Injectable drugs and administration devices for the treatment of metabolic diseases

Abstract

This relates to injectable drugs and administration devices for the treatment of metabolic diseases. [Solution] The injectable preparation comprises a lipid matrix composition, a specific amount of a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion. This allows for the formation of a depot upon contact of the injectable preparation with an aqueous liquid. This depot releases the GLP-1 receptor agonist sustainably in or out of the body. The injectable preparation for the treatment of metabolic diseases can be administered to individuals with reduced dosing frequency and does not require storage for subsequent administrations. For administration devices, the injectable preparation is filled into vials, pre-filled syringes, or pre-filled cartridges. Therefore, by designing the injectable preparation for single use, individual convenience, compliance, and adherence can be improved.

Description

[Technical Field]

[0001] The present invention relates to an injectable agent, a method for treating metabolic diseases, and an administration device. Specifically, the injectable agent comprises a lipid matrix composition, a specific amount of a glucagon-like peptide-1 receptor agonist (GLP-1 receptor agonist), and at least one pharmaceutically acceptable ion, such that a depot is formed upon contact with an aqueous liquid. This depot is characterized by the sustained release of the GLP-1 receptor agonist. [Background technology]

[0002] Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat type 2 diabetes, obesity, and related metabolic diseases. Specifically, GLP-1 receptor agonists in pancreatic β-cells can increase body mass and suppress apoptosis, and because their insulin secretion-promoting effect is glucose-dependent, they can effectively reduce the risk of hypoglycemia. When blood glucose is low, GLP-1 receptor agonists do not increase insulin secretion. GLP-1 receptor agonists also act on pancreatic α-cells to suppress glucagon secretion. GLP-1 receptor agonists also mimic natural hormones released after meals. They slow gastric emptying by slowing the movement of nutrients from the stomach to the small intestine, thus helping to regulate blood glucose levels. In addition, GLP-1 receptor agonists induce central satiety, reducing food intake and leading to weight loss.

[0003] However, GLP-1 receptor agonists are degraded by dipeptidyl peptidase-4 (DPP-4) in the blood and tissues of individuals. Consequently, the duration of action of GLP-1 receptor agonists is shortened. Therefore, in order to maintain their blood concentration within the therapeutic range, it is necessary to administer conventional injectable formulations containing GLP-1 receptor agonists to individuals once daily or once weekly.

[0004] Furthermore, conventional injectable drugs are administered according to a predetermined dosing schedule. Such schedules require more frequent administration, such as once a day or once a week, and patient compliance and adherence tend to decline over time.

[0005] In light of the above shortcomings, it is urgent to develop novel injectable agents containing GLP-1 receptor agonists, novel methods for treating metabolic diseases, and novel administration devices to solve the aforementioned problems. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] One aspect of the present invention provides a single-dose injectable formulation comprising phosphatidyl choline (PC), diacyl lipid, at least one biocompatible organic solvent, a specific amount of a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion. Upon contact with an aqueous liquid, the injectable formulation forms a depot. This depot releases the GLP-1 receptor agonist sustainably in or out of the body. Consequently, the frequency of administration of the injectable formulation can be reduced, and there is no need to store the formulation for subsequent administrations. Accordingly, the injectable formulation can be designed for single use to improve patient convenience, compliance, and adherence.

[0007] Another aspect of the present invention provides a method for treating metabolic diseases. In this method for treating metabolic diseases, a depot is formed, which reduces the frequency of administration of injectable drugs.

[0008] Another aspect of the present invention provides an administration device, which includes a vial, pre-filled syringe, or pre-filled cartridge containing an injectable drug. To reduce the frequency of administration, the injectable drug may be designed for single use, thereby improving patient convenience. [Means for solving the problem]

[0009] According to one aspect of the present invention, a single-dose injectable preparation is provided. This injectable preparation comprises phosphatidylcholine, a diacyl lipid, at least one biocompatible organic solvent, a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion. The at least one biocompatible organic solvent is selected from the group consisting of propylene glycol, N-methyl-2-pyrrolidone, ethanol, and glycerol. The at least one pharmaceutically acceptable ion is selected from the group consisting of alkali metal ions and phosphate ions. The concentration of the GLP-1 receptor agonist is 0.08 wt.% to 5.0 wt.% by weight of the injectable preparation. When the injectable preparation comes into contact with an aqueous liquid, a deposit is formed.

