Pharmaceutical formulations comprising a cyclodextrin

Abstract

Disclosed herein is a liquid pharmaceutical formulation comprising an amylin receptor agonist, a GLP-1 receptor agonist and a cyclodextrin comprising hydroxypropyl substitutions. Said co-formulation may be used for the medical treatment of subjects with overweight or obesity, with or without associated co-morbidities; diabetes, with or without associated comorbidities; cardiovascular diseases, non-alcoholic steatohepatitis (NASH) and cognitive impairment, such as that caused by Alzheimer’s disease.

Description

[Technical Field]

[0001] This invention relates to a pharmaceutical formulation, which is a co-formulation of a GLP-1 receptor agonist and an amyloid receptor agonist. The pharmaceutical formulation can be used for the medical treatment of overweight or obesity with or without one or more related comorbidities; diabetes with or without one or more related comorbidities; cardiovascular disease; non-alcoholic steatosis (NASH); and individuals with cognitive impairment, such as those with Alzheimer's disease. [Previous Technology]

[0002] Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist and is the active pharmaceutical ingredient in 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.

[0003] Semaglutide is also an active pharmaceutical ingredient in Wegovy®. Ozempic® is indicated as an adjunct to a calorie-reducing diet and increased physical activity for chronic weight management in adult patients with an initial body mass index of 30 kg / m2 or higher in the presence of at least one weight-related comorbidity.

[0004] Ozempic® and Wegovy® are liquid pharmaceutical formulations containing 8 mM phosphate and having a pH of approximately 7.4.

[0005] A fixed-dose combination of the amyloid receptor agonist caglitinide and the GLP-1 receptor agonist semaglutide has been investigated for the treatment of overweight and obesity (Lancet 2021; 397: 1736–48). The investigated pharmaceutical products are in the form of separate liquid pharmaceutical formulations for subcutaneous use, comprising either caglitinide or semaglutide.

[0006] To date, the possibility of co-formulating semaglutide and cagliottide has not been considered due to the different physicochemical properties of these active pharmaceutical ingredients. Semaglutide (a GLP-1 receptor agonist) has an isoelectric point incompatible with cagliottide (an amyloid receptor agonist) at its optimal pH. Semaglutide is most stable at pH 7.4 and has previously required formulation in neutral to slightly alkaline solutions at pH 7 to 8 to ensure its solubility in aqueous solutions. Cagliottide is most stable at pH 4.0 and has previously required formulation in acidic solutions, as increasing the pH would accelerate its chemical degradation. The different physicochemical properties of cagliottide and semaglutide preclude a simple mixture of these two peptides. This also applies to other combinations of GLP-1 receptor agonists and amyloid receptor agonists where the two have incompatible optimal pH ranges.

[0007] There is still a need in the art for a simple means of co-administering GLP-1 receptor agonists (such as semaglutide) and amyloid receptor agonists (such as caglinide). [Summary of the Invention]

[0008] This document discloses a method for co-regulating an amyloid receptor agonist and a GLP-1 receptor agonist. This document discloses a liquid pharmaceutical formulation comprising an amyloid receptor agonist, a GLP-1 receptor agonist, and a cyclodextrin comprising a hydrophilic chemical substitution (such as hydroxypropyl substitution). The cyclodextrin may be an α-type hydroxypropyl-substituted cyclodextrin comprising six ring-arranged glucose units. The cyclodextrin may be a β-type hydroxypropyl-substituted cyclodextrin comprising seven ring-arranged glucose units. The pharmaceutical formulation may also include a buffer solution (such as histidine), a tonic agent (such as sorbitol), and / or a surfactant (such as polysorbate 80); and has a pH of about 5.5 to 6.5. The pharmaceutical formulation disclosed herein can be administered by non-gastrointestinal injection, preferably subcutaneously.

[0009] The pharmaceutical formulations disclosed herein may be used to medically treat individuals who are overweight or obese with or without related comorbidities; who have or without related comorbidities, diabetes; have cardiovascular disease; non-alcoholic steatosis (NASH); and who have cognitive impairment, such as those caused by Alzheimer's disease. The pharmaceutical formulations disclosed herein can improve convenience, treatment compliance, and ultimately improve clinical outcomes in patients.

Implementation Method

[0011] The present invention is a liquid pharmaceutical formulation comprising an amyloid receptor agonist, a GLP-1 receptor agonist, and a cyclodextrin comprising a hydroxypropyl substituted group.

[0012] The pharmaceutical formulation disclosed herein includes two active pharmaceutical ingredients, namely a GLP-1 receptor agonist and an amyloid receptor agonist.

[0013] This document discloses a method for co-regulating an amyloid receptor agonist and a GLP-1 receptor agonist, wherein the GLP-1 receptor agonist has an isoelectric point that excludes co-regulatory compounds within a pH range, thereby providing chemical stability to the amyloid receptor agonist. This document also discloses a method for co-regulating a GLP-1 receptor agonist (such as 3.5 to 6.0, or 4.0 to 6.0) having an isoelectric point (pI) below 6.0 with an amyloid receptor agonist.

[0014] The optimal pH for amyloid receptor agonists is the pH at which they are most chemically and physically stable. The optimal pH for GLP-1 receptor agonists is the pH at which they are most chemically and physically stable. The physical stability of GLP-1 receptor agonists may reflect their isoelectric point, which may be consistent with the pH at which the worst physical stability is expected.

[0015] This document discloses a method for preparing amyloid receptor agonists and GLP-1 receptor agonists, wherein the optimal pH values ​​differ by at least about two pH units, such as 2 to 5 pH units, such as 2 to 4 pH units, such as 3 to 5 pH units.

[0016] The GLP-1 receptor agonist may be semaglutide. The amyloid receptor agonist may be caglinide or a bioactive metabolite of caglinide. The formulations disclosed herein improve the chemical and physical stability of those active pharmaceutical ingredients; preserve the bioavailability and pharmacokinetic profile of the active pharmaceutical ingredients in terms of exposure; and exhibit acceptable local tolerability upon subcutaneous injection.

[0017] The terms “medical formulation”, “co-formulation” and “pharmaceutical product” may be used interchangeably in this document to refer to liquid pharmaceutical formulations including GLP-1 receptor agonists and amyloid receptor agonists.

[0018] The pharmaceutical formulations disclosed herein are suitable for non-gastrointestinal injection, preferably subcutaneous injection. Amylin

[0019] The term "amyloid" in this document refers to polypeptides having the same amino acid sequence as endogenous amyloids, such as human amyloids. Amyloid receptor

[0020] Amyloid compounds can target the calcitonin receptor (CTR) and / or the amyloid receptor (AMYR). The latter consists of a two-component heteroplast: the calcitonin receptor (CTR) and one of the three receptor-modifying proteins (RAMP1–3) that lead to the three possible complexes AMYR1–3. Amyloid receptor agonists

[0021] The pharmaceutical formulations disclosed in this invention include amyloid receptor agonists. An "amyloid receptor agonist" can be defined as a chemical entity capable of binding to and activating an amyloid receptor. In the context of this invention, an "amyloid receptor agonist" can at least bind to and activate amyloid receptor 3 (AMYR3). Amyloid receptor agonists can also agonize calcitonin receptors and AMYR1-2.

[0022] Examples of endogenous amyloid receptor agonists are human amyloid and human calcitonin. Examples of exogenous amyloid receptor agonists are caglionein and pramlinin.

[0023] The amyloid receptor agonist in the pharmaceutical formulation disclosed herein may be caglinide or a bioactive metabolite of caglinide.

[0024] The bioactive metabolite of caglinide may have aspartate (Asp) at position 21 or 22. The bioactive metabolite of caglinide may have isoaspartate (iso-Asp) at position 21 or 22. Caglinide

[0025] Caglitinide is an amyloid receptor agonist, also known as AM833. It is the compound of Example 53 in WO2012 / 168432: N-α-[(S)-4-carboxy-4-(19-carboxy-nonadecanyl)butyryl]-[Glu14,Arg17,Pro37]-pramlinide. Caglitinide can be prepared as described on pages 153 to 155 of WO2012 / 168432.

[0026] Caglitinide may be in salt form, preferably in a pharmaceutically acceptable form.

[0027] The concentration of caglinide in the pharmaceutical formulations disclosed herein can range from about 0.25 mg / ml to about 22 mg / ml.

[0028] The pharmaceutical formulations disclosed herein may include caglitazone at concentrations of about 0.33 to 18 mg / ml; such as 0.25 to 0.5 mg / ml, such as about 0.33 mg / ml; such as 0.5 to 1.0 mg / ml, such as about 0.67 mg / ml; such as 1.0 to 1.5 mg / ml, such as about 1.33 mg / ml; such as 1.5 to 2.0 mg / ml, such as about 1.5 mg / ml; such as 2.0 to 2.5 mg / ml; such as 2.5 to 3.0 mg / ml; such as 3.0 to 3.5 mg / ml; such as about 3.2 mg / ml; such as 3.5 to 4.0 mg / ml; such as 4.0 to 5.0 mg / ml; such as 5.0 to 6.0 mg / ml; such as 6.0 to 7.0 mg / ml, such as 7.0 to 8.0 mg / ml, such as 8.0 to 9.0 mg / ml, such as 9.0 to 10.0 mg / ml. mg / ml, such as about 9.6 mg / ml; such as 10 to 11 mg / ml, such as 11.0 to 12.0 mg / ml, such as 11 to 13 mg / ml; such as 13 to 22 mg / ml, such as about 18 mg / ml; such as about 20 to 22 mg / ml.

[0029] The pharmaceutical formulations disclosed herein may include caglinide at a concentration not exceeding 22 mg / ml. The pharmaceutical formulations disclosed herein may include caglinide at a concentration not exceeding 12 mg / ml. GLP-1

[0030] The term "GLP-1" or "natural GLP-1" herein refers to human glucagon-like peptide-1 (GLP-1(7-37)). GLP-1 receptor agonist

[0031] The pharmaceutical formulations disclosed herein include GLP-1 receptor agonists. A "GLP-1 receptor agonist" can be defined as a ligand that binds to the GLP-1 receptor and produces a biological response similar to that of the endogenous ligand glucagon peptide 1 (GLP-1(7-37)). All GLP-1 receptor agonists can be defined as GLP-1 receptor agonists that elicit a biological response of the same magnitude as that of GLP-1(7-37).

[0032] An example of an exogenous GLP-1 receptor agonist is semaglutide. An example of an exogenous GLP-1 receptor agonist is tesipatide. semaglutide

[0033] Semaglutide is a GLP-1 receptor agonist, also known as N6,26-{18-[N-(17-carboxyheptadecyl)-L-γ-glutamyl]-10-sideoxy-3,6,12,15-tetraoxa-9,18-diazaoctadecyl}-[8-(2-amino-2-propionic acid),34-L-arginine]human glucagon peptide 1 (7-37). Simaglutide can be prepared as described in Example 4 of WO2006 / 097537.

[0034] Semaglutide may exist in the composition in a fully or partially ionized form; for example, one or more carboxylic acid groups (-COOH) may be deprotonated to carboxyl groups (-COO-) and / or one or more amino groups (-NH2) may be protonated to -NH3+ groups.

[0035] Simaglutide may be in salt form, preferably a pharmaceutically acceptable salt.

[0036] The concentration of semaglutide in the pharmaceutical formulations disclosed herein can range from about 0.25 mg / ml to about 22 mg / ml.

[0037] Pharmaceutical formulations may include semaglutide at concentrations of about 0.33 to 18 mg / ml; such as 0.25 to 0.5 mg / ml, such as about 0.33 mg / ml; such as 0.5 to 1.0 mg / ml, such as about 0.67 mg / ml; such as 1.0 to 1.5 mg / ml, such as about 1.33 mg / ml; such as 1.5 to 2.0 mg / ml, such as about 1.5 mg / ml; such as 2.0 to 2.5 mg / ml; such as about 2.2 mg / ml; such as 2.5 to 3.0 mg / ml; such as 3.0 to 3.5 mg / ml; such as about 3.2 mg / ml; such as 3.5 to 4.0 mg / ml; such as 4.0 to 5.0 mg / ml; such as about 4.8 mg / ml; such as 5.0 to 6.0 mg / ml; such as 6.0 to 7.0 mg / ml, such as about 6.4 mg / ml; such as 7.0 to 8.0 mg / ml. mg / ml, such as about 8.0 mg / ml; such as 8.0 to 9.0 mg / ml, such as 9.0 to 10.0 mg / ml, such as about 9.6 mg / ml; such as 10 to 11 mg / ml, such as about 10.7 mg / ml; such as 11.0 to 12.0 mg / ml, such as 11 to 13 mg / ml; such as about 12.8 mg / ml; such as 13 to 22 mg / ml, such as about 16 mg / ml; such as about 18 mg / ml; such as about 20 to 22 mg / ml.

[0038] The pharmaceutical formulations disclosed herein may include semaglutide at a concentration not exceeding 22 mg / ml. The pharmaceutical formulations disclosed herein may include semaglutide at a concentration not exceeding 12 mg / ml. Isoelectric point

[0039] The isoelectric point (pI) of a molecule is the pH value at which the molecule carries no net charge. The pI of a peptide can be theoretically calculated from the pK values ​​of its amino acids and terminal amine and carboxyl groups, and can be used to predict the solubility of the peptide at a given pH.

[0040] The theoretically calculated isoelectric point of GLP-1 receptor agonists may be in the range of 3.5 to 6.0, such as 4.0 to 6.0, such as 3.8 to 4.9, such as 4.0 to 4.5. Simaglutide has a theoretically calculated isoelectric point of approximately 4.37.

[0041] Amyloid receptor agonists theoretically have isoelectric points (pI) ranging from 8 to 12, such as 8 to 9. Caglioside has a theoretically calculated isoelectric point of approximately 8.56. Cyclodextrin

[0042] The pharmaceutical formulations disclosed herein include cyclodextrins containing hydroxypropyl-substituted compounds. Pharmaceutical formulations may include approximately 10% to 25% w / v of hydroxypropyl-substituted cyclodextrins. Pharmaceutical formulations may include more than 10% w / v of hydroxypropyl-substituted cyclodextrins. Pharmaceutical formulations may include less than 22% w / v of hydroxypropyl-substituted cyclodextrins. Pharmaceutical formulations may include approximately 10% to 20% w / v, approximately 15% to 25% w / v, approximately 12% to 18% w / v, approximately 10% to 17.5% w / v, approximately 11.25% to 15%, such as approximately 15% w / v of hydroxypropyl-substituted cyclodextrins.

[0043] Cyclodextrins are oligosaccharide starch derivatives composed of 6, 7, or 8 α-(1,4)-glucanose (glucose) units arranged in a cyclic pattern, and are represented as α, β, or γ types, respectively. Cyclodextrins have a wide range of applications as pharmaceutical excipients [P. Breen & SS Jambhekar, Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, and complexation efficiency, Drug Discovery Today, Vol. 21, February 2, 2016]. The European Medicines Agency (EMA) has described guidelines for their use as pharmaceutical excipients [Background review for cyclodextrins used as excipients, 2014, EMA / CHMP / 333892 / 2013, Committee for Human Medicinal Products (CHMP)] and [Cyclodextrins used as excipients, 2017, EMA / CHMP / 333892 / 2013, Committee for Human Medicinal Products (CHMP)]. Cyclodextrins without hydrophilic substitutions have poor solubility and are rarely used in non-gastrointestinal pharmaceutical products.

[0044] To improve the solubility of cyclodextrins, the hydroxyl groups of the glucose units of cyclodextrins can be hydrophilically substituted with varying numbers of, for example, hydroxypropyl groups, resulting in different degrees of substitution. This can be described as the average number of hydroxypropyl groups per cyclodextrin molecule (abbreviated as DS) or as the molar degree of substitution, which corresponds to the average number of hydroxypropyl groups per glucose unit present in the relevant cyclodextrin (abbreviated as MS). The hydroxypropyl value of each cyclodextrin can be obtained by multiplying the molar degree of substitution by the number of glucose units included in the relevant cyclodextrin. Differences in the degree of substitution can lead to changes in physicochemical properties, such as surface activity and complexing ability. The hydroxyl groups can also be chemically substituted with sulfobutyl ether groups. Such major hydrophilic modifications have yielded cyclodextrin derivatives highly suitable for non-gastrointestinal administration [Cyclodextrins used as excipients, 2017, EMA / CHMP / 333892 / 2013, Committee for Human Medicinal Products (CHMP)]. Cyclodextrins containing hydroxypropyl-substituted compounds are typically abbreviated as HP-CD, while those containing sulfobutyl ether-substituted compounds are abbreviated as SBE-CD.

[0045] The hydrophilically substituted cyclodextrins employ a cone-shaped structure with a hydrophobic inner cavity and a hydrophilic outer surface formed by a number of hydrophilic substituents capable of forming hydrogen bonds with neighboring water molecules, thereby improving water solubility [T. Loftsson, Cyclodextrins in Parenteral Formulations, Journal of Pharmaceutical Sciences, 2020, 1-11].

[0046] The hydrophobic microenvironment within the cavities of these cone-shaped structures allows them to form drug-cyclodextrin complexes primarily through hydrophobic interactions [T. Loftsson, Cyclodextrins in Parenteral Formulations, Journal of Pharmaceutical Sciences, 2020, 1-11]. When cyclodextrins form complexes with drug molecules possessing one or more hydrophobic regions, these regions, as well as the hydrophobic regions of the cyclodextrin, are masked by water, thereby increasing the solubility of the complex compared to the solubility of the individual components. Furthermore, once cyclodextrins form complexes with peptide molecules, they impair the intermolecular interactions that normally lead to aggregation [T. Loftsson, Cyclodextrins in Parenteral Formulations, Journal of Pharmaceutical Sciences, 2020, 1-11].

[0047] Surprisingly, compared with the same type of cyclodextrin with sulfobutyl ether substitution, cyclodextrin with hydroxypropyl substitution was found to have an advantage in stabilizing co-regulations of caglione and semaglutide.

