canagliflozin formulation according to any one of claims 1-4 for the preparation of a medicament.

12. The use according to claim 11, wherein the drug is for the treatment and / or prevention of obesity, diabetes, non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis, cardiovascular disease and / or Alzheimer's disease.

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