[0010] In one example, phosphatidylcholine is soybean phosphatidylcholine.

[0011] In one example, the diacyllipid is glycerol dioleate.

[0012] In one example, with the weight percentage of the injectable drug being 100 wt.%, the concentration of the GLP-1 receptor agonist was 0.1 wt.% to 4.0 wt.%.

[0013] In another example, the isoelectric point of the GLP-1 receptor agonist is greater than 3 and less than 7.

[0014] In another embodiment, the GLP-1 receptor agonist has a peptide backbone and a side chain connected thereto, the peptide backbone consisting of 28 to 40 amino acids, and the side chain has the structure shown in formula I below. [ka]

[0015] In formula I, n is an integer from 16 to 24, m is an integer from 0 to 3, * is a connection point, and the carbonyl group of the side chain is connected to an amino group of one of the 28 to 40 amino acids in the peptide backbone.

[0016] In another embodiment, n is an integer from 16 to 20.

[0017] In another embodiment, m is an integer from 0 to 2.

[0018] In another embodiment, the amino acid having an amino group to which the side chain is connected is lysine.

[0019] In another embodiment, the GLP-1 receptor agonist is liraglutide, semaglutide, bofanglutide, tirzepatide, or ecnoglutide.

[0020] In another embodiment, the alkali metal ion is selected from the group consisting of sodium ion, potassium ion, and lithium ion.

[0021] In another embodiment, the molar ratio of the alkali metal ion to the GLP-1 receptor agonist is greater than 0 and less than or equal to 25.

[0022] In another embodiment, the molar ratio of the phosphate ion to the GLP-1 receptor agonist is from 0.01 to 1.2.

[0023] In another embodiment, at least one pharmaceutically acceptable ion is an alkali metal ion and a phosphate ion.

[0024] In another embodiment, the alkali metal ion is a sodium ion.

[0025] In another example, the molar ratio of sodium ions to GLP-1 receptor agonist is 4 to 25.

[0026] In another embodiment, the injectable preparation for single administration further comprises an organic acid ion, halogen ion, basic amino acid, or a combination thereof, having a molecular weight of less than 200 g / mol (g / mol).

[0027] In another embodiment, the organic acid ion is selected from the group consisting of acetate ions, tartrate ions, and citrate ions.

[0028] In another embodiment, the organic acid ion is a tartrate ion, a citrate ion, or a combination thereof.

[0029] In another example, the molar ratio of acetate ions to the GLP-1 receptor agonist is 2.7 or less.

[0030] In another example, the molar ratio of organic acid ions to GLP-1 receptor agonists is 0.1 to 5.

[0031] In another embodiment, the halogen ion is selected from the group consisting of chloride ions, bromide ions, and iodide ions.

[0032] In another example, the molar ratio of halogen ions to GLP-1 receptor agonists is 0.1 to 20.

[0033] In another example, the molar ratio of chloride ions to the GLP-1 receptor agonist is 20 or less.

[0034] In another example, the weight ratio of diacyl lipids to phosphatidylcholine is 0.5 to 1.8.

[0035] In another example, the weight ratio of phosphatidylcholine to GLP-1 receptor agonist is 10 to 85.

[0036] In another example, the weight ratio of diacyl lipid to GLP-1 receptor agonist is 3 to 110.

[0037] In another example, with the weight percentage of the injectable agent being 100 wt.%, the concentration of at least one biocompatible organic solvent is 10 wt.% to 35 wt.%.

[0038] In another example, with N-methyl-2-pyrrolidone at a weight percentage of 100 wt.%, the concentration of propylene glycol is 2 wt.% to 10 wt.%.

[0039] In another example, with a weight percentage of ethanol of 100 wt.%, the concentration of propylene glycol is 80 wt.% to 120 wt.%.

[0040] In another example, the basic amino acid is selected from the group consisting of histidine, lysine, and arginine.

[0041] In another example, the molar ratio of basic amino acids to GLP-1 receptor agonists is 0.1 to 2.0.

[0042] In another embodiment, the injectable solution further contains water, and the concentration of water is 0 wt.% to 1.5 wt.%, with the weight percentage of the injectable solution being 100 wt.%.

[0043] According to another aspect of the present invention, a method for treating metabolic diseases is provided. In this method for treating metabolic diseases, an injectable agent for single administration is injected into the individual once every 20 to 45 days, the injectable agent comprising a lipid matrix composition, a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion. The at least one pharmaceutically acceptable ion is selected from the group consisting of alkali metal ions and phosphate ions. The content of the GLP-1 receptor agonist is 1.0 mg to 20 mg.