[0048] The cyclodextrin system can be hydroxypropyl-substituted α-type, comprising six cyclically arranged glucose units. The hydroxypropyl-substituted α-type cyclodextrin system is abbreviated as HP-A-CD. Hydroxypropyl-α-cyclodextrin (CAS: 128446-33-3 / 99241-24-4) is commercially available and has an average molar substitution (MS) of 0.8 and a molar substitution range of 0.5 to 0.9.

[0049] The pharmaceutical formulations disclosed herein may include cyclodextrin, which is a β-type hydroxypropyl-substituted compound comprising seven cyclically arranged glucose units.

[0050] The abbreviation for β-type hydroxypropyl-substituted cyclodextrins is HP-B-CD.

[0051] Hydroxypropyl-β-cyclodextrin is a well-known pharmaceutical excipient, commonly used in small molecule pharmaceutical formulations, primarily to increase solubility and bioavailability [T. Loftsson, Cyclodextrins in Parenteral Formulations, Journal of Pharmaceutical Sciences, 2020, 1-11]. To date, the use of cyclodextrins and substituted cyclodextrin derivatives in protein and peptide-based pharmaceutical formulations has been limited.

[0052] According to the European and American Pharmacopoes [USP 38 NF 33, Pharm Eur 8, estimated according to the method described in USP<761> / Pharm. Eur. 2.2.33], the degree of hydroxypropyl substitution (DS) of commercially available hydroxypropyl-β-cyclodextrins as pharmaceutical excipients ranges from 2.8 to 10.5, which is equivalent to 0.4 to 1.5 hydroxypropyl groups (MS) per glucose unit. Commercially available cyclodextrins (such as hydroxypropyl-β-cyclodextrin) are generally described by the average molar substitution (MS) of their molar substitution range.

[0053] Hydroxypropyl-β-cyclodextrin (CAS: 128446-35-5 / 94035-02-6) is commercially available and can be used as an excipient, having the following average molar substitutions (MS): MS: 0.62, molar substitution range from 0.58 to 0.68; MS: 0.67, molar substitution range from (0.6 to 0.9); MS: 0.68, molar substitution range from (0.58 to 0.72); MS: 0.84, molar substitution range from (0.8 to 1.0); MS: 0.92, molar substitution range from (0.81 to 0.99); MS: 1.08, molar substitution range from (0.86 to 1.14); where each value describes the number of hydroxypropyl groups per glucose unit.

[0054] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having at least about 0.4 hydroxypropyl groups in each glucose unit. The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having at most about 1.0 hydroxypropyl groups in each glucose unit.

[0055] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having a substitution range of 0.58 to 1.0 hydroxypropyl groups per glucose unit. The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having an average molar substitution (MS) range of about 0.62 to 0.92 hydroxypropyl groups per glucose unit.

[0056] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having an average molar substitution (MS) of about 0.62 to 0.84 hydroxypropyl groups per glucose unit.

[0057] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having about 0.4 to 0.75 hydroxypropyl groups in each glucose unit.

[0058] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having approximately 0.75 hydroxypropyl groups in each glucose unit.

[0059] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having an average molar substitution (MS) of about 0.62 per glucose unit. The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having about 0.58 to 0.68 hydroxypropyl groups per glucose unit.

[0060] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having an average molar substitution (MS) of about 0.68 per glucose unit. The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having about 0.58 to 0.72 hydroxypropyl groups per glucose unit.

[0061] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having an average molar substitution (MS) of about 0.67. The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having about 0.6 to 0.9 hydroxypropyl groups per glucose unit.

[0062] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having an average molar substitution (MS) of about 0.84. The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having about 0.8 to 1.0 hydroxypropyl groups per glucose unit.

[0063] The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having an average molar substitution (MS) of about 0.92. The pharmaceutical formulations disclosed herein may include hydroxypropyl-β-cyclodextrin having about 0.81 to 0.99 hydroxypropyl groups per glucose unit.

[0064] The pharmaceutical formulations disclosed herein may include 10% to 25% w / v (such as about 10% to 20% w / v, such as about 15% to 25% w / v, such as about 12% to 18% w / v, such as about 10% to 17.5% w / v, such as about 11.25% to 15%, such as about 15% w / v) of hydroxypropyl-β-cyclodextrin having at least about 0.4 hydroxypropyl units per glucose unit and at most about 1.0 hydroxypropyl units per glucose unit; such as an average of 0.62 to 0.92 hydroxypropyl units per glucose unit; such as about 0.75 hydroxypropyl units per glucose unit; such as 0.62 to 0.84 hydroxypropyl units per glucose unit; such as about 0.4 to 0.75 hydroxypropyl units per glucose unit; such as an average of 0.62 hydroxypropyl units per glucose unit; such as about 0.58 to 0.68 hydroxypropyl units per glucose unit. Other excipients

[0065] Pharmaceutical compoundings may include buffer solutions. The use of buffer solutions in pharmaceutical compoundings is well known to those skilled in the art. For convenience, see Remington: The Science and Practice of Pharmacy, 20th edition, 2000.

[0066] pH can be measured at "room temperature", typically defined as 15 to 25°C or 15 to 20°C. pH values ​​are preferably measured at about 20°C.

[0067] The pharmaceutical formulations disclosed herein may include buffer solutions having a pKa close to the desired pH of the solution. Pharmaceutical formulations may include buffer solutions having at least one of a pKa of about 5.0 to 7.0. Pharmaceutical formulations may include buffer solutions having a pKa of about 5.0 to 7.0. Pharmaceutical formulations may include buffer solutions selected from histidine, citrate, and / or phosphate. The buffer solution may be citrate with a concentration of 3-30 mM. The buffer solution may be histidine with a concentration of 3-30 mM. The buffer solution may be phosphate with a concentration of 3-30 mM.

[0068] Pharmaceutical formulations may further include one or more reagents for adjusting pH, such as NaOH and / or HCl.

[0069] The required pH for pharmaceutical preparations may be about 5.5 to 6.5. The pH is preferably 5.6 to 6.0. The pH value may be about 5.6, such as about 5.7, such as about pH 5.8, such as about 5.9, such as about 6.0.

[0070] Pharmaceutical formulations may include tension agents. The use of tension agents in pharmaceutical formulations is well known to those skilled in the art. For convenience, see Remington: The Science and Practice of Pharmacy, 20th edition, 2000.

[0071] The purpose of a tension agent is to protect living tissue when the formulation is injected into the body. The tension agent may be selected from the group consisting of mannitol, sorbitol, or trehalose, or combinations thereof. In some embodiments, the tension agent is mannitol. In some embodiments, the tension agent is sorbitol. In some embodiments, the tension agent is trehalose.

[0072] The concentration of the tensioning agent makes the formulation is isotonic. The tensioning agent is mannitol, which can be present at a concentration of 16.5 to 37.5 mg / ml, such as about 20 mg / ml. The tensioning agent is sorbitol, which can be present at a concentration of about 10 to 40 mg / ml, such as about 16.5 to 37.5 mg / ml; such as about 10 to 30 mg / ml; such as about 16 to 28 mg / ml; such as about 16.5 to 25 mg / ml; such as about 16 to 26 mg / ml; such as about 16 to 24 mg / ml; such as about 26 mg / ml; such as about 24 mg / ml; such as about 22 mg / ml; such as about 20 mg / ml; such as about 18 mg / ml; such as about 16 mg / ml; such as about 12 mg / ml. The tensioning agent is trehalose, which can be present at a concentration of 33 to 75 mg / ml, such as about 38 mg / ml.

[0073] Pharmaceutical formulations may include surfactants. Surfactants may also include those that increase the physical stability and robustness of the formulation during preparation, storage, and use as a pharmaceutical product; for example, those that preserve the stability of the formulation when exposed to air within the container. The use of surfactants in pharmaceutical compositions is well known to those skilled in the art. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 20th edition, 2000.

[0074] The surfactant may be selected from the group consisting of: polysorbate 20 and / or polysorbate 80. The surfactant may be polysorbate 20. The surfactant may be polysorbate 80.

[0075] Pharmaceutical formulations may include polysorbate 20 at a concentration of 0.01 mg / ml or higher and up to 2.0 mg / ml, such as polysorbate 20 at a concentration of up to 1.5 mg / ml, such as polysorbate 20 at a concentration of about 0.01 to 1.0 mg / ml, such as polysorbate 20 at a concentration of about 0.05 mg / ml.

[0076] Pharmaceutical formulations may include polysorbate 80 at a concentration of 0.01 mg / ml or higher and up to 2.0 mg / ml, such as polysorbate 80 at a concentration of up to 1.5 mg / ml, such as polysorbate 80 at a concentration of about 0.01 to 1.0 mg / ml, such as polysorbate 80 at a concentration of about 0.05 mg / ml.

[0077] Pharmaceutical formulations include water for injection (WFI). Pharmaceutical formulations may include more than 75% w / w water, such as 80% w / w water, such as about 85% w / w water, such as up to 90% w / w water.

[0078] The pharmaceutical formulations disclosed herein may exclude preservatives. Medical Use

[0079] The pharmaceutical formulations disclosed herein may be used for medical purposes.

[0080] The pharmaceutical preparations disclosed herein can be administered via non-gastrointestinal injection. The pharmaceutical preparations disclosed herein can be administered via subcutaneous injection.

[0081] As used herein, the term "treatment" means medical treatment given to any human or other vertebrate individual in need. The individual should undergo a physical examination by a licensed physician or veterinarian who has given a preliminary or definitive diagnosis indicating that the specific treatment will be beneficial to the health of the human or other vertebrate. The timing and purpose of the treatment may vary depending on the individual's health condition. Therefore, the treatment may be preventative (preventable), soothing, symptomatic, and / or curative.

[0082] In some embodiments, the pharmaceutical preparation system is administered to a human individual.

[0083] The pharmaceutical 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 (adult-onset diabetes in adolescents), gestational diabetes, and / or reduction of HbA1c; (ii) delaying or preventing the progression of diabetes, such as the progression of type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulin-dependent type 2 diabetes, and / or delaying the progression of insulin-independent type 2 diabetes to insulin-dependent type 2 diabetes; (iii) prevention and / or treatment of eating disorders, such as obesity, for example by reducing food intake, reducing weight, suppressing appetite, inducing satiety; treatment and / or prevention of bulimia, impulsive eating, bulimia nervosa, and / or obesity induced by antipsychotic drugs or steroids; reducing gastrointestinal motility; and / or delaying gastric emptying; (iv) Prevention and / or treatment of cardiovascular diseases, such as delaying or reducing the development of major adverse cardiovascular events (MACEs) selected from the following: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, vascular remodeling, hospitalization for unstable angina, and hospitalization for heart failure; (v) Prevention and / or treatment of non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic lipohepatitis (NASH); (vi) Prevention and / or treatment of cognitive impairments, such as Alzheimer's disease.

[0084] In some embodiments, the indication is (i). In some embodiments, the indication is (ii). In a further specific aspect, the indication is (iii). In a further specific aspect, the indication is (iv). In a further specific aspect, the indication is (v). In a further specific aspect, the indication is (vi). In some embodiments, the indication is type 2 diabetes and / or obesity.

[0085] Generally, all individuals suffering from obesity are also considered overweight. This document discloses a method for treating or preventing obesity. This document also discloses the use of the formulations disclosed herein for treating or preventing obesity. In some embodiments, the obese individual is a human being, such as an adult or a child (including infants, children, and adolescents).

[0086] Body Mass Index (BMI) is a measurement of body fat based on height and weight. The formula is BMI = weight (kg) / height (m²). An obese human individual may have a BMI of 30 kg / m² or higher; such an individual may also be referred to as obese. In some embodiments, the obese human individual may have a BMI ≥35 or a BMI range ≥30 to <40. In some embodiments, obesity is severe obesity or morbid obesity, in which the human individual may have a BMI ≥40.

[0087] This document discloses a method for treating or preventing overweight in the presence of at least one weight-related comorbidity. This document also discloses the optional use of the disclosed formulation for treating or preventing overweight in the presence of at least one weight-related comorbidity.

[0088] In some embodiments, the overweight individual is a human being, such as an adult or a child (including infants, children, and adolescents). In some embodiments, the overweight human individual may have a BMI of 25 kg / m² or higher, such as 27 kg / m² or higher. In some embodiments, the overweight human individual has a BMI range of 25 to <30 or 27 to <30.

[0089] An elevated BMI increases the risk of developing any of a number of diseases or comorbidities. Weight-related comorbidities may be one of the diseases mentioned above, or a combination thereof. In some embodiments, weight-related comorbidities are selected from the group consisting of: hypertension, diabetes (such as type 2 diabetes), dyslipidemia, high cholesterol, and obstructive sleep apnea.

[0090] This document discloses a method for reducing weight. Humans undergoing weight loss may have a BMI of 25 kg / m² or higher, such as a BMI of 27 kg / m² or higher (overweight) or a BMI of 30 kg / m² or higher (obese). In some embodiments, humans undergoing weight loss may have a BMI of 35 kg / m² or higher or a BMI of 40 kg / m² or higher. The term "weight loss" may include treating or preventing obesity and / or being overweight.

[0091] In some embodiments, administration of the semaglutide and caglinide pharmaceutical formulation disclosed herein may be used as an adjunct to a calorie-reducing diet and an increase in physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg / m² or higher (obese) or 27 kg / m² or higher (overweight) in the presence of at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, jaundice, or dyslipidemia).

[0092] In some embodiments, administration of the semaglutide and caglinide pharmaceutical formulation disclosed herein may result in >15% weight loss within 26 weeks after the start of treatment, such as >20% weight loss, such as >25% weight loss, such as >30% weight loss, such as about 15% to 40% weight loss, such as about 20% to 35% weight loss, such as about 25% to 30% weight loss.

[0093] In some embodiments, administration of the semaglutide and caglinide pharmaceutical formulation disclosed herein may result in >15% weight loss within 26 weeks after the start of treatment, such as >20% weight loss, such as >25% weight loss, such as >30% weight loss, such as about 15% to 40% weight loss, such as about 20% to 35% weight loss, such as about 25% to 30% weight loss.

[0094] In some embodiments, administration of the semaglutide and cagliolitin pharmaceutical formulation disclosed herein resulted in a higher reduction in HbA1c, in %-points, compared to treatment with semaglutide alone or cagliolitin alone. Dosage

[0095] The pharmaceutical preparations of the present invention can be administered in a single dose at predetermined time intervals.

[0096] The single-dose pharmaceutical formulations disclosed herein may contain any of the following doses of an amyloid receptor agonist, such as caglitinide, and a GLP-1 receptor agonist, such as semaglutide.

[0097] Effective amounts of amyloid receptor agonists (such as caglinide) and GLP-1 receptor agonists (such as semaglutide) can be administered to individuals in need.

[0098] In some embodiments, the dosage 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).

[0099] In some embodiments, the dose is administered to an individual suffering from any or more of the above-listed diseases or comorbidities. In some preferred embodiments, the dose is administered to an individual suffering from obesity (BMI ≥ 30 kg / m²). In some preferred embodiments, the dose is administered to an overweight individual (BMI ≥ 27 kg / m² to < 30 kg / m²) who also suffers from at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, or dyslipidemia).

[0100] In some embodiments, weekly treatment resulted in statistically significant, dose-dependent weight loss.

[0101] In some preferred embodiments, the dose is administered as an adjunct to diet and physical activity to improve glycemic control in adults with type 2 diabetes.

[0102] After treatment begins, it may be beneficial to administer escalating doses of amyloid receptor agonists (such as caglinide) and GLP-1 receptor agonists (such as semaglutide) to individuals in need. Once individuals have adapted to this treatment, it may be beneficial to administer maintenance doses of amyloid receptor agonists (such as caglinide) and GLP-1 receptor agonists (such as semaglutide) to individuals in need.

[0103] In some embodiments, treatment is performed once a week, with a dose escalation period of 16 weeks.

[0104] In some embodiments, treatment is performed once a week, with dose escalation occurring approximately once a week.

[0105] In some embodiments, treatment is performed once a week, with dose escalation occurring approximately every other week.

[0106] In some embodiments, treatment is performed once a week, with dose escalation occurring approximately every three weeks.

[0107] In some embodiments, treatment is performed once a week, with dose escalation occurring approximately every four weeks.

[0108] The dose of the amyloid receptor agonist administered may be about 0.25 to 16 mg, such as about 0.25 to 9.0 mg, such as about 0.25 to 4.5 mg, such as about 0.25 to 2.4 mg.

[0109] The dose of caglitinide administered may be about 0.25-16 mg, such as about 0.25 to 9.0 mg, such as about 0.25 to 4.5 mg, such as about 0.25 to 2.4 mg.

[0110] In some embodiments, the dose of caglione peptide administered is about 0.25 mg.

[0111] In some embodiments, the dose of caglione peptide administered is about 0.5 mg.

[0112] In some embodiments, the dose of caglione peptide administered is about 1.0 mg.

[0113] In some embodiments, the dose of caglione peptide administered is about 1.5 mg.

[0114] In some embodiments, the dose of caglione peptide administered is about 1.7 mg.

[0115] In some embodiments, the dose of caglitazone administered is about 2.4 mg.

[0116] In some embodiments, the dose of caglitazone administered is about 3.4 mg.

[0117] In some embodiments, the dose of caglitazone administered is about 3.6 mg.

[0118] In some embodiments, the dose of caglitazone administered is about 4.5 mg.

[0119] In some embodiments, the dose of caglitazone administered is about 7.2 mg.

[0120] In some embodiments, the dose of caglione peptide administered is about 8.0 mg.

[0121] In some embodiments, the dose of caglione peptide administered is about 9.0 mg.

[0122] In some embodiments, the dose of caglione peptide administered is about 16.0 mg.