[0044] In one example, the GLP-1 receptor agonist content is 10 to 20 milligrams.

[0045] In another embodiment, the metabolic disease is selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases.

[0046] In another example, the lipid matrix composition comprises phosphatidylcholine, diacyl lipids, and at least one biocompatible organic solvent.

[0047] In another embodiment, the injectable agent is administered by subcutaneous injection, intramuscular injection, or intradermal injection.

[0048] In another embodiment, the method for treating a metabolic disorder further comprises administering a titration dose of a GLP-1 receptor agonist to the individual before administering a single-dose injectable agent. The titration dose is less than the amount of GLP-1 receptor agonist contained in the single-dose injectable agent.

[0049] In another example, the GLP-1 receptor agonist content was 10-20 milligrams.

[0050] In another example, the isoelectric point of the GLP-1 receptor agonist is greater than 3 and less than 7.

[0051] In another embodiment, the GLP-1 receptor agonist has a peptide backbone and a side chain attached thereto, the peptide backbone consisting of 28 to 40 amino acids, and the side chain has the structure shown in formula I below. [ka]

[0052] In formula I, n is an integer between 16 and 24, m is an integer between 0 and 3, and * is a connection point, which connects the carbonyl group of the side chain to one amino group among the 28 to 40 amino acids in the peptide backbone.

[0053] In another embodiment, n is an integer between 16 and 20.

[0054] In another embodiment, m is an integer between 0 and 2.

[0055] In another example, the amino acid having an amino group connected to the side chain is lysine.

[0056] In another example, the GLP-1 receptor agonist is liraglutide, semaglutide, bofunglutide, tilzepatide, or echnoglutide.

[0057] In another embodiment, the alkali metal ion is selected from the group consisting of sodium ions, potassium ions, and lithium ions.

[0058] In another example, the molar ratio of alkali metal ions to GLP-1 receptor agonists is greater than 0 and less than or equal to 25.

[0059] In another example, the molar ratio of phosphate ions to GLP-1 receptor agonists is 0.01 to 1.2.

[0060] In another embodiment, the single-dose injectable preparation further comprises an organic acid ion, a halogen ion, a basic amino acid, or a combination thereof, having a molecular weight of less than 200 g / mol.

[0061] In another embodiment, the organic acid ion is selected from the group consisting of acetate ions, tartrate ions, and citrate ions.

[0062] In another example, the molar ratio of organic acid ions to GLP-1 receptor agonists is 0.1 to 5.

[0063] In another embodiment, the halogen ion is selected from the group consisting of chloride ions, bromide ions, and iodide ions.

[0064] In another example, the molar ratio of halogen ions to GLP-1 receptor agonists is 0.1 to 20.

[0065] In another example, the weight ratio of diacyl lipids to phosphatidylcholine is 0.5 to 1.8.

[0066] In another example, with the weight percentage of the injectable agent being 100 wt.%, the concentration of at least one biocompatible organic solvent is 10 wt.% to 35 wt.%.

[0067] In another example, the basic amino acid is selected from the group consisting of histidine, lysine, and arginine.

[0068] In another example, the molar ratio of basic amino acids to GLP-1 receptor agonists is 0.1 to 2.0.

[0069] In another embodiment, the injectable solution further contains water, and the concentration of water is 0 wt.% to 1.5 wt.%, with the weight percentage of the injectable solution being 100 wt.%.

[0070] In another example, a titration dose of a GLP-1 receptor agonist is administered to the individual before administering a single-dose injection, and the titration dose is less than the GLP-1 receptor agonist content of the single-dose injection.

[0071] In another example, the ratio of the titration dose to the GLP-1 receptor agonist content of the injectable solution was 0.01 to 0.7.

[0072] According to another aspect of the present invention, the use of the above-mentioned injectable agent in the manufacture of a pharmaceutical composition for the treatment of metabolic diseases is provided.

[0073] According to another aspect of the present invention, a pharmaceutical composition comprising the above-mentioned injectable agent for the treatment of metabolic diseases is provided.

[0074] According to another aspect of the present invention, an injectable agent for the treatment of metabolic diseases is provided.