[0123] The dose of the GLP-1 receptor agonist administered may be about 0.25 to 16 mg, such as about 0.25 to 9.0 mg, such as about 0.25 to 4.5 mg, such as about 0.25 to 2.4 mg.

[0124] The dose of semaglutide administered may be about 0.25 to 16 mg, such as about 0.25 to 9.0 mg, such as about 0.25 to 4.5 mg, such as about 0.25 to 2.4 mg.

[0125] In some embodiments, the dose of semaglutide administered is about 0.25 mg.

[0126] In some embodiments, the dose of semaglutide administered is about 0.5 mg.

[0127] In some embodiments, the dose of semaglutide administered is about 1.0 mg.

[0128] In some embodiments, the dose of semaglutide administered is about 1.5 mg.

[0129] In some embodiments, the dose of semaglutide administered is about 1.7 mg.

[0130] In some embodiments, the dose of semaglutide administered is about 2.4 mg.

[0131] In some embodiments, the dose of semaglutide administered is about 3.6 mg.

[0132] In some embodiments, the dose of semaglutide administered is about 4.5 mg.

[0133] In some embodiments, the dose of semaglutide administered is about 4.8 mg.

[0134] In some embodiments, the dose of semaglutide administered is about 6.0 mg.

[0135] In some embodiments, the dose of semaglutide administered is approximately 6.9 mg.

[0136] In some embodiments, the dose of semaglutide administered is about 7.2 mg.

[0137] In some embodiments, the dose of semaglutide administered is about 8.0 mg.

[0138] In some embodiments, the dose of semaglutide administered is about 9.0 mg.

[0139] In some embodiments, the dose of semaglutide administered is about 12 mg.

[0140] In some embodiments, the dose of semaglutide administered is about 16.0 mg. In some embodiments, the dose of semaglutide administered is about 16.0 mg.

[0141] In some embodiments, the ratio of amyloid receptor agonist to GLP-1 receptor agonist is about 1:2. In some embodiments, the ratio of caglinide to semaglutide is about 1:2.

[0142] In some embodiments, the dose of caglinide is about 0.125 mg and the dose of semaglutide is about 0.25 mg.

[0143] In some embodiments, the dose of caglinide is about 0.25 mg and the dose of semaglutide is about 0.5 mg.

[0144] In some embodiments, the dose of caglinide is about 0.5 mg and the dose of semaglutide is about 1.0 mg.

[0145] In some embodiments, the dose of caglinide is about 0.75 mg and the dose of semaglutide is about 1.5 mg.

[0146] In some embodiments, the dose of caglinide is about 0.85 mg and the dose of semaglutide is about 1.7 mg.

[0147] In some embodiments, the dose of caglinide is about 1.2 mg and the dose of semaglutide is about 2.4 mg.

[0148] In some embodiments, the dose of caglinide is about 2.25 mg and the dose of semaglutide is about 4.5 mg.

[0149] In some embodiments, the dose of caglitinide administered is about 3.6 mg, and the dose of semaglutide is about 7.2 mg.

[0150] In some embodiments, the dose of caglinide is about 4.0 mg and the dose of semaglutide is about 8.0 mg.

[0151] In some embodiments, the dose of caglinide is about 7.2 mg and the dose of semaglutide is about 14.4 mg.

[0152] In some embodiments, the dose of caglinide is about 8.0 mg and the dose of semaglutide is about 16.0 mg.

[0153] In some embodiments, the maintenance dose of caglitinide is about 1.2 mg and the maintenance dose of semaglutide is about 2.4 mg.

[0154] In some embodiments, the maintenance dose of caglitinide is about 2.25 mg and the dose of semaglutide is about 4.5 mg.

[0155] In some embodiments, the maintenance dose of caglitinide is about 4.0 mg, and the maintenance dose of semaglutide is about 8.0 mg.

[0156] In some embodiments, the maintenance dose of caglitinide is about 8.0 mg, and the maintenance dose of semaglutide is about 16.0 mg.

[0157] In some embodiments, the ratio of amyloid receptor agonist to GLP-1 receptor agonist is approximately 1:1. In some embodiments, the ratio of caglinide to semaglutide is approximately 1:1.

[0158] In some embodiments, the dose of caglinide is about 0.25 mg, and the dose of semaglutide is about 0.25 mg.

[0159] In some embodiments, the dose of caglinide is about 0.5 mg, and the dose of semaglutide is about 0.5 mg.

[0160] In some embodiments, the dose of caglinide is about 1.0 mg and the dose of semaglutide is about 1.0 mg.

[0161] In some embodiments, the dose of caglinide is about 1.7 mg and the dose of semaglutide is about 1.7 mg.

[0162] In some embodiments, the dose of caglinide is about 2.4 mg, and the dose of semaglutide is about 2.4 mg.

[0163] In some embodiments, the maintenance dose of caglitinide is about 2.4 mg, and the maintenance dose of semaglutide is about 2.4 mg.

[0164] In some embodiments, the dose of caglinide is about 4.5 mg and the dose of semaglutide is about 4.5 mg.

[0165] In some embodiments, the dose of caglinide is about 8.0 mg and the dose of semaglutide is about 8.0 mg.

[0166] In some embodiments, the dose of caglinide is about 16.0 mg, and the dose of semaglutide is about 16.0 mg.

[0167] In some embodiments, the ratio of amyloid receptor agonist to GLP-1 receptor agonist is between 1:1 and 1:7.

[0168] In some embodiments, the dose of caglinide is about 2.4 mg, and the dose of semaglutide is from about 2.4 mg to 16.0 mg.

[0169] In some embodiments, the dose of caglinide is about 2.4 mg, and the dose of semaglutide is from about 3.6 mg to 16.0 mg.

[0170] In some embodiments, the dose of caglinide is about 2.4 mg, and the dose of semaglutide is from about 2.4 mg to 13.5 mg.

[0171] In some embodiments, the dose of caglinide is about 2.4 mg, and the dose of semaglutide is about 3.6 mg to 13.5 mg.

[0172] In some embodiments, the dose of caglinide is about 2.4 mg and the dose of semaglutide is about 3.6 mg.

[0173] In some embodiments, the dose of caglinide is about 2.4 mg and the dose of semaglutide is about 4.8 mg.

[0174] In some embodiments, the dose of caglinide is about 2.4 mg and the dose of semaglutide is about 6.0 mg.

[0175] In some embodiments, the dose of caglinide is about 2.4 mg and the dose of semaglutide is about 6.9 mg.

[0176] In some embodiments, the dose of caglinide is about 2.4 mg and the dose of semaglutide is about 7.2 mg.

[0177] In some embodiments, the dose of caglinide is about 2.4 mg and the dose of semaglutide is about 8.0 mg.

[0178] In some embodiments, the dose of caglinide is about 2.4 mg and the dose of semaglutide is about 12 mg.

[0179] In some embodiments, the dose of caglinide is about 3.4 mg and the dose of semaglutide is about 13.5 mg.

[0180] In some embodiments, caglinide and semaglutide are administered once weekly at an initial dose of 0.25 mg, then increased to subsequent dose levels of 0.5 mg, 1.0 mg, and 1.7 mg until a target / maintenance dose of 2.4 mg is reached once weekly.

[0181] In some embodiments, caglinide and semaglutide are administered once weekly at a dose of 0.25 mg, then increased every four weeks to subsequent dose levels of 0.5 mg, 1.0 mg, and 1.7 mg, until a target / maintenance dose of 2.4 mg once weekly is reached.

[0182] In some embodiments, caglinide and semaglutide are administered once weekly at a dose of 0.25 mg, then increased every four weeks to subsequent dose levels of 0.5 mg, 1.0 mg and 1.7 mg, until a target / maintenance dose of 2.4 mg once weekly is reached.

[0183] In some embodiments, 0.25 mg caglinide and 0.25 mg semaglutide are administered once weekly for four weeks (weeks 0 to 3), then every four weeks the dose is increased to the following levels: 0.5 mg caglinide and 0.5 mg semaglutide (weeks 4 to 7), 1.0 mg caglinide and 1.0 mg semaglutide (weeks 8 to 11), and 1.7 mg caglinide and 1.7 mg semaglutide (weeks 12 to 15), until the target / maintenance dose of 2.4 mg caglinide and 2.4 mg semaglutide once weekly (weeks 16 and thereafter) is reached.

[0184] In some embodiments, caglinide and semaglutide are administered once weekly at an initial dose of 0.25 mg, then increased to subsequent dose levels of 0.5 mg, 1.0 mg, 1.7 mg and 2.4 mg until a target / maintenance dose of 4.5 mg once weekly is reached.

[0185] In some embodiments, caglinide and semaglutide are administered once weekly at an initial dose of 0.25 mg, then increased to subsequent dose levels of 0.5 mg, 1.0 mg, 1.7 mg, 2.4 mg, 3.6 mg and 4.5 mg until a target / maintenance dose of 7.2 mg once weekly is reached.

[0186] In some embodiments, caglinide and semaglutide are administered once weekly at an initial dose of 0.25 mg, then increased to subsequent dose levels of 0.5 mg, 1.0 mg, and 1.7 mg, 2.4 mg, 3.6 mg, 4.5 mg, and 7.2 mg until a target / maintenance dose of 8.0 mg is reached once weekly.

[0187] In some embodiments, caglinide and semaglutide are administered once weekly at an initial dose of 0.25 mg, then increased to subsequent dose levels of 0.5 mg, 1.0 mg and 1.7 mg, 2.4 mg, 3.6 mg and 4.5 mg, 7.2 mg and 8.0 mg, until a target / maintenance dose of 16.0 mg is reached once weekly.

[0188] In this document, a specific value related to a number or range may be interpreted as a specific value or an approximate value (such as a specific value plus or minus 10%, 15% or 20% when the quantity is available by weight; such as a specific value plus or minus 0.4 when measuring pH).

[0189] The following is a non-limiting list of embodiments of the present invention. Example 1. A liquid pharmaceutical formulation comprising an amyloid receptor agonist, a GLP-1 receptor agonist, and a cyclodextrin comprising a hydroxypropyl-substituted compound. 2. The liquid pharmaceutical formulation of Example 1, wherein the GLP-1 receptor agonist has an isoelectric point incompatible with the optimal pH of the amyloid receptor agonist. 3. The liquid pharmaceutical formulation of any of the foregoing examples, wherein the optimal pH of the GLP-1 receptor agonist and the amyloid receptor agonist differs by at least about two pH units, such as 2 to 5 pH units, such as 2 to 4 pH units, such as 3 to 5 pH units. 4. The liquid pharmaceutical formulation of any of the foregoing examples, wherein the optimal pH of the amyloid receptor agonist is 3.5 to 4.5, such as about 4.0. 5. The pharmaceutical formulation of any of the foregoing examples, wherein the amyloid receptor agonist is caglionein. 6. A liquid pharmaceutical formulation according to any of the foregoing embodiments, wherein the GLP-1 receptor agonist has an isoelectric point of less than 5.0, such as 3.0 to 5.0, or such as 3.8 to 4.9. 7. A pharmaceutical formulation according to any of the foregoing embodiments, wherein the GLP-1 receptor agonist is semaglutide. 8. A pharmaceutical formulation according to any of the foregoing embodiments, wherein the cyclodextrin is an α-type comprising six cyclically arranged glucose units substituted with hydroxypropyl groups, or a β-type comprising seven cyclically arranged glucose units substituted with hydroxypropyl groups. 9. A pharmaceutical formulation according to any of the foregoing embodiments, wherein the cyclodextrin is an α-type comprising six cyclically arranged glucose units substituted with hydroxypropyl groups. 10. A pharmaceutical formulation according to any of the foregoing embodiments, wherein the cyclodextrin is a β-type comprising seven cyclically arranged glucose units substituted with hydroxypropyl groups. 11. A pharmaceutical formulation according to any of the foregoing embodiments, wherein each glucose unit of the hydroxypropyl-β-cyclodextrin comprises at most about 1.0 hydroxypropyl groups. 12. In any of the foregoing embodiments, each glucose unit of the hydroxypropyl-β-cyclodextrin comprises at most about 0.92 hydroxypropyl groups. 13. In any of the foregoing embodiments, each glucose unit of the hydroxypropyl-β-cyclodextrin comprises at most about 0.75 hydroxypropyl groups. 14. In any of the foregoing embodiments, each glucose unit of the hydroxypropyl-β-cyclodextrin comprises at most about 0.68 hydroxypropyl groups. 15. In any of the foregoing embodiments, each glucose unit of the hydroxypropyl-β-cyclodextrin comprises at least about 0.4 hydroxypropyl groups. 16. In any of the foregoing embodiments, each glucose unit of the hydroxypropyl-β-cyclodextrin comprises at least about 0.58 hydroxypropyl groups.17. A pharmaceutical formulation according to any of the foregoing embodiments, wherein each glucose unit of the hydroxypropyl-β-cyclodextrin comprises about 0.58 to 1.0 hydroxypropyl groups. 18. A pharmaceutical formulation according to Example 17, wherein each glucose unit of the hydroxypropyl-β-cyclodextrin comprises an average (MS) 0.62 to 0.92 hydroxypropyl groups. 19. A pharmaceutical formulation according to Example 17, wherein each glucose unit of the hydroxypropyl-β-cyclodextrin comprises an average (MS) about 0.62 to 0.84 hydroxypropyl groups. 20. A pharmaceutical formulation according to Example 17, wherein each glucose unit of the hydroxypropyl-β-cyclodextrin comprises an average (MS) about 0.62 hydroxypropyl groups. 21. A pharmaceutical formulation according to Example 17, wherein each glucose unit of the hydroxypropyl-β-cyclodextrin comprises about 0.4 to 0.75 hydroxypropyl groups, such as about 0.58 to 0.68 hydroxypropyl groups per glucose unit. 22. A pharmaceutical formulation according to any of the foregoing embodiments, comprising about 10% to 25% w / v cyclodextrin. 23. A pharmaceutical formulation according to any of the foregoing embodiments, comprising more than 10% cyclodextrin. 24. A pharmaceutical formulation according to any of the foregoing embodiments, comprising less than 22% w / v cyclodextrin. 25. A pharmaceutical formulation according to any of the foregoing embodiments, comprising less than 20% w / v cyclodextrin. 26. A pharmaceutical formulation according to any of the foregoing embodiments, comprising about 10% to 20% w / v of the cyclodextrin. 27. A pharmaceutical formulation according to any of the foregoing embodiments, comprising about 10% to 17.5% w / v cyclodextrin. 28. A pharmaceutical formulation according to any of the foregoing embodiments, comprising about 12% to 18% w / v cyclodextrin. 29. A pharmaceutical formulation according to any of the foregoing embodiments, comprising about 11.25% to 15% w / v HP-β-CD. 30. A pharmaceutical formulation according to any of the foregoing embodiments, comprising about 15% w / v cyclodextrin. 31. A pharmaceutical formulation according to any of the foregoing embodiments, comprising at least about 1 mg / ml of the GLP-1 receptor agonist. 32. A pharmaceutical formulation according to any of the foregoing embodiments, comprising up to about 22 mg / ml of the GLP-1 receptor agonist. 33. A pharmaceutical formulation according to any of the foregoing embodiments, comprising about 1 to 12 mg / ml of the GLP-1 receptor agonist. 34. A pharmaceutical formulation according to any of the foregoing embodiments, comprising at least about 1 mg / ml of the amyloid receptor agonist. 35. A pharmaceutical formulation according to any of the foregoing embodiments, comprising up to about 22 mg / ml of the amyloid receptor agonist. 36. A pharmaceutical formulation according to any of the foregoing embodiments, comprising about 1 to 12 mg / ml of an amyloid receptor agonist.37. A pharmaceutical formulation according to any of the foregoing embodiments, comprising 0.25 to 22 mg / ml of caglinide. 38. A pharmaceutical formulation according to any of the foregoing embodiments, comprising 0.25 to 22 mg / ml of semaglutide. 39. A pharmaceutical formulation according to any of the foregoing embodiments, comprising 0.25 to 22 mg / ml of caglinide and 0.25 to 22 mg / ml of semaglutide. 40. A pharmaceutical formulation according to any of the foregoing embodiments, comprising an effective amount of caglinide and semaglutide. 41. A pharmaceutical formulation according to any of the foregoing embodiments, further comprising a tension agent, wherein the tension agent is not sodium chloride. 42. A pharmaceutical formulation according to the foregoing embodiments, wherein the tension agent is mannitol, sorbitol, or trehalose, or a combination thereof. 43. A pharmaceutical formulation according to the foregoing embodiments, wherein the tension agent is mannitol. 44. A pharmaceutical formulation according to the foregoing embodiments, comprising mannitol at a concentration of about 16.5 to 37.5 mg / ml, such as about 20 mg / ml. 45. A pharmaceutical formulation according to Example 41, wherein the tonic is sorbitol. 46. A pharmaceutical formulation according to the foregoing embodiments, comprising sorbitol at a concentration of about 10 to 40 mg / ml (such as about 10 to 30 mg / ml, such as about 16 to 28 mg / ml, such as about 16.5 to 37.5 mg / ml, such as about 16.5 to 25 mg / ml, such as about 16 to 24 mg / ml; such as about 24 mg / ml, such as about 20 mg / ml, such as about 16 mg / ml, such as about 12 mg / ml). 47. A pharmaceutical formulation according to Example 41, wherein the tonic is trehalose. 48. The pharmaceutical formulation according to the foregoing embodiments includes trehalose at a concentration of about 33 to 75 mg / ml, such as about 33 to 45 mg / ml, such as about 38 mg / ml. 49. The pharmaceutical formulation according to any of the foregoing embodiments further includes a buffer having a pKa of about 5.0 to 7.0. 50. The pharmaceutical formulation according to any of the foregoing embodiments further includes a buffer selected from histidine, citrate, and / or phosphate. 51. The pharmaceutical formulation according to any of the foregoing embodiments includes a buffer of up to 30 mM. 52. The pharmaceutical formulation according to any of the foregoing embodiments includes about 3 to 30 mM of citrate. 53. The pharmaceutical formulation according to any of the foregoing embodiments includes about 3 to 30 mM of histidine, such as 3 to 15 mM of histidine, such as 3 to 10 mM of histidine, such as about 6 mM of histidine. 54. The pharmaceutical formulation according to any of the foregoing embodiments comprises about 3 to 30 mM of phosphate. 55. The pharmaceutical formulation according to any of the foregoing embodiments further comprises a surfactant.56. A pharmaceutical formulation according to the foregoing embodiments, wherein the surfactant is polysorbate 20 and / or polysorbate 80. 57. A pharmaceutical formulation according to the foregoing embodiments, comprising up to about 2.0 mg / ml of polysorbate 20 and / or polysorbate 80. 58. A pharmaceutical formulation according to the foregoing embodiments, comprising up to about 1.5 mg / ml of polysorbate 20 and / or polysorbate 80. 59. A pharmaceutical formulation according to the foregoing embodiments, wherein the surfactant is polysorbate 80. 60. A pharmaceutical formulation according to any of the foregoing embodiments, wherein the pH is about 5.5 to 6.5, preferably 5.6 to 6.0, such as about 5.7, such as about pH 5.8, such as about 5.9, such as about 6.0. 61. A pharmaceutical formulation according to any of the foregoing embodiments, comprising at least 75% w / w water, such as about 80% w / w water, such as about 85% w / w water, such as up to about 90% w / w water. 62. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: effective amounts of caglionein and semaglutide, hydroxypropyl β-cyclodextrin comprising at least about 0.4 hydroxypropyl groups per glucose unit and at most about 1.0 hydroxypropyl group per glucose unit, histidine, sorbitol, polysorbate 80, and about 75 to 90% w / w water; and having a pH of 5.6 to 6.0. 63. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: an effective amount of caglinide and semaglutide, hydroxypropyl β-cyclodextrin comprising up to about 0.58 to 1.0 hydroxypropyl units per glucose unit, histidine, sorbitol, polysorbate 80, and about 75 to 90% w / w water; and having a pH of 5.6 to 6.0. 64. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: an effective amount of caglinide and semaglutide, hydroxypropyl β-cyclodextrin comprising an average of 0.62 to 0.92 hydroxypropyl units per glucose unit, histidine, sorbitol, polysorbate 80, and about 75 to 90% w / w water; and having a pH of 5.6 to 6.0. 65. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: effective amounts of cagliolitin and semaglutide, hydroxypropyl β-cyclodextrin comprising an average of 0.62 to 0.84 hydroxypropyl groups per glucose unit, histidine and / or citrate, sorbitol, polysorbate 80, and about 75 to 90% w / w water; and having a pH of 5.6 to 6.0.66. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: effective amounts of cagliottide and semaglutide, hydroxypropyl β-cyclodextrin comprising an average of 0.62 to 0.68 hydroxypropyl groups per glucose unit, histidine and / or citrate, sorbitol, polysorbate 80, and about 75 to 90% w / w water; and having a pH of 5.6 to 6.0. 67. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: effective amounts of cagliottide and semaglutide, hydroxypropyl β-cyclodextrin comprising an average of 0.62 hydroxypropyl groups per glucose unit, histidine and / or citrate, sorbitol, polysorbate 80, and about 75 to 90% w / w water; and having a pH of 5.6 to 6.0. 68. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: an effective amount of caglitinide and semaglutide, hydroxypropyl β-cyclodextrin comprising up to about 0.75 hydroxypropyl groups per glucose unit, such as about 0.4 to 0.75 hydroxypropyl groups per glucose unit, histidine, sorbitol, polysorbate 80, and about 75 to 90% w / w water; and having a pH of 5.5 to 6.5. 69. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: an effective amount of caglitinide and semaglutide, hydroxypropyl β-cyclodextrin comprising up to about 0.75 hydroxypropyl groups per glucose unit, such as about 0.4 to 0.75 hydroxypropyl groups per glucose unit, histidine and / or citrate, sorbitol, polysorbate 20 and / or 80, and about 75 to 90% w / w water; and having a pH of 5.6 to 6.0. 70. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: - effective amounts of caglionein and semaglutide; - more than 10% w / v and less than 22% w / v, such as 10% to 20% w / v of hydroxypropyl-β-cyclodextrin (0.58 to 1.0 hydroxypropyl units per glucose unit); - about 3 to 30 mM of histidine; - about 10 to 40 mg / ml of sorbitol; - up to 2.0 mg / ml of polysorbate 20 and / or polysorbate 80; - a pH of 5.6-6.0, preferably pH 5.8; - water for injection.71. A pharmaceutical formulation according to any of the foregoing embodiments, comprising primarily the following: - effective amounts of caglionein and semaglutide; - more than 10% w / v and less than 22% w / v, such as 10% to 20% w / v of hydroxypropyl-β-cyclodextrin, comprising an average of 0.62 to 0.84 hydroxypropyl groups per glucose unit; - about 3 to 30 mM of histidine and / or citrate; - about 10 to 40 mg / ml of sorbitol; - up to 2.0 mg / ml of polysorbate 20 and / or polysorbate 80; - a pH of 5.6-6.0, preferably pH 5.8; - water for injection. 72. The pharmaceutical formulation according to any of the foregoing embodiments is primarily composed of: - 0.25 to 22 mg / ml caglionepeptide, - 0.25 to 22 mg / ml semaglutide, - more than 10% w / v and less than 22% w / v, such as 10% to 20% w / v hydroxypropyl-β-cyclodextrin (0.58 to 1.0 hydroxypropyl units per glucose unit), - about 6 mM histidine, - about 10 to 40 mg / ml sorbitol, - up to 2.0 mg / ml polysorbate 20 and / or 80, - pH 5.6-6.0, preferably pH 5.8, - water for injection. 73. The pharmaceutical formulation according to any of the foregoing embodiments is intended for use as a pharmaceutical product. 74. A pharmaceutical preparation according to any of the preceding Examples 1 to 72, for treating an individual with an initial body mass index (BMI) of 27 or higher (such as 30 or higher). 75. A pharmaceutical preparation according to any of the preceding Examples 1 to 72, for treating an individual with an initial body mass index (BMI) of 27 or higher and suffering from at least one weight-related comorbidity. 76. A pharmaceutical preparation according to any of the preceding Examples 1 to 72, used as an adjunct to a calorie-reducing diet and increased physical activity for chronic weight management in an adult individual with an initial body mass index (BMI) of 30 kg / m² or higher (obese) or 27 kg / m² or higher (overweight) in the presence of at least one weight-related comorbidity. 77. The use according to any of Examples 73 to 76, wherein the comorbidity is diabetes and / or cardiovascular disease and / or NASH. 78. A pharmaceutical preparation according to any one of Examples 1 to 72 above, intended for treating an individual with diabetes (such as type II diabetes). 79. A pharmaceutical preparation according to any one of Examples 1 to 72 above, intended as an adjunct to diet and exercise to improve glycemic control in an adult individual with type 2 diabetes. 80. A pharmaceutical preparation according to any one of Examples 1 to 72 above, intended for treating and / or preventing cardiovascular disease.81. A pharmaceutical preparation according to any one of Examples 1 to 72 above, for the treatment and / or prevention of NASH. 82. A pharmaceutical preparation according to any one of Examples 1 to 72 above, for the treatment and / or prevention of cognitive impairment, such as diseases caused by Alzheimer's disease. 83. A pharmaceutical preparation for any one of Examples 1 to 72 above, for any one of Examples 73 to 82 above, characterized in that the preparation is administered by non-gastrointestinal injection. 84. A pharmaceutical preparation for any one of Examples 1 to 72 above, for any one of Examples 73 to 82 above, characterized in that the preparation is administered by subcutaneous injection. 85. A pharmaceutical preparation for any one of Examples 1 to 72 above, for any one of Examples 73 to 84 above, characterized in that the preparation is administered approximately once a week. 86. A pharmaceutical formulation for use in any of Examples 1 to 72 of the preceding examples according to any of Examples 73 to 85, wherein the ratio of the dose of caglinide to the dose of semaglutide is approximately 1:1. 87. A pharmaceutical formulation for use in any of Examples 1 to 72 of the preceding examples according to any of Examples 73 to 85, wherein the ratio of the dose of caglinide to the dose of semaglutide is from 1:1 to 1:7. 88. A pharmaceutical formulation for use in any of Examples 1 to 72 of the preceding examples according to any of Examples 73 to 85, wherein the ratio of the dose of caglinide to the dose of semaglutide is approximately 1:2. Example 1: Effect of hydroxypropyl-β-cyclodextrin (HP-B-CD) on the chemical stability of caglinide.

[0190] This example demonstrates the effect of HP-B-CD on the chemical stability of caglinide in degradation products using caglinide purity and caglinide-related high molecular weight protein (HMWP) parameters. Caglinide is most stable at pH 4.0, and its chemical degradation rate typically accelerates with increasing pH. Unexpectedly, this example shows that when formulated with HP-B-CD, a stable caglinide formulation can be obtained at pH 6. Composition

[0191] The compositions of caglinide formulations 1, 2, and 3 are shown in Table 1. Table 1 Compositions of caglinide formulations 1, 2, and 3 Element Carglin peptide formulation 1 2 3 Carglinide drug substance (mg / ml) 18 18 18 HP-B-CD KLEPTOSE ® (Roquette) (% w / v) (Average MS: 0.92, MS range: 0.81-0.99) 1 0 0 25 Citrate, 1 H2O 2 (mM) 6.1 3.7 3.7 Disodium hydrogen phosphate, 2 H2O 2 (mM) 7.7 12.6 12.6 HCl qs qs qs NaOH qs qs qs Water for Injection (WFI) Prepare to a volume of 1 ml Prepare to a volume of 1 ml Prepare to a volume of 1 ml. pH 4.0 6.0 6.0 1MS: mol substitution, corresponding to hydroxypropyl 2 per glucose unit, is used in different formulations with different buffer concentrations to ensure buffering processes are performed at different pH levels.

[0192] The formulation was prepared by dissolving the excipient in water and the drug substance in the excipient solution. The pH of the solution was adjusted and water was added to reach the final desired volume before sterilization by filtration through a 0.22 µm sterile filter. After filtration, the formulation was filled into 1 ml pre-filled syringes. Method

[0193] The samples were stored at 37°C for up to 21 days and analyzed after 14 and 21 days to determine the purity of HMWP and caglinide.

[0194] The extent of covalently bound HMWP was quantified using size exclusion chromatography (SEC). Samples were analyzed using a WATERS HMWP column (7.8 x 300 mm) and eluted isocratically with an eluent consisting of 500 mM sodium chloride, 10 mM sodium dihydrogen phosphate monohydrate, 5 mM orthophosphate, and 50% (v / v) isopropanol. Chromatography was performed at 50°C with UV detection (215 nm) at a flow rate of 0.5 ml / min using an injection volume of 10 μl. HMWP was quantified as the area of ​​all components eluted before the main peak divided by the area of ​​the main peak x 100%.

[0195] The purity of caglinide was determined using reversed-phase high-performance liquid chromatography (RP-UHPLC). Samples were analyzed using a Kinetex C18, 1.7 μm, 100 Å column (2.1 x 150 mm), with gradient elution using eluent A consisting of 90% v / v 0.09 M phosphate solution, pH 3.6, and 10% v / v acetonitrile, and eluent B consisting of 60% v / v acetonitrile and 20% v / v isopropanol. Chromatography was performed at 60°C with UV detection (215 nm) using injection volumes ranging from 2 to 7.5 μl and flow rates of 0.25 ml / min. Purity was estimated as the area of ​​the main peak divided by the area of ​​all peaks x 100%. Table 2 Chemical purity (%) of caglinide with or without HP-B-CD at pH 4.0 and 6.0. Carglin peptide formulation pH HP-B-CD (MS: 0.92) 1 Relationship between HMWP content (%) and time (days) at 37°C Relationship between purity (%) of caglinide at 37°C and time (days) 0 14 twenty one 0 14 twenty one 1 4.0 0% w / v 0.0% 0.2% 0.2% 90.4% 88.2% 87.4% 2 6.0 0% w / v 0.1% 7.7% 9.8% 90.1% 74.0% 67.1% 3 6.0 25% w / v 0.1% 0.3% 0.5% 90.2% 79.9% 75.3% 1MS: Morphological substitutions, corresponding to a summary of hydroxypropyl groups per glucose unit.

[0196] Table 2 shows that when cagliottide was stored at 37°C and pH 4.0, very low HMWP formation was observed, with only a slight decrease in cagliottide purity. Conversely, at pH 6.0, the rate of HMWP formation and the rate of decrease in cagliottide purity accelerated. Unexpectedly, this rapid chemical degradation was counteracted by the addition of HP-B-CD to the formulation, allowing cagliottide to be formulated at pH 6. Example 2: Effect of HP-B-CD on the physical stability of semaglutide

[0197] This example demonstrates the effect of HP-B-CD on the physical stability of semaglutide, specifically its tendency to form peptide fibers. This effect is evident when semaglutide is formulated at a suboptimal pH. Composition

[0198] The compositions of semaglutide formulations 1, 2, and 3 are shown in Table 3. Table 3 Compositions of semaglutide formulations 1, 2, and 3 Element Simalutide formulation 1 2 3 Simaglutide drug substance (mg / ml) 4.8 4.8 4.8 HP-B-CD KLEPTOSE ® (Roquette) (% w / v) (Average MS: 0.92, MS range: 0.81-0.99) 1 0 25 0 Citrate, 1 H2O 2 (mM) 3.7 3.7 0.9 Disodium hydrogen phosphate, 2 H2O 2 (mM) 12.6 12.6 18.2 HCl qs qs qs NaOH qs qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 6.0 6.0 7.4 1MS: mol substitution, corresponding to hydroxypropyl 2 per glucose unit, is used in different formulations with different buffer concentrations to ensure buffering processes are performed at different pH levels.

[0199] The formulation was prepared as described in Example 1. Method

[0200] The aggregation and tendency to form peptide fibers of semaglutide were measured using thioflavin T (ThT) fluorescence stress assay. The analysis of the presence of peptide fibers was based on the fluorescence properties of the ThT probe, which showed low fluorescence in the unbound / native peptide-bound state but high fluorescence when bound to peptide fibers, and a redshift in the wavelength of maximum fluorescence when bound to fibers.

[0201] Two samples were collected, and 1400 μl of the sample was added to 28 μl of 1 mM ThT stock solution. Then, 200 μl of this solution was transferred to six different wells in a 96-well microplate, one of which contained a glass bead. This assay was performed for 169 hours at 40°C using a BMG CLARIOstar fluorescent disc reader equipped with a monochromator, with dual-track oscillation at 300 rpm and excitation and emission at 450 nm and 480 nm, respectively. The delay time was measured from the start of the experiment until fibrosis occurred, showing an increase in ThT fluorescence. Table 4 shows the physical stability of semaglutide at pH 6.0 and 7.4. Simalutide formulation pH HP-B-CD (MS: 0.92) 3 Delay time until fibrosis 1 6.0 0% w / v 2.35 hours 1 2 6.0 25% w / v >169 hours 1,2 3 7.4 0% w / v >169 hours 1,2 1. Results were the average of 6 replicates. 2. No fibrosis was observed in any of the 6 replicates during the 169-hour experimental period. 3. MS: Morphine substitution, corresponding to hydroxypropyl groups per glucose unit.

[0202] The semaglutide formulations were subjected to shear stress-induced conditions, and the tendency to form peptide fibrils was measured. Unexpectedly, the presence of HP-B-CD was found to inhibit the formation of semaglutide peptide fibrils. When semaglutide was formulated at pH 6 in the absence of HP-B-CD (semaglutide formulation 1), fibrilation occurred after 2.35 hours; that is, semaglutide is physically unstable under these conditions. When semaglutide was formulated at pH 6 in the presence of HP-B-CD (semaglutide formulation 2), no fibrilation was observed throughout the experiment; that is, semaglutide is physically stable. Furthermore, when formulated at pH 6 in the presence of HP-B-CD (semaglutide formulation 2), the physical stability of semaglutide was found to be comparable to that of semaglutide (semaglutide formulation 3) under its optimal formulation conditions at pH 7.4 in the absence of HP-B-CD. Example 3: The effect of HP-B-CD on the chemical stability of semaglutide

[0203] This example demonstrates the effect of HP-B-CD on the chemical stability of semaglutide in degradation products using semaglutide purity and semaglutide-related high molecular weight protein (HMWP) parameters. Composition

[0204] Use the same formulation as in Example 2. Process

[0205] The formulation was prepared as described in Example 1. Method

[0206] The HMWP content and semaglutide purity were determined after storage at 37°C for 0, 14 and 21 days.

[0207] The purity of semaglutide was determined using reversed-phase high-performance liquid chromatography (RP-HPLC) with a Kinetex C18 2.6 μm column (4.6 x 150 mm) for analysis. Gradient elution was performed using eluent A, consisting of 90% v / v 0.09 M phosphate solution, pH 3.6, and 10% v / v acetonitrile, and eluent B, consisting of 60% v / v acetonitrile and 20% v / v isopropanol. Chromatography was performed at 30°C with UV detection (210 nm) using injection volumes of 10 to 100 μl and a flow rate of 0.7 ml / min. Purity was quantified as the area of ​​the main peak divided by the area of ​​all peaks x 100%.

[0208] The extent of covalently bound HMWP was determined using size exclusion chromatography (SEC). Samples were analyzed using a Waters SEC 1.7 μm column (4.6 x 150 mm) and eluted isocratically with an inductively coupled eluent consisting of 300 mM sodium chloride, 10 mM sodium dihydrogen phosphate monohydrate, 5 mM orthophosphate, and 50% v / v 2-propanol. Chromatography was performed at 50°C with UV detection (280 nm) using injection volumes from 1 to 10 μl and a flow rate of 0.3 ml / min. HMWP was quantified as the area of ​​all components eluted before the main peak divided by the area of ​​the main peak x 100%. Table 5: Purity of semaglutide at suboptimal and optimal pH. Simalutide formulation pH HP-B-CD (MS: 0.92) 1 Relationship between semaglutide purity (%) and time (days) at 37°C Relationship between HMWP content (%) and time (days) at 37°C 0 14 twenty one 0 14 twenty one 1 6.0 0% w / v 96.89% 94.58% 93.48% 0.12% 0.25% 0.35% 2 6.0 25% w / v 96.51% 94.53% 93.73% 0.04% 0.11% 0.11% 3 7.4 0% w / v 96.82% 95.56% 94.81% 0.12% 0.32% 0.40% 1MS: Morphological substitutions, corresponding to a summary of hydroxypropyl groups per glucose unit.

[0209] Table 5 shows how the chemical purity of semaglutide decreases over time. When semaglutide (semaglutide formulation 1) is formulated at pH 6.0, the chemical purity decreases more rapidly compared to when it is formulated at the optimal pH 7.4 (semaglutide formulation 3). Unexpectedly, when semaglutide (semaglutide formulation 2) is formulated at pH 6.0, HP-B-CD improves the chemical stability of semaglutide (in terms of purity decrease and HMWP formation). Example 4: Effect of HP-B-CD molar substitution on the physical stability of cagliottide / semaglutide co-formulations

[0210] This example demonstrates the effect of HP-B-CD moryl substitution on the physical stability of cagliolitin and semaglutide. Composition

[0211] The composition systems of co-blended compound 1 and co-blended compound 2 are shown in Table 6. Table 6 Composition systems of co-blended compound 1 and co-blended compound 2 Element Co-mixing 1 2 Carglinide drug substance (mg / ml) 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.92, MS range: 0.81-0.99) 1 25 - HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 - 25 Citrate, 1 H2O (mM) 3 3 HCl qs qs NaOH qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.7 5.7 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0212] The formulation was prepared as described in Example 1. Method

[0213] All samples were stored under pressure conditions, defined as follows: - Duration: 28 days - Temperature: 30°C ± 2°C - Pressure conditions: During storage, samples were inverted 360° to simulate patient use outside the cold storage room. The inversion was performed 20 times for three days per week and 40 times for two days per week.

[0214] The number of particles visible only under a microscope quantifies the physical stability of the mixture of caglitinide and semaglutide, and is obtained by microfluidic imaging (MFI, see Sharma, DK et al., AAPS J. (2010), 12: 455-464 on the principles of MFI techniques). The following procedure was performed on each syringe sample for analysis: The experiment was conducted at ambient temperature. Liquid was first removed from each syringe by removing the plunger and then pipetting the liquid into the sample container. The sample was transferred to a 96-well deep-well plate, which was inserted into the sample processing unit (Bot1) of a Protein Simple MFI™ 5200 instrument equipped with a standard Protein Simple MFI™ 100 μm flow cell. Analysis of the sample using the standard MFI system setup means that liquid is pipetted into a reservoir connected to the flow cell, the liquid is illuminated by 10 LEDs (470 nm), and the contents of the flow cell are recorded as bright-field images using a digital camera (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 proprietary software MFI data validator to obtain the number of individual particles (normalized to counts per milliliter of analytical solution) and presented by size; >5 µm, >10 µm, and >25 µm, which are the standard size ranges for particles visible under a microscope. It should be noted that the number of particles >5 μm includes all particles with a diameter greater than 5 μm (>5 μm, >10 μm, and >25 μm), and the number of particles >10 μm includes all particles with a diameter greater than 10 μm (>10 μm and >25 μm). Particle size was defined as equivalent circle diameter (ECD).

[0215] The presence of amyloid peptide fibers was analyzed using thioflavin-T (ThT) fluorescence assay. The experiment was performed at 25 °C. Liquid was first removed from each syringe by removing the plunger and then pipetting the liquid into sample containers. Subsequently, 500 µl of sample was mixed with approximately 9 µl of ThT stock solution in a separate sample container to achieve a final ThT concentration of 20 μM. The samples were incubated in the dark at ambient temperature for 25 minutes. 200 µl of sample was transferred to one well of a 96-well microplate. The samples were measured on a BMG CLARIOstar fluorescent optical disc reader equipped with a monochromator, with excitation and emission at 440 nm and 470–550 nm, respectively.

[0216] Data acquisition was performed using CLARIOstar control software. In this assay, the maximum emission was observed at a wavelength of approximately 485 nm; the analytical result is therefore reported as ThT fluorescence at 485 nm, expressed in relative fluorescence units (RFU). Table 8 Physical stability of HP-B-CD co-regulations with high or medium molar substitution. Co-mixing HP-B-CD Average Mole Substitution The relationship between the number of particles visible only under a microscope and time (days) 0 14 twenty one 28 Particle size > 5μm 1 HP-B-CD (MS: 0.92) 1 459 334 1754 22433 2 HP-B-CD (MS: 0.62) 1 256 379 715 245 Particle size > 10 μm 1 HP-B-CD (MS: 0.92) 1 52 27 602 10598 2 HP-B-CD (MS: 0.62) 1 39 39 132 122 Particle size > 25 μm 1 HP-B-CD (MS: 0.92) 1 0 0 2 644 2 HP-B-CD (MS: 0.62) 1 6 0 8 4 ThT fluorescence at 485 nm 1 HP-B-CD (MS: 0.92) 1 3357 3538 3588 13640 2 HP-B-CD (MS: 0.62) 1 3784 3720 3967 3463 The number of particles visible only under a microscope is the average of three replicates, rounded to the nearest integer. 1MS: mole substitution, corresponding to the sum of hydroxypropyl groups per glucose unit.

[0217] The results in Table 7 show that the co-modification 2 containing HP-B-CD produced the fewest particles (mean MS: 0.62). Furthermore, during the 28-day experiment, no increase in the number of particles visible only under a microscope or in ThT fluorescence was observed in the case of co-modification 2.

[0218] Conversely, in the case of co-modification 1 containing HP-B-CD (average MS: 0.92), an increase in the number of particles that could only be seen under a microscope after 21 days was observed, and an increase in ThT fluorescence was observed after 28 days.

[0219] Among these other similar citrate-buffered co-regulations of semaglutide and caglionetin, co-regulation (2) including HP-B-CD (mean MS: 0.62) was physically more stable than co-regulation (1) including HP-B-CD (mean MS: 0.92). Example 5: Effect of hydroxypropyl-B-cyclodextrin concentration on the chemical stability of semaglutide

[0220] This example demonstrates the concentration-dependent effect of HP-B-CD on the chemical stability of semaglutide. Composition

[0221] The compositions of co-blended compound 3, co-blended compound 4, and co-blended compound 5 are shown in Table 8. Table 8 Compositions of co-blended compound 3, co-blended compound 4, and co-blended compound 5 Element Co-mixing 3 4 5 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 11.25 12.5 15 L-histidine (mM) 6 6 6 Sorbitol 2 (mg / ml) 26 twenty four 20 Polysorbate 80 (mg / ml) 0.05 0.05 0.05 HCl qs qs qs NaOH qs qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.7 5.7 5.7 1MS: mol substitution, corresponding to hydroxypropyl 2 per glucose unit. Due to the different HP-B-CD concentrations tested, different sorbitol concentrations are required to obtain isotonic preparations.

[0222] The formulation was prepared as described in Example 1. Method

[0223] The samples were stored at 37°C for 28 days, and analyzed after 14, 21 and 28 days to determine the chemical purity of semaglutide.

[0224] The purity of semaglutide was determined using reversed-phase ultra-high performance liquid chromatography (RP-UHPLC) with samples analyzed on a Waters Acquity phenyl-hexyl 1.7 μm column (2.1 x 150 mm). Gradient elution was performed using eluent A consisting of 0.09% TFA in MQ water and eluent B consisting of 0.09% TFA in MQ water and 0.09% TFA in MQ water containing 80% acetonitrile. Chromatography was performed at 62°C with UV detection (215 nm) at injection volumes of 2 to 14 μl and a flow rate of 0.25 ml / min. Purity was quantified as the area of ​​the semaglutide main peak divided by the area of ​​all relevant peaks x 100%.

[0225] It should be noted that the same method was used to determine the purity of caglitinide in other experiments. Table 9 Chemical purity (%) of semaglutide with different HP-B-CD concentrations Co-mixing HP-B-CD (MS: 0.62) 1 Relationship between semaglutide purity (%) and time (days) at 37°C 0 14 twenty one 28 3 11.25% w / v 96.90% 90.72% 88.65% 87.52% 4 12.5% ​​w / v 96.87% 92.90% 91.25% 89.81% 5 15% w / v 96.83% 93.61% 92.92% 91.67% 1MS: Morphological substitutions, corresponding to a summary of hydroxypropyl groups per glucose unit.

[0226] The results in Table 9 show that the chemical stability and purity of semaglutide also depend on the HP-B-CD concentration. Semaglutide maintained chemical stability in all co-regulations (including 11.25% to 15% w / v HP-B-CD). However, when the co-regulation included 15% w / v HP-B-CD, the chemical stability and purity of semaglutide were the highest. Example 6: Effect of different tonics on the physical stability of co-regulations

[0227] This example demonstrates the effect of different tonic agents on the physical stability of other co-formulated compounds of the same cagliottide and semaglutide. Composition

[0228] The compositions of co-blended compounds 6 to 12 are shown in Table 10. Table 10 Compositions of co-blended compounds 6 to 12 Element Co-mixing 6 7 8 9 10 11 12 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 10 10 10 10 10 10 10 L-histidine (mM) 6 6 6 6 6 6 6 Polysorbate 20 (mg / ml) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Glycerin (mg / ml) - 16 - - - - - Sorbitol (mg / ml) - - 34 - - - - Mannitol (mg / ml) - - - 34 - - - Trehalose (mg / ml) - - - - 63 - - Sucrose (mg / ml) - - - - - 63 - NaCl (mg / ml) - - - - - - 6.0 HCl qs qs qs qs qs qs qs NaOH qs qs qs qs qs qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.7 5.7 5.7 5.7 5.7 5.7 5.7 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0229] The formulation was prepared as described in Example 1. Method

[0230] All samples were stored under pressure conditions, defined as: ․ Duration: 18 days ․ Temperature: 37°C ± 2°C ․ Pressure conditions: During storage, samples were inverted 360° to simulate patient use outside the cold storage room. 100 rotations were performed per week for five days. The number of particles visible only under a microscope was quantified as described in Example 4. Table 11 Effects of different tonics on the physical stability of the co-formulated compounds Co-mixing Tensioner The relationship between the number of particles visible only under a microscope and time (days) 0 7 11 14 18 Particle size > 5μm 6 none 256 385 429 952 1296 7 glycerin 292 241 292 466 691 8 Sorbitol 212 341 340 517 345 9 Mannitol 94 438 177 245 360 10 Trehalose 121 155 213 504 472 11 sucrose 59 104 140 539 749 12 NaCl 1 36 946 - - - Particle size > 10 μm 6 without 4 27 96 216 377 7 glycerin 10 twenty three twenty three 48 106 8 Sorbitol 6 54 42 36 73 9 Mannitol 2 twenty three 12 8 50 10 Trehalose 4 10 40 50 69 11 sucrose 2 8 13 142 253 12 NaCl 1 2 403 - - - Particle size > 25 μm 6 none 0 4 4 27 75 7 glycerin 0 0 4 6 4 8 Sorbitol 0 0 2 4 0 9 Mannitol 0 0 0 0 0 10 Trehalose 0 0 0 0 4 11 sucrose 0 0 2 15 55 12 NaCl 1 0 106 - - - The result is the average of two replicates and has been rounded to the nearest integer value (-). No sampling was performed. Regarding the co-mixture containing NaCl, sampling was stopped earlier than for other mixtures due to the rapid increase in the number of particles visible only under a microscope. Summary

[0231] The results in Table 11 show that the number of particles visible only under a microscope increased most rapidly in the co-blended formulation (co-blended formulation 12) which included NaCl as a tensiating agent. After 7 days, the number of particles significantly exceeded the number of particles determined by the other co-blended formulations. Therefore, sampling and analysis of the number of particles visible only under a microscope in the co-blended formulation containing NaCl was stopped after 7 days.

[0232] After 14 days, an increase in the number of microscopically visible particles was observed in the co-blended formulations containing glycerol and sucrose, and these two co-blended formulations were considered comparable in terms of physical stability. In the co-blended formulations containing mannitol, sorbitol, or trehalose, the number of particles remained at its lowest. In these co-blended formulations, almost no increase in the number of microscopically visible particles was observed during the 18-day period of storage under pressure conditions.

[0233] Among the tested co-regulations, those containing mannitol, sorbitol, or trehalose as tensioning agents remained the most stable over time. Example 7: The effect of different surfactants on the physical stability of co-regulations.

[0234] This example demonstrates the effect of different surfactants on the physical stability of other co-formulated compounds of the same cagliottide and smarutide. Composition

[0235] The compositions of co-blended compound 13, co-blended compound 14, and co-blended compound 15 are shown in Table 12. Table 12 Compositions of co-blended compound 13, co-blended compound 14, and co-blended compound 15 Element Co-mixing 13 14 15 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 10 10 10 L-histidine (mM) 6 6 6 Polysorbate 20 (mg / ml) 0.05 - - Polysorbate 80 (mg / ml) - 0.05 - Poloxamer 188 (mg / ml) - - 0.5 HCl qs qs qs NaOH qs qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.7 5.7 5.7 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0236] The formulation was prepared as described in Example 1. Method

[0237] All samples were stored under pressure conditions, defined as: ․ Duration: 17 days ․ Temperature: 37°C ± 2°C ․ Pressure conditions: During storage, samples were inverted 360° to simulate patient use outside the cold storage room. 100 rotations were performed per week for five days. The number of particles visible only under a microscope was quantified as described in Example 4. Table 13 Effects of different surfactants on the physical stability of the co-formulated compounds Co-mixing surfactants The relationship between the number of particles visible only under a microscope and a point in time (day). 0 7 10 14 17 Particle size > 5μm 13 Polysorbate 20 464 304 396 772 2803 14 Polysorbate 80 566 292 520 286 1 348 15 Polosham 188 1235 1278 2783 940 1 1704 Particle size > 10 μm 13 Polysorbate 20 twenty three twenty three 43 143 297 14 Polysorbate 80 19 31 76 57 1 48 15 Polosham 188 100 245 301 290 1 523 Particle size > 25 μm 13 Polysorbate 20 0 2 6 11 13 14 Polysorbate 80 0 0 0 4 1 0 15 Polosham 188 0 13 17 61 1 52 The result is the average of 2 repetitions, rounded to the nearest integer value. Only 1 repetition is used for the summary.

[0238] After 17 days of storage under pressure, co-formulation 14 contained the lowest number of microscopically visible particles. An increase in microscopically visible particles was observed in co-formulation 13 containing polysorbate 20 after 14 days, while in co-formulation 15 containing poloxamer 188, microscopically visible particles formed after 7 days of storage under pressure. Clearly, the co-formulation containing polysorbate 80 was the most stable, and the co-formulation containing polysorbate 20 was also acceptablely stable. Example 8: Effect of different buffer substances on the physical stability of co-formulations

[0239] This example demonstrates the effect of buffer substances on the physical stability of other co-formulated compounds of the same cagliottide and smarutide. Composition

[0240] The compositions of co-blended compound 1 and co-blended compound 16 are shown in Table 14. Table 14 Compositions of co-blended compound 1 and co-blended compound 16 Element Co-mixing 1 16 Carglinide drug substance (mg / ml) 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.92, MS range: 0.81-0.99) 1 25 25 Citrate, 1 H2O (mM) 3 - L-histidine (mM) - 6 HCl qs qs NaOH qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.7 5.7 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0241] The formulation was prepared as described in Example 1. Method

[0242] All samples were stored under pressure conditions defined as follows: ○ Duration: 21 days ○ Temperature: 37°C ± 2°C ○ Pressure conditions: During storage, samples were inverted 360° to simulate patient use outside the cold storage room. 100 rotations were performed for five days per week. The number of particles visible only under a microscope was quantified as described in Example 4. Table 15 Effect of buffer substances on the physical stability of co-formulated compounds Co-mixing Buffer substances The relationship between the number of particles visible only under a microscope and time (days) 0 7 11 14 18 twenty one Particle size > 5μm 1 citrate 459 668 408 409 4717 3115 16 histidine 386 752 569 571 2495 2392 Particle size > 10 μm 1 citrate 52 117 55 125 2114 1446 16 histidine 68 80 103 151 969 760 Particle size > 25 μm 1 citrate 0 0 0 16 542 332 16 histidine 2 0 4 13 162 117 The result is the average of two repetitions, summarized and rounded to the nearest integer value.

[0243] Up to day 14 of storage under pressure, the physical stability of the two co-formulations was similar and acceptable. However, after 18 days, the number of microscopically visible particles in the citrate-buffered co-formulation (co-formulation 1) was greater than that in the histidine-buffered co-formulation (co-formulation 16). The histidine-buffered co-formulation 16 was the most stable. Example 9: Effect of different buffer concentrations on the chemical stability of co-formulations

[0244] This example demonstrates the effect of buffer concentration on the chemical stability of other identical co-formulated compounds. Composition

[0245] The compositions of co-blended compound 17 and co-blended compound 18 are shown in Table 16. Table 16 Compositions of co-blended compound 17 and co-blended compound 18 Element Co-mixing 17 18 Carglinide drug substance (mg / ml) 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 10 10 L-histidine (mM) 6 20 HCl qs qs NaOH qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.7 5.7 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0246] The formulation was prepared as described in Example 1. Method

[0247] Samples were stored at 30°C for 21 days and analyzed after 7, 14, and 21 days to determine the chemical purity of caglinide. The purity of caglinide was determined as described in Example 5 (for semaglutide). Table 17 Effect of buffer concentration on the chemical stability of caglinide in co-formulated compounds. Co-mixing Buffer concentration Relationship between caglinide purity (%) and time (days) at 30°C 0 7 14 twenty one 17 Histidine: 6 mM 89.2% 88.2% 86.5% 84.2% 18 Histidine: 20 mM 89.2% 87.9% 86.0% 83.5% Summarize

[0248] The results in Table 17 show that both co-regulations are stable. However, the chemical purity of caglinide is the highest in co-regulation 17. The purity of caglinide decreases rapidly over time when the histidine concentration is 20 mM. Example 10: Effect of different buffer concentrations on the physical stability of co-regulations

[0249] This example demonstrates the effect of histidine buffer concentration on the physical stability of the co-formulated compound. Components

[0250] The composition of the tested co-blended compounds is shown in Table 16. Process

[0251] The formulation was prepared as described in Example 1. Method

[0252] All samples were stored under pressure conditions defined as follows: ․ Duration: 18 days ․ Temperature: 37°C ± 2°C ․ Pressure conditions: During storage, samples were inverted 360° to simulate patient use outside the refrigeration room. 100 rotations were performed per week for five days. The number of particles visible only under a microscope was quantified as described in Example 4. Table 18 Effect of buffer concentration on the physical stability of the co-formulated compound. Co-mixing Buffer concentration The relationship between the number of particles visible only under a microscope and a point in time (day). 0 7 10 14 18 Particle size > 5μm 17 Histidine: 6 mM 239 392 165 189 266 18 Histidine: 20 mM 50 262 197 1029 926 Particle size > 10 μm 17 Histidine: 6 mM 4 8 15 17 46 18 Histidine: 20 mM 2 17 17 461 423 Particle size > 25 μm 17 Histidine: 6 mM 0 0 2 0 2 18 Histidine: 20 mM 0 0 0 120 104 The result is the average of two repeated values, rounded to the nearest integer. Summary

[0253] The difference in physical stability between co-constitutes 17 and 18 became most pronounced after 14 days. Data in Table 18 show that the number of microscopically visible particles observed in co-constitute 18 (containing 20 mM histidine) was greater than that observed in co-constitute 17 (containing 6 mM histidine). In other words, the co-constitute containing 6 mM histidine is the most physically stable. Example 11: Effect of HP-B-CD concentration on subcutaneous tolerability after subcutaneous injection.

[0254] This example demonstrates the concentration-dependent effect of HP-B-CD on subcutaneous tissue after subcutaneous injection. Composition

[0255] The compositions of the tested co-modified carriers prepared with different HP-B-CD concentrations are shown in Table 19. Table 19 Compositions of co-modified carriers containing different concentrations of HP-B-CD Element Co-modified carrier 1 2 3 4 5 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 10 12.5 15 17.5 20 L-histidine (mM) 6 6 6 6 6 Sorbitol 2 (mg / ml) 28 twenty four 20 16 12 Polysorbate 80 (mg / ml) 0.05 0.05 0.05 0.05 0.05 HCl qs qs qs qs qs NaOH qs qs qs qs qs WFI Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml pH 6.0 6.0 6.0 6.0 6.0 1MS: Morpho-substituted hydroxypropyl 2-sorbitol concentration per glucose unit is varied with HP-B-CD concentration to maintain isotonic conditions in the process.

[0256] Except for omitting the addition of active pharmaceutical ingredients, the formulation system was prepared as described in Example 1. Method

[0257] Following subcutaneous administration of a formulation containing HP-B-CD, local (subcutaneous) tolerance was assessed in five Landrace × Yorkshire × Duroc (LYD) pigs by using a syringe equipped with a 25 G needle and a 5 mm stopper to evaluate skin lesions resulting 6 days after subcutaneous administration of 600 µl (post-mortem). Skin samples measuring 2 x 2 cm were collected at post-mortem, fixed in neutral-buffered formalin, trimmed with a multi-blade technique, embedded in paraffin, cut into 4 µm thin layers, mounted on glass slides, and subsequently stained with hematoxylin and eosin (HE). The degree of subcutaneous tissue necrosis was assessed using an optical microscope and scored on a numerical scale, with code 1 indicating "no necrosis" and code 4 indicating "moderate necrosis." A total of five skin samples were collected for each co-constituted carrier. However, due to the changes in subcutaneous tissue sections required for successful assessment of necrosis, not all injection sites could be assigned a score: 1, No necrosis; 2, Very little necrosis; 3, Mild necrosis; 4, Moderate necrosis. This assessed the degree of subcutaneous necrosis induced by subcutaneous injection of isotonic co-modified carrier preparations containing 10% w / v to 20% w / v HP-B-CD. The results are presented in Table 20. Table 20: Necrosis score of subcutaneous tissue necrosis 6 days after injection of co-modified carriers with different percentages of HP-B-CD. Co-modified carrier HP-B-CD concentration Necrosis, subcutaneous Number of skin samples that were successfully scored out of the total 1 10% w / v 2,2,2,2,3 5 out of 5 2 12.5% ​​w / v 3,3 2 out of 5 3 15% w / v 2,2,3 3 out of 5 4 17.5% w / v 2,2,3 3 out of 5 5 20% w / v 2,3,3,4 4 out of 5 Summarize

[0258] A correlation was observed between increased HP-B-CD concentration in co-modified carriers and injection site necrosis. In one case, a co-modified carrier containing 20% ​​w / v HP-B-CD caused moderate subcutaneous necrosis at the injection site. Modifications containing less than 20% w / v HP-B-CD all produced only mild or minimal subcutaneous necrosis at the injection site. All co-modified carriers containing 10% to 20% w / v HP-B-CD were tolerated to an acceptable degree, preferably those containing 10% to 17.5% w / v HP-B-CD. Example 12: Effect of different tonic agents on subcutaneous tolerability during subcutaneous injection.

[0259] This example demonstrates the effect of any of three different tonic agents (sorbitol, mannitol, and trehalose) on local tolerance in other identical isotonic co-modified carriers. Composition

[0260] The composition of the tested co-modified formulations is shown in Table 21. Table 21 Composition of isotonic co-modified formulations prepared with different tonic agents Element Co-modified carrier 6 7 8 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 15 15 15 L-histidine (mM) 6 6 6 Polysorbate 20 (mg / ml) 0.1 0.1 0.1 Sorbitol (mg / ml) twenty four - - Mannitol (mg / ml) - 25 - Trehalose (mg / ml) - - 46 HCl qs qs qs NaOH qs qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 6.0 6.0 6.0 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0261] Except for omitting the addition of active pharmaceutical ingredients, the formulation system was prepared as described in Example 1. Method

[0262] Subcutaneous administration and local tolerance of an isotonic carrier preparation containing HP-B-CD and three different tonic agents were investigated in two live Landrace × Yorkshire × Duroc (LYD) pigs by evaluating skin responses to 600 µL of the carrier preparation. The preparation was injected using a syringe fitted with a 25 G needle and a 5 mm stopper. Approximately 24 hours after injection, necropsy was performed, and 2 x 2 cm skin samples were fixed in neutral buffered formalin, trimmed to a 4 µm thin layer using a multi-blade technique, embedded in paraffin, and subsequently stained with hematoxylin and eosin (HE). For both samples, the severity of subcutaneous tissue necrosis, inflammatory cell infiltration, and hemorrhage distribution was assessed by a trained toxicological pathologist using optical microscopy and scored on a numerical scale, with code 1 reflecting "no abnormality" and code 3 reflecting "mild severity": 1, No abnormality; 2, Very little severity; 3, Mild severity. Table 22: Severity scores of subcutaneous tissue necrosis, inflammatory cell infiltration, and hemorrhage distribution 24 hours after subcutaneous injection of a co-modified carrier containing three types of tonic agents. Co-modified carrier Tensioner Necrosis Inflammatory cell infiltration Bleeding distribution 6 Sorbitol 2,1 2,1 1,1 7 Mannitol 2,2 2,3 1,2 8 Trehalose 1,1 2,2 1,2 Summarize

[0263] The data presented in Table 22 show that, overall, sorbitol was the tension agent that caused the least severe necrosis, inflammatory cell infiltration, and hemorrhage. These observations confirm that sorbitol is a preferred tension agent for achieving good and acceptable subcutaneous tolerability in co-formulations containing the active pharmaceutical ingredient. Example 13: Confirmation of the effect of the type of tension agent in the composition of histidine buffer and citrate buffer on subcutaneous tolerability during subcutaneous injection.

[0264] This experiment examined: (1) the effect of the type of tonic agent on the local tolerance profile after subcutaneous injection of other co-mixed formulations with the same histidine buffer; and (2) the effect of subcutaneous injection of a co-mixed carrier containing a citrate buffer and without a tonic agent on the local tolerance profile. Composition

[0265] The composition systems of the evaluated co-regulations are described in Tables 23a and 23b. Table 23a Composition of the isotonic histidine buffer co-regulation carrier Element Co-mixing 19 20 Carglinide drug substance (mg / ml) 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 15 15 L-histidine (mM) 6 6 Trehalose (mg / ml) 38.6 - Sorbitol (mg / ml) - 20 Polysorbate 80 (mg / ml) 0.05 0.05 HCl qs qs NaOH qs qs WFI Up to 1 ml Up to 1 ml pH 6.0 6.0 1MS: Mole substitution, corresponding to hydroxypropyl per glucose unit. Table 23b. Composition of isotonic citrate buffer co-regulatory carrier. Element Co-modified carrier twenty one HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.92, MS range: 0.81-0.99) 1 25 Citrate, 1 H2O (mM) 3 HCl qs NaOH qs WFI Up to 1 ml pH 5.7 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0266] Co-formulations 19 and 21 were prepared as described in Example 1. Except for omitting the addition of the active pharmaceutical ingredient, the carrier 21 was prepared as described in Example 1. Method

[0267] Local tolerance to the subcutaneous administration of the co-constitutes described in Tables 23a and 23b was investigated in eight live miniature pigs. Skin lesions resulting 6 days after subcutaneous administration of 750 µl of the sample size (6 days after necropsy) were assessed using a syringe fitted with a 25 G needle and a 5 mm stopper. Skin samples measuring 2 x 2 cm were collected at necropsy, fixed in neutral-buffered formalin, trimmed with a multi-blade, embedded in paraffin, cut into 4 µm thin slices, mounted on glass slides, and subsequently stained with hematoxylin and eosin (HE). The severity of subcutaneous tissue necrosis was assessed by a trained toxicological pathologist using an optical microscope and scored on a numerical scale, with code 1 indicating "no abnormality" and code 5 indicating "significant severity": 1, no abnormality; 2, very little severity; 3, mild severity; 4, moderate severity; 5, significant severity. The results of the necrosis scores are shown in Tables 24a and 24b. Table 24a Severity scores of subcutaneous tissue necrosis 6 days after injection of histidine buffer co-constitutes Co-mixing buffer solution Tensioner Necrosis fraction of four skin samples 19 histidine Trehalose 1,2,3,3 20 histidine Sorbitol 2,2,2,2 Table 24b: Score of subcutaneous tissue necrosis severity 6 days after injection of citrate-buffered co-modified carrier. Co-modified carrier buffer solution Tensioner Necrosis fraction of eight skin samples twenty one citrate none 3,4,4,4,4,5,5,5 Summarize

[0268] The results presented in Table 24a show that the type of tonic agent included in the formulation affects its local tolerability in vivo. The tonic agent was correlated with the subcutaneous necrosis observed at the injection site. Subcutaneous injection of co-formulation 19, which included trehalose, resulted in two mild necrosis events (score 3). Subcutaneous injection of co-formulation 20, which included sorbitol, resulted in only minimal necrosis (score 2), which was a better outcome. These results confirm that, in the same co-formulation carrier scenario, formulations including 15% w / v HP-B-CD (mean MS: 0.62) and sorbitol are better than formulations including 15% w / v HP-B-CD (mean MS: 0.62) and trehalose.

[0269] The results presented in Table 24b show that three significant necrosis events (score 5) were observed using co-concentrate 21, which included 25% w / v HP-B-CD (mean MS: 0.92), citrate, and no tonic agent, confirming that this particular co-concentrate is not suitable for subcutaneous injection. Example 14: Effects of different types of hydroxypropyl-substituted cyclodextrins on the physical and chemical stability of co-concentrates of caglionein and semaglutide.

[0270] This example demonstrates the effects of hydroxypropyl-α-cyclodextrin (HP-A-CD), hydroxypropyl-β-cyclodextrin (HP-B-CD), and hydroxypropyl-γ-cyclodextrin (HP-G-CD) on the formation of microscopically visible particles and the chemical degradation of caglinide in other co-formulated caglinide and smarutide formulations. Composition

[0271] The compositions of co-blended compounds 22, 23, and 24 are shown in Table 25. Table 25 Compositions of co-blended compounds 22, 23, and 24 Element Co-mixing twenty two twenty three twenty four Carglinide drug substance (mg / ml) 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 3.2 HP-A-CD (CycloLab) (% w / v) (Average MS: 0.8, MS range: 0.5-0.9) 1 15 - - HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 - 15 - HP-G-CD (CycloLab) (% w / v) (Average MS: 0.6, MS range: 0.4-0.7) 1 - - 15 L-histidine (mM) 6 6 6 Sorbitol (mg / ml) 20 20 20 Polysorbate 80 (mg / ml) 0.05 0.05 0.05 HCl qs qs qs NaOH qs qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.8 5.8 5.8 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0272] The formulation was prepared as described in Example 1. Method

[0273] Samples used to determine the number of particles visible only under a microscope were stored under pressure conditions defined as follows: - Duration: 42 days - Temperature: 30°C ± 2°C - Pressure conditions: During storage, the samples were inverted 360° to simulate patient use outside a cold storage room. Rotation was performed 20 times for three days per week and 40 times for two days per week. The number of particles visible only under a microscope was determined as described in Example 4.

[0274] Samples used for determining the purity of caglitazone were stored at 37°C for up to 42 days. The purity of semaglutide was determined using the following reversed-phase high-performance liquid chromatography (RP-HPLC) method, in which samples were analyzed using a Kinetex C18, 2.6 μm column (4.6 x 150 mm), and gradient elution was performed with eluent A consisting of 90% v / v 0.09 M phosphate solution, pH 3.6, and 10% v / v acetonitrile, and eluent B consisting of 60% v / v acetonitrile and 20% v / v isopropanol. Chromatography was performed at 30°C with UV detection (210 nm) using injection volumes of 10 to 100 μl and a flow rate of 0.7 ml / min. The purity of caglitazone was quantified by dividing the area of ​​the main peak by the area of ​​all relevant peaks x 100%.

[0275] The purity of semaglutide was determined using the same method in other experiments. Table 26 Physical stability of cagliolipid and semaglutide co-formulations formulated with different types of hydroxypropyl cyclodextrin. Co-mixing Types of hydroxypropyl-substituted cyclocorals The relationship between the number of particles visible only under a microscope and time (days) 0 14 twenty one 28 35 42 Grain size>5μm twenty two HP-A-CD 65 196 270 441 523 690 twenty three HP-B-CD 49 122 61 245 324 503 twenty four HP-G-CD 1 453537 - - - - - Grain size>10μm twenty two HP-A-CD 4 7 14 27 47 41 twenty three HP-B-CD 4 8 5 20 20 116 twenty four HP-G-CD 1 107013 - - - - - Grain size>25μm twenty two HP-A-CD 0 0 0 1 3 0 twenty three HP-B-CD 0 1 1 1 4 15 twenty four HP-G-CD 1 316 - - - - - The number of particles visible only under a microscope is the average of three replicates and has been rounded to the nearest integer (-). No sampling was performed. Regarding co-formulation 24 containing HP-G-CD, sampling was stopped earlier than for other formulations due to the rapid increase in particle number. Table 27 Chemical purity (%) of cagliottine in co-formulations of cagliottine and semaglutide formulated with different types of hydroxypropyl cyclodextrins. Co-mixing Types of hydroxypropyl cyclodextrin Relationship between caglinide purity (%) and time (days) at 37°C 0 14 28 42 twenty two HP-A-CD 94.0% 87.2% 79.0% 71.1% twenty three HP-B-CD 96.8% 88.9% 81.9% 75.0% Summarize

[0276] The results presented in Table 26 show that a high number of microscopically visible particles were observed in co-blended compound 24 (HP-G-CD) at time point zero, ruling out the use of HP-G-CD to co-blend caglionetin and semaglutide. Sampling for microscopically visible particle number analysis of co-blended compound 24 containing HP-G-CD was stopped after preliminary analysis at time point zero. For co-blended compounds 22 (HP-A-CD) and 23 (HP-B-CD), almost no increase in the number of microscopically visible particles was observed.

[0277] The chemical purity results of carglinide using HP-A-CD or HP-B-CD presented in Table 27 show that the purity of carglinide in co-regulation 22 containing HP-A-CD decreased slightly more rapidly compared with co-regulation 23 containing HP-B-CD.

[0278] Based on the results in Table 26, HP-A-CD or HP-B-CD systems can be used for co-regulations of caglitinide and semaglutide. However, based on the results in Table 27, HP-B-CD is preferred over HP-A-CD for co-regulations of caglitinide and semaglutide due to the higher purity of caglitinide when co-regulated with HP-B-CD. Example 15: Effect of the molar substitution degree of HP-B-CD on the physical and chemical stability of co-regulations of caglitinide and semaglutide.

[0279] This example demonstrates the effect of molar substitution of HP-B-CD on the formation of microscopically visible particles, HMWP content, and semaglutide chemical purity in other identical citrate-buffered co-formulations of caglionepeptide and semaglutide. Composition

[0280] The compositions of co-formulations 25 to 32 are shown in Table 28. Table 28 Compositions of citrate-buffered caglionein and semaglutide co-formulations containing HP-B-CD excipients with different degrees of hydroxypropyl molar substitution. Element Co-mixing 25 26 27 28 29 30 31 32 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 15 - 25 - - - - - HP-B-CD (CycloLab) (% w / v) (Mean MS: 0.67, MS range: 0.6-0.9) 1 - - - 25 - - - - HP-B-CD Cavitron ® (Ashland) (% w / v) (Mean MS: 0.68, MS range: 0.58-0.72) 1 - - - - 25 - - - HP-B-CD Trappsol ® (CTD, Inc.) (% w / v) (Mean MS: 0.84, MS range: 0.8–1.0) 1 - - - - - 25 - - HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.92, MS range: 0.81-0.99) 1 - 15 - - - - 25 - HP-B-CD Cavitron ® (Ashland) (%w / v) (Average MS: 1.08, MS range: 0.86-1.14) 1 - - - - - - - 25 Citrate, 1 H2O (mM) 3 3 3 3 3 3 3 3 HCl qs qs qs qs qs qs qs qs NaOH qs qs qs qs qs qs qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. match Prepare a 1 ml volume Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.8 5.8 5.8 5.8 5.8 5.8 5.8 5.8 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0281] The formulation was prepared as described in Example 1. Method

[0282] Samples used to determine the number of particles visible only under a microscope were stored under pressure conditions defined as follows: - Duration: 28 days - Temperature: 30°C ± 2°C - Pressure conditions: During storage, the samples were inverted 360° to simulate patient use outside a cold storage room. The inversion was performed 20 times for three days per week and 40 times for two days per week.

[0283] The number of particles that can only be seen under a microscope is quantified as described in Example 4.

[0284] Samples used to determine the purity and HMWP content of semaglutide were stored at 37°C for up to 28 days. The purity of semaglutide was determined as in Example 14.

[0285] The extent of covalently bound HMWP was determined using size exclusion chromatography (SEC). Samples were analyzed using a Waters SEC 1.7 μm column (4.6 x 150 mm) and eluted isocratically with an inductively coupled eluent consisting of 185 mM sodium chloride, 5 mM sodium dihydrogen phosphate monohydrate, 3 mM orthophosphate, and 47% (v / v) isopropanol. Chromatography was performed at 50°C with UV detection (215 nm) using injection volumes of 1 to 8 μl and a flow rate of 0.3 ml / min. HMWP was quantified as the area of ​​all components eluted before the main peak divided by the area of ​​the main peak x 100%. Table 29 shows the microscopic particle content in citrate-buffered caglionein and semaglutide co-formulations containing HP-B-CD excipients with varying degrees of hydroxypropyl molar substitution. Co-mixing HP-B-CD Average Mole Substitution 1 The relationship between the number of particles visible only under a microscope and time (days) 0 14 twenty one 28 Particle size > 5μm 25 0.62 82 342 1232 25324 26 0.92 89 10108 13381 49863 27 0.62 126 550 370 448 28 0.67 59 356 191 887 29 0.68 77 27 629 4323 30 0.84 97 374 381 7031 31 0.92 106 244 761 3161 32 1.08 95 32626 54994 114586 Particle size > 10 μm 25 0.62 11 73 349 4799 26 0.92 9 4007 5128 20604 27 0.62 13 175 93 131 28 0.67 13 103 53 262 29 0.68 6 10 131 1542 30 0.84 18 129 135 2224 31 0.92 32 59 271 765 32 1.08 6 13421 29840 59104 Particle size > 25 μm 25 0.62 0 3 39 330 26 0.92 1 627 830 3461 27 0.62 0 3 8 13 28 0.67 0 1 6 27 29 0.68 0 1 5 245 30 0.84 1 3 34 296 31 0.92 3 4 46 56 32 1.08 1 825 7895 15815 The number of particles visible only under a microscope is the average of three replicates, rounded to the nearest integer. 1MS: molar substitution, corresponding to hydroxypropyl per glucose unit. Table 30: HMWP content in citrate-buffered caglionein and semaglutide co-formulations containing HP-B-CD excipients with different degrees of hydroxypropyl molar substitution. Co-mixing HP-B-CD molar replacement 1 Relationship between HMWP content (%) and time (days) at 37°C 0 14 twenty one 28 25 0.62 0.03% 0.08% 0.13% 0.18% 26 0.92 0.05% 0.12% 0.18% 0.22% 27 0.62 0.04% 0.08% 0.14% 0.15% 28 0.67 0.05% 0.11% 0.17% 0.20% 29 0.68 0.04% 0.09% 0.16% 0.20% 30 0.84 0.05% 0.12% 0.17% 0.21% 31 0.92 0.04% 0.13% 0.22% 0.27% 32 1.08 0.11% 0.47% 0.61% 0.76% 1MS: Morphine substitution, corresponding to hydroxypropyl per glucose unit. Table 31. Chemical purity (%) of semaglutide in citrate-buffered caglionein and semaglutide co-formulations containing HP-B-CD excipients with different degrees of hydroxypropyl morphine substitution. Co-mixing HP-B-CD molar replacement 1 Relationship between semaglutide purity (%) and time (days) at 37°C 0 14 twenty one 28 25 0.62 97.0% 95.3% 94.4% 93.8% 26 0.92 97.0% 95.1% 93.9% 93.4% 27 0.62 97.0% 95.2% 94.3% 93.4% 28 0.67 96.9% 95.0% 94.1% 93.5% 29 0.68 97.0% 95.3% 94.4% 93.5% 30 0.84 97.1% 95.4% 94.6% 93.8% 31 0.92 96.9% 94.4% 93.4% 92.3% 32 1.08 96.6% 91.4% 89.1% 87.5% 1MS: mol substitution, corresponding to hydroxypropyl total per glucose unit

[0286] The results presented in Tables 29, 30, and 31 show that physical stability, HMWP formation, and the chemical purity of semaglutide depend on the molar substitution of HP-B-CD when studied in citrate-buffered cagliolitin and semaglutide co-formulations. At 28 days, co-formulation 27, containing 25% w / v HP-B-CD (mean MS: 0.62), showed the lowest HMWP content and almost no increase in particle number. In contrast, co-formulation 32, containing 25% w / v HP-B-CD (mean MS: 1.08), showed a significant increase in particle number visible only under a microscope after just 14 days, and the highest HMWP content was observed at 28 days.

[0287] All citrate-buffered caglitinide and semaglutide co-formulations containing 25% w / v HP-B-CD (mean MS: 0.92 or less) are physically and chemically stable, with those containing 25% w / v HP-B-CD having a mean MS of 0.68 or less being the most stable.

[0288] Just 14 days later, an increase in the number of particles that could only be seen under a microscope was observed in co-regulation 26 containing 15% w / v HP-B-CD (mean MS: 0.92), indicating the physical instability of this particular co-regulation.

[0289] Co-blended compound 25 containing 15% w / v HP-B-CD (mean MS: 0.62) showed acceptable chemical and physical stability.

[0290] However, co-formulations 33 to 37 of caglinide and semaglutide containing 15% w / v HP-B-CD in a histidine buffer are preferred due to their superior physical stability. Using histidine as the buffer and sorbitol as the tonic, the preferred HP-B-CD molar substitution range is extended to an average of 0.62 to 0.92 (or a total of 0.58 to 1.0). Example 16: Effect of HP-B-CD molar substitution degree on the physical stability of caglinide and semaglutide co-formulations.

[0291] This example demonstrates the effect of the molar substitution degree of HP-B-CD on the microscopic particle content in other similar histidine-buffered caglionein and semaglutide co-formulations. Composition

[0292] The compositions of co-formulations 33 to 38 are shown in Table 32. Table 32 Compositions of histidine-buffered caglinide and semaglutide co-formulations 33 to 38 containing HP-B-CD excipients with different degrees of hydroxypropyl molar substitution. Element Co-mixing 33 34 35 36 37 38 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 15 - - - - - HP-B-CD (CycloLab) (% w / v) (Mean MS: 0.67, MS range: 0.6-0.9) 1 - 15 - - - - HP-B-CD Cavitron ® (Ashland) (% w / v) (Mean MS: 0.68, MS range: 0.58-0.72) 1 - - 15 - - - HP-B-CD Trappsol ® (CTD, Inc.) (% w / v) (Mean MS: 0.84, MS range: 0.8–1.0) 1 - - - 15 - - HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.92, MS range: 0.81-0.99) 1 - - - - 15 - HP-B-CD Cavitron ®(Ashland) (%w / v) (Average MS: 1.08, MS range: 0.86-1.14) 1 - - - - - 15 L-histidine (mM) 6 6 6 6 6 6 Sorbitol (mg / ml) 20 20 20 20 20 20 Polysorbate 80 (mg / ml) 0.05 0.05 0.05 0.05 0.05 0.05 HCl qs qs qs qs qs qs NaOH qs qs qs qs qs qs WFI Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. Prepare to a volume of 1 ml. pH 5.8 5.8 5.8 5.8 5.8 5.8 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0293] The formulation was prepared as described in Example 1. Method

[0294] Samples used to determine the number of microscopically visible particles were stored under pressure conditions defined as follows: - Duration: 28 days - Temperature: 30°C ± 2°C - Pressure conditions: During storage, the samples were inverted 360° to simulate patient use outside a cold storage room. Twenty rotations were performed for three days per week, and forty rotations were performed for two days per week. The number of microscopically visible particles was quantified as described in Example 4. Table 33 Number of microscopically visible particles in histidine-buffered caglionein and semaglutide co-formulations containing HP-B-CD with different degrees of hydroxypropyl molar substitution. Co-mixing HP-B-CD molar replacement 1 The relationship between the number of particles visible only under a microscope and time (days) 0 14 twenty one 28 Particle size > 5μm 33 0.62 19 300 252 460 34 0.67 37 176 220 66 35 0.68 twenty two 175 453 290 36 0.84 17 270 221 112 37 0.92 51 873 804 473 38 1.08 71 1311 1765 1621 Particle size > 10 μm 33 0.62 1 14 6 61 34 0.67 6 9 6 4 35 0.68 1 5 twenty three 56 36 0.84 1 13 0 6 37 0.92 3 45 twenty four 117 38 1.08 4 143 416 579 Particle size > 25 μm 33 0.62 0 0 0 3 34 0.67 0 0 0 0 35 0.68 0 3 0 1 36 0.84 0 0 0 4 37 0.92 0 1 1 20 38 1.08 1 0 14 27 The number of particles visible only under a microscope is the average of three replicates, rounded to the nearest integer. 1MS: mole substitution, corresponding to the sum of hydroxypropyl groups per glucose unit.

[0295] The results presented in Table 33 show that co-formulations 33 to 37, which include histidine buffers with HP-B-CD having extensive molar substitution (mean MS: 0.62 to 0.92), remained physically stable for 28 days.

[0296] In contrast, co-regulation 38, which includes HP-B-CD (mean MS: 1.08), is not physically stable after 14 days.

[0297] The results showed that the synergistic effect between cyclodextrin and other excipients in the co-regulation expanded the preferred range of molar substitution (mean MS: 0.62 to 0.92). Example 17: Effect of β-cyclodextrin substitution type on the physical stability of the co-regulation.

[0298] This example demonstrates the effect of sulfobutyl ether-β-cyclodextrin (SBE-B-CD) and hydroxypropyl-β-cyclodextrin on the physical stability of other co-formulated compounds of the same caglionemine and semaglutide. Composition

[0299] The composition systems of co-blended compounds 39 and 40 are shown in Table 36. Table 36 Compositions containing HP-B-CD or SBE-B-CD co-blended compounds Element Co-mixing 39 40 Carglinide drug substance (mg / ml) 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 15 - SBE-B-CD (CycloLab) (%w / v) (Average MS: 0.87, MS range: 0.84-0.99) 1 - 15 L-histidine (mM) 6 6 Sorbitol (mg / ml) 20 20 Polysorbate 80 (mg / ml) 0.05 0.05 HCl qs qs NaOH qs qs WFI Up to 1 ml Up to 1 ml pH 5.8 5.8 1MS: Morphine substitution, corresponding to the sulfobutyl ether / hydroxypropyl process per glucose unit.

[0300] The formulation was prepared as described in Example 1. Method

[0301] Samples used to determine the number of microscopically visible particles were stored under pressure conditions defined as follows: - Duration: 35 days - Temperature: 30°C ± 2°C - Pressure conditions: During storage, the samples were inverted 360° to simulate patient use outside a cold storage room. Twenty rotations were performed for three days per week, and forty rotations were performed for two days per week. The number of microscopically visible particles was quantified as described in Example 4. Table 37 Microscopically visible particle content in co-formulated caglinide and semaglutide containing HP-B-CD or SBE-B-CD Co-mixing Replacement type The relationship between the number of particles visible only under a microscope and time (days) 0 14 twenty one 28 35 Particle size > 5μm 39 HP-B-CD 49 122 61 245 324 40 SBE-B-CD 317 1686 6940 20714 280478 Particle size > 10 μm 39 HP-B-CD 4 8 5 20 20 40 SBE-B-CD 13 640 3503 10248 138324 Particle size > 25 μm 39 HP-B-CD 0 1 1 1 4 40 SBE-B-CD 0 126 738 2008 29834 The number of particles visible only under a microscope is the average of three replicates, summarized and rounded to the nearest integer.

[0302] The results in Table 37 show that when SBE-B-CD was used to co-regulate caglitinide and semaglutide, a significant increase in microscopically visible particles was observed after 14 days; that is, the co-regulated compound was physically unstable. When HP-B-CD was used instead, almost no increase was observed during the 35-day study period; that is, the co-regulated compound was physically stable.

[0303] Contrary to our previous findings regarding hydroxypropyl-β-cyclodextrin, these results demonstrate that sulfobutyl ether-β-cyclodextrin (SBE-B-CD) is not a suitable cyclodextrin for co-regulating cagliolitin and semaglutide. Example 18: Effect of pH on the physical and chemical stability of co-regulated compounds.

[0304] This example demonstrates the effect of pH on the physical and chemical stability of caglitazone in other identical caglitazone and smarutide co-formulations. Composition

[0305] The compositions of co-blended compounds 41 to 45 are shown in Table 38. Table 38 Compositions of co-blended compounds with different pH values Element Co-mixing 41 42 43 44 45 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 15 15 15 15 15 L-histidine (mM) 6 6 6 6 6 Sorbitol (mg / ml) 20 20 20 20 20 Polysorbate 80 (mg / ml) 0.05 0.05 0.05 0.05 0.05 HCl qs qs qs qs qs NaOH qs qs qs qs qs WFI (ml) Amount up to 1 Amount up to 1 Amount up to 1 Amount up to 1 Amount up to 1 pH 5.5 5.6 5.7 5.8 6.0 1MS: Morphine substitution, corresponding to hydroxypropyl per glucose unit.

[0306] The preparation method of the formulation is as described in Example 1.

[0307] Samples used to determine the number of particles visible only under a microscope were stored under pressure conditions defined as follows: - Duration: 28 days - Temperature: 30°C ± 2°C - Pressure conditions: During storage, the samples were inverted 360° to simulate patient use outside the refrigeration room. Twenty rotations were performed for three days each week, and forty rotations were performed for two days each week. The number of particles visible only under a microscope was quantified as described in Example 4.

[0308] Samples used to determine the purity of caglitinide were stored at 37°C for up to 28 days. The purity of caglitinide was determined as described in Example 14. Table 39 shows the physical stability of the co-formulations of caglitinide and smarutide in a pH range of 5.5 to 6.0 with different pH values. Co-mixing pH The relationship between the number of particles visible only under a microscope and time (days) 0 14 twenty one 28 Particle size > 5μm 41 5.5 70 6594 - 523259 42 5.6 69 174 730 1355 43 5.7 120 117 232 297 44 5.8 49 122 61 245 45 6.0 33 178 133 60 Particle size > 10 μm 41 5.5 6 851 - 385284 42 5.6 6 9 200 476 43 5.7 3 5 8 18 44 5.8 4 8 5 20 45 6.0 4 6 3 9 Particle size > 25 μm 41 5.5 1 4 - 190781 42 5.6 0 0 18 64 43 5.7 0 0 0 0 44 5.8 0 1 1 1 45 6.0 1 0 0 1 The number of particles visible only under a microscope is the average of three replicates and has been rounded to the nearest integer. (-) No sampling was performed. Table 40: Chemical purity (%) of caglinide in caglinide and smarutide co-regulations at pH ranges of 5.5 to 6.0. Co-mixing pH Relationship between caglinide purity (%) and time (days) at 37°C 0 14 28 41 5.5 97.1% 92.1% 85.9% 42 5.6 97.1% 91.6% 85.0% 43 5.7 97.0% 90.6% 83.2% 44 5.8 96.9% 88.9% 81.9% 45 6.0 96.9% 88.2% 78.3% Summarize

[0309] The results presented in Tables 39 and 40 show that the physical and chemical stability of semaglutide and cagliottide depends on the pH of the formulation: the highest pH resulted in the lowest cagliottide purity at 37°C after 28 days; the lowest pH resulted in an increase in the number of microscopically visible particles after 14 days. Based on these physical and chemical stability results, the preferred pH range for this particular cagliottide and semaglutide co-formulation is 5.6 to 6.0, while a pH of 5.5 did not result in a co-formulation with acceptable physical stability. Example 19: Effect of cagliottide and semaglutide concentration ratio on the physical stability of the co-formulation This example shows the effect of different concentration ratios of cagliottide and semaglutide on the microscopically visible particle content observed in the formulation.

[0310] The compositions of histidine buffer co-regulations 46 to 50 are shown in Table 41, and histidine buffer co-regulations 51 to 61 with slightly modified compositions are shown in Table 42. Table 41 Compositions of histidine buffer co-regulations with different concentration ratios of caglionein and smarutide. Element Co-mixing 46 47 48 49 50 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 Simalutide drug substance (mg / ml) 3.2 4.8 6.4 8.0 9.6 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 15 15 15 15 15 L-histidine (mM) 6 6 6 6 6 Sorbitol (mg / ml) 20 20 20 20 20 Polysorbate 80 (mg / ml) 0.05 0.05 0.05 0.05 0.05 HCl qs qs qs qs qs NaOH qs qs qs qs qs WFI Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml pH 5.8 5.8 5.8 5.8 5.8 1MS: Morphine substitution, corresponding to hydroxypropyl per glucose unit. Table 42. Histidine buffer co-regulatory compositions containing various concentration ratios of caglionein and smarutide. Element Co-mixing 51 52 53 54 55 56 57 58 59 60 61 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 4.8 6.4 8.0 9.6 9.6 9.6 9.6 10.7 12.8 16 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 20 20 20 20 15 20 20 20 20 20 20 L-histidine (mM) 6 6 6 6 6 6 6 6 6 6 6 Sorbitol (mg / ml) 35 35 35 35 35 20 35 35 35 35 35 Polysorbate 80 (mg / ml) 1.78 1.78 1.78 1.78 0.05 0.05 0.05 1.78 1.78 1.78 1.78 HCl qs qs qs qs qs qs qs qs qs qs qs NaOH qs qs qs qs qs qs qs qs qs qs qs WFI Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml pH 5.8 5.8 5.8 5.8 5.8 5.8 5.8 5.8 5.8 5.8 5.8 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0311] The formulation was prepared as described in Example 1. Method

[0312] Samples used to determine the number of microscopically visible particles were stored under pressure conditions defined as follows: - Duration: 28 days - Temperature: 30°C ± 2°C - Pressure conditions: During storage, the samples were inverted 360° to simulate patient use outside a cold storage room. Twenty rotations were performed for three days per week, and forty rotations were performed for two days per week. The number of microscopically visible particles was quantified as described in Example 4. Table 43: Content of microscopically visible particles in co-formulations containing different concentration ratios of caglitinide and semaglutide. Co-mixing Carglinide / Simaglutide concentration (ratio) The relationship between the number of particles visible only under a microscope and time (days) 0 14 twenty one 28 Particle size > 5μm 46 3.2 / 3.2 mg / ml (1:1) 207 214 542 341 47 3.2 / 4.8 mg / ml (1:1.5) 65 133 214 591 48 3.2 / 6.4 mg / ml (1:2) 55 76 198 134 49 3.2 / 8.0 mg / ml (1:2.5) 44 86 262 139 50 3.2 / 9.6 mg / ml (1:3) 56 184 137 540 51 3.2 / 3.2 mg / ml (1:1) 297 467 650 11684 52 3.2 / 4.8 mg / ml (1:1.5) 377 541 331 14453 53 3.2 / 6.4 mg / ml (1:2) 588 501 980 45916 54 3.2 / 8.0 mg / ml (1:2.5) 452 341 712 13108 55 3.2 / 9.6 mg / ml (1:3) 37 226 121 161 56 3.2 / 9.6 mg / ml (1:3) 55 77 290 315 57 3.2 / 9.6 mg / ml (1:3) 41 181 273 368 58 3.2 / 9.6 mg / ml (1:3) 312 457 445 25494 59 3.2 / 10.7 mg / ml (1:3.33) 1240 594 !043 53301 60 3.2 / 12.8 mg / ml (1:4) 1459 549 320 77697 61 3.2 / 16 mg / ml (1:5) 1025 568<s 877 5202 Particle size > 10μm 46 3.2 / 3.2 mg / ml (1:1) 18 31 25 51 47 3.2 / 4.8 mg / ml (1:1.5) 5 9 22 106 48 It should be noted that there seems to be a typo in the translation of "1043" as "!043" which should be corrected to "1043" in the above translation.3.2 / 6.4 mg / ml (1:2) 3 9 18 24 49 3.2 / 8.0 mg / ml (1:2.5) 10 9 13 13 50 3.2 / 9.6 mg / ml (1:3) 1 9 8 130 51 3.2 / 3.2 mg / ml (1:1) 38 45 79 1146 52 3.2 / 4.8 mg / ml (1:1.5) 69 94 80 2053 53 3.2 / 6.4 mg / ml (1:2) 74 81 171 7608 54 3.2 / 8.0 mg / ml (1:2.5) 78 57 118 1651 55 3.2 / 9.6 mg / ml (1:3) 5 9 5 14 56 3.2 / 9.6 mg / ml (1:3) 4 8 22 59 57 3.2 / 9.6 mg / ml (1:3) 0 15 27 61 58 3.2 / 9.6 mg / ml (1:3) 50 79 74 3233 59 3.2 / 10.7 mg / ml (1:3.33) 147 72 165 6793 60 3.2 / 12.8 mg / ml (1:4) 155 84 51 10270 61 3.2 / 16 mg / ml (1:5) 80 99 189 382 Particle size > micron 46 3.2 / 3.2 mg / ml (1:1) 1 0 4 1 47 3.2 / 4.8 mg / ml (1:1.5) 0 1 0 6 48 3.2 / 6.4 mg / ml (1:2) 0 1 3 3 49 3.2 / 8.0 mg / ml (1:2.5) 1 0 3 [[ID=,106]]3 50 3.2 / 9.6 mg / ml (1:3) 0 1 0 9 51 3.2 / 3.2 mg / ml (1:1) 0 0 1 13 52 3.2 / 4.8 mg / ml (1:1.5) 4 0 3 60 53 3.2 / 6.4 mg / ml (1:2) 8 4 6 157 54 3.2 / 8.0 mg / ml (1:2.5) 8 3 3 25 55 3.2 / 9.6 mg / ml (1:3) 0 0 1 0 56 3.2 / 9.6 mg / ml (1:3) 3 0 0 3 57 3.2 / 9.6 mg / ml (1:3) 0 0 4 0 58 3.2 / 9.6 mg / ml (1:3) 1 5 0 42 59 3.2 / 10.7 mg / ml (1:3.33) 1 0 5 97 60 3.2 / 12.8 mg / ml (1:4) 3 3 1 68 61 3.2 / 16 mg / ml (1:5) 8 4 26 8 The number of particles visible only under a microscope is the average of three replicates, summarized and rounded to the nearest integer.

[0313] The results presented in Table 43 show that after 21 days, almost no increase in the number of particles that could only be seen under a microscope was observed in co-formulations 46 to 60 containing 3.2 mg / ml caglitinide and up to 12 mg / ml semaglutide.

[0314] After 14 days, an increase in the number of particles visible only under a microscope was observed in the co-blended compound 61 containing 3.2 mg / ml caglinide and 16 mg / ml smarutide.

[0315] All histidine buffer co-regulations 46 to 61, including 3.2 mg / ml caglionetide and up to 16 mg / ml semaglutide, are physically stable. Example 20: Effect of HP-B-CD concentration on the physical stability of co-regulations.

[0316] This example demonstrates the effect of HP-B-CD concentration on the physical stability of a co-formulated compound of caglitazone and semaglutide, wherein the co-formulated compound was exposed to physical pressure. Components

[0317] The compositions of co-formulations 62 to 65 containing histidine buffer components are shown in Table 44. Table 44 Compositions of co-formulations containing different concentrations of HP-B-CD Element Co-mixing 62 63 64 65 Carglinide drug substance (mg / ml) 3.2 3.2 3.2 3.2 Simaglutide drug substance (mg / ml) 3.2 3.2 3.2 3.2 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 7.5 10 12.5 15 L-histidine (mM) 6 6 6 6 Sorbitol (mg / ml) 20 20 20 20 Polysorbate 80 (mg / ml) 0.05 0.05 0.05 0.05 HCl qs qs qs qs NaOH qs qs qs qs WFI Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml pH 5.8 5.8 5.8 5.8 1MS: Morphine substitution, corresponding to the hydroxypropyl process per glucose unit.

[0318] The formulation was prepared as described in Example 1. Method

[0319] The aggregation and tendency of caglinide and semaglutide in the co-blended formulations were measured using the thioflavin T (ThT) fluorescence stress assay as described in Example 2. Table 45 shows the physical stability of the co-blended formulations of caglinide and semaglutide with different HP-B-CD concentrations. Co-mixing HP-B-CD (MS: 0.62) 2 Delay time until fibrosis 62 7.5% w / v 17.66 hours 1 63 10% w / v 28.06 hours 1 64 12.5% ​​w / v 70.97 hours 1 65 15% w / v 119.0 hours 1 The result is the average 2MS of 6 replicates: mole substitution, corresponding to the hydroxypropyl content per glucose unit.

[0320] The results presented in Table 45 show that the physical stability of the co-formulations of caglitinide and semaglutide depends on the concentration of HP-B-CD; lower concentrations result in shorter hysteresis times for fibrosis. The co-formulation containing 7.5% w / v HP-B-CD was the least stable. The co-formulation containing 15% w / v HP-B-CD was the most stable. Example 21: Local subcutaneous tolerance of carrier formulations with different HP-B-CD contents, molar substitution degrees, and overall buffer composition upon subcutaneous injection.

[0321] This experiment examined: (1) the effects of HP-B-CD concentration and mean MS (0.62 vs. 0.92) on the local tolerance profile after subcutaneous injection; and (2) the effects of the formulation carrier on the local tolerance profile after subcutaneous injection in the presence of HP-B-CD. (Components)

[0322] The composition of the co-constituted carriers tested is shown in Table 46. Table 46 Composition of co-constituted carriers with different HP-B-CD content, molar substitution degree, and overall buffer composition. Element Co-modified carrier 9 10 11 12 13 14 15 16 HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.62, MS range: 0.58-0.68) 1 15 20 twenty two twenty two 25 20 twenty two - HP-B-CD KLEPTOSE® (Roquette) (% w / v) (Average MS: 0.92, MS range: 0.81-0.99) 1 - - - - - - - twenty two L-histidine (mM) 6 6 6 6 6 - - - Citrate, 1 H2O (mM) - - - - - 3 3 3 Sorbitol (mg / ml) 20 20 20 35 20 - - - Polysorbate 80 (mg / ml) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 HCl qs qs qs qs qs qs qs qs NaOH qs qs qs qs qs qs qs qs WFI Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml Up to 1 ml pH 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 1MS: Morphine substitution, corresponding to hydroxypropyl per glucose unit.

[0323] Except for the absence of added active pharmaceutical ingredients, the formulation was prepared as described in Example 1. Method

[0324] Following subcutaneous administration of a formulation containing HP-B-CD, local (subcutaneous) tolerance was assessed in four Landrace × Yorkshire × Duroc (LYD) pigs by using NovoPen 4 (32 G / 4 mm) with a NovoFine Plus needle to evaluate skin lesions resulting 6 days after subcutaneous administration of 200 µl (post-mortem examination). Skin samples measuring 2 x 2 cm were collected at post-mortem examination, fixed in neutral buffered formalin, trimmed with a multi-blade technique, embedded in paraffin, cut into 4 µm thin layers, mounted on glass slides, and subsequently stained with hematoxylin and eosin (HE). For the four samples, the severity of subcutaneous tissue necrosis and inflammatory cell infiltration was assessed by a trained toxicological pathologist using optical microscopy and scored on a numerical scale, with code 1 indicating "no abnormality detected" and code 5 indicating "significant severity": 1, No abnormality detected; 2, Very low severity; 3, Mild severity; 4, Moderate severity; 5, Significant severity.

[0325] The degree of subcutaneous tissue necrosis and inflammatory cell infiltration induced by the co-modified carrier after subcutaneous injection were evaluated. The results are presented in Table 47. Table 47: Severity score of subcutaneous tissue necrosis and inflammatory cell infiltration 6 days after injection of co-modified carriers with different HP-B-CD contents, molar substitution degrees, and buffer compositions. Co-modified carrier Necrosis Inflammatory cell infiltration, granulomatous 9 1,1,1,1 2,2,2,2 10 1,1,2,2 2,2,2,3 11 2,3,4,4 3,3,4,4 12 2,4,4,4 3,3,4,4 13 3,4,4,4 3,3,4,5 14 1,3,3,3 1,3,3,3 15 3,4,5,5 4,4,4,5 16 1,5,4,5 2,4,4,5 Summarize

[0326] The results in Table 47 show that in vivo local subcutaneous tolerability depends on the concentration of HP-B-CD and the overall buffer composition. Co-conjugated carriers containing histidine and sorbitol showed better tolerability than those co-conjugated carriers containing citrate.

[0327] Co-constitutes containing 20% ​​w / v or less HP-B-CD primarily resulted in no or very little necrosis or inflammatory cell infiltration (1 or 2 points) and mild inflammatory cell infiltration in a single observation (3 points). Co-constitutes containing 22% w / v or more HP-B-CD resulted in very little to moderate necrosis and inflammatory cell infiltration (scores up to 4). Based on these results, co-constitutes containing less than 22% HP-B-CD appear suitable for subcutaneous use.

[0328] Co-conjugated carriers containing 20% ​​w / v and 22% w / v HP-B-CD and citrate (co-conjugated carriers 14 and 15) resulted in significant necrosis and inflammatory cell infiltration (scores up to 5). Surprisingly, co-conjugated carriers containing 20% ​​w / v and 22% w / v HP-B-CD, histidine, and sorbitol (co-conjugated carriers 10 and 11) were better tolerable, resulting in moderate necrosis and inflammatory cell infiltration (scores up to 4).

[0329] While certain features of the invention have been described and illustrated herein, many modifications, substitutions, variations, and equivalents will now occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and alterations that fall within the true spirit of the invention. [Simplified Explanation of the Diagram]

[0010] None

Claims

1. A liquid pharmaceutical formulation comprising an amyloid receptor agonist, a GLP-1 receptor agonist, and a hydroxypropyl-substituted α- or β-cyclodextrin, and having a pH of 5.5 to 6.5, preferably 5.6 to 6.

0.

2. The pharmaceutical formulation as claimed in claim 1, wherein the GLP-1 receptor agonist is semaglutide.

3. The pharmaceutical formulation as claimed in any of the preceding claims, wherein the amyloid receptor agonist is caglionein.

4. The pharmaceutical compound as described in any of the preceding claims, having a pH value of about 5.6 to 6.

0.

5. The pharmaceutical compound as claimed in any of the preceding claims, wherein the cyclodextrin is a β-type substituted with hydroxypropyl.

6. The pharmaceutical formulation as claimed in any of the preceding claims, wherein the cyclodextrin comprises at least about 0.4 hydroxypropyl groups in each glucose unit and at most about 1.0 hydroxypropyl groups in each glucose unit.

7. The pharmaceutical compound as described in any of the preceding claims, comprising more than 10% w / v and less than 22% w / v of cyclodextrin, such as 10% to 20% w / v, such as about 15% w / v of cyclodextrin.

8. The pharmaceutical compound as described in any of the preceding claims, comprising effective amounts of caglitinide and semaglutide.

9. The pharmaceutical compound as claimed in any of the preceding claims further includes a tension agent, provided that the tension agent is not sodium chloride.

10. The pharmaceutical formulation as claimed in any of the preceding claims, wherein the tensioning agent is sorbitol, mannitol or trehalose; preferably sorbitol.

11. The pharmaceutical formulation as claimed in any of the preceding claims further comprises a buffer having at least one of a pKa of about 5.0 to 7.0, such as citrate or histidine; preferably histidine.

12. The pharmaceutical formulation as described in any of the preceding claims further includes surfactants such as polysorbate 20 and / or polysorbate 80.

13. The pharmaceutical compound as described in any of the preceding claims, comprising: - Effective amounts of cagliolitin and semaglutide, - hydroxypropyl β-cyclodextrin comprising at least about 0.4 hydroxypropyl groups per glucose unit and at most about 1.0 hydroxypropyl groups per glucose unit, such as 0.58 to 1.0 hydroxypropyl groups per glucose unit, - histidine, - sorbitol, - polysorbate 20 and / or 80, - water for injection, and - having a pH of 5.6 to 6.

0.

14. A pharmaceutical preparation comprising: - Effective amounts of cagliolitin and semaglutide, - More than 10% w / v and less than 22% w / v, such as 10% to 20% w / v hydroxypropyl β-cyclodextrin comprising at least about 0.4 and at most about 1.0 hydroxypropyl units per glucose unit, such as 0.58 to 1.0 hydroxypropyl units per glucose unit, - About 3 to 30 mM of histidine, - About 10 to 40 mg / ml of sorbitol, - Up to 2.0 mg / ml, such as up to 1.5 mg / ml of polysorbate 20 and / or 80, - About 75% to 90% w / w of water and - Having a pH of 5.6 to 6.

0.

15. A pharmaceutical preparation comprising: - Effective amounts of cagliolitin and semaglutide, - More than 10% w / v and less than 22% w / v, such as 10% to 20% w / v of hydroxypropyl β-cyclodextrin, which comprises an average of 0.62 to 0.84 hydroxypropyl groups per glucose unit, - About 3 to 30 mM of histidine and / or citrate, - About 10 to 40 mg / ml of sorbitol, - Up to 2.0 mg / ml, such as up to 1.5 mg / ml of polysorbate 20 and / or 80, - About 75% to 90% w / w of water and - Having a pH of 5.6 to 6.

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16. The pharmaceutical preparation as described in any of the preceding claims, which is used as a medicine.

17. The pharmaceutical compound as claimed in any of the preceding claims, for the treatment of overweight or obesity with or without one or more related comorbidities; diabetes with or without one or more related comorbidities; cardiovascular disease; non-alcoholic steatosis (NASH); and cognitive impairment.

18. The pharmaceutical preparation of any one of claims 1 to 14, used in any one of claims 16 to 17, characterized in that the preparation is administered by non-gastrointestinal injection, preferably subcutaneous injection.

19. The pharmaceutical compound of any one of claims 1 to 14, used in any one of claims 15 to 17, wherein the ratio of the dose of caglitinide administered to the dose of semaglutide administered is from 1:1 to 1:7.