[0075] According to another aspect of the present invention, an administration device is provided. The administration device comprises a vial, a pre-filled syringe, or a pre-filled cartridge containing a single-dose injectable preparation. The injectable preparation comprises a lipid matrix composition, a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion. The at least one pharmaceutically acceptable ion is selected from the group consisting of alkali metal ions and phosphate ions. The concentration of the GLP-1 receptor agonist is 0.08 wt.% to 5.0 wt.% by weight of the injectable preparation, with a weight percentage of 100 wt.%.

[0076] In one example, with the weight percentage of the injectable drug being 100 wt.%, the concentration of the GLP-1 receptor agonist was 0.1 wt.% to 4.0 wt.%.

[0077] In another embodiment, the lipid matrix composition comprises phosphatidylcholine, diacyl lipids, and at least one biocompatible organic solvent.

[0078] In another embodiment, the vial, pre-filled syringe, and pre-filled cartridge are made of glass or plastic material.

[0079] In another embodiment, the plastic material is a cycloolefin polymer (COP), a cycloolefin copolymer (COC), polypropylene (PP), polyethylene (PE), or a mixture thereof. [Effects of the Invention]

[0080] In the application of the single-dose injectable preparation of the present invention, the injectable preparation comprises a lipid matrix composition, a specific amount of a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion, forming a depot that sustainably releases the GLP-1 receptor agonist in or out of the body. Therefore, in the treatment method for metabolic diseases of the present invention, the frequency of administration of the injectable preparation can be reduced. Furthermore, there is no need to store the injectable preparation for the next administration. Accordingly, the injectable preparation can be designed for single use. As for the administration device, the injectable preparation is filled in a vial, pre-filled syringe, or pre-filled cartridge, improving patient convenience, compliance, and adherence.

[0081] By referring to the following explanation in conjunction with the drawings, the embodiments and advantages of the present invention can be better understood. [Brief explanation of the drawing]

[0082] [Figure 1] Figure 1 shows the viscosity of several injectable formulations from the examples and comparative examples, measured at 20°C with shear rates ranging from 0.1 s⁻¹ to 1000 s⁻¹. However, Figure 1 includes Examples 1 to 3, Examples 6 to 10, Example 13, and Comparative Examples 1 to 3. [Figure 2] Figure 2 shows the viscosity of several injectable formulations from the examples and comparative examples, measured at 20°C with shear rates ranging from 0.1 s⁻¹ to 1000 s⁻¹. However, Figure 2 includes Examples 4-5, Examples 11-12, and Comparative Examples 1-3. [Modes for carrying out the invention]

[0083] Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. definition

[0084] One aspect of the present invention provides a single-dose injectable preparation. The injectable preparation comprises a lipid matrix composition, a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion. The lipid matrix composition consists of phosphatidylcholine, diacyl lipids, and at least one biocompatible organic solvent. When the injectable preparation comes into contact with an aqueous liquid, a depot is formed. This depot is used to extend the time for sustained release of the GLP-1 receptor agonist in or out of the body.

[0085] As used herein, the term "single administration" refers to administering an injectable drug to an individual in need in a single dose. After administration, the injectable drug is used up and discarded. There is no need to store the injectable drug for future administration.

[0086] As used herein, the term “depot” refers to a gel having a liquid crystalline structure. Specifically, when the injectable agent comes into contact with an aqueous liquid, the biocompatible organic solvent in the injectable agent disperses in the aqueous liquid, and the water in the aqueous liquid diffuses into the injectable agent. Thus, the lipid matrix composition is converted into a lipid matrix that embeds the GLP-1 receptor agonist, forming a gel having a liquid crystalline structure.

[0087] As used herein, the term “aqueous fluid” means a liquid containing water, such as the tissue fluid of an organism or an artificial aqueous solution under simulated physiological conditions, to which a GLP-1 receptor agonist is expected to be exposed. Examples include water, saline, and buffer solutions. Specifically, buffer solutions include, but are not limited to, phosphate buffers, citrate buffers, tris-hydroxymethylaminomethane buffers (tris buffer), and any buffer solution with a pH of 5 to 8 that is well known to those skilled in the art. On the other hand, the tissue fluid of an organism includes, but is not limited to, the subcutaneous, intramuscular, or intradermal fluid of a mammal, and the mammals include, for example, humans, dogs, monkeys, rabbits, rats, mice, and pigs.

[0088] As used herein, the terms “release in vivo” and “in-vivo release” refer to the release of a GLP-1 receptor agonist from a depot located within the body or body cavity of an individual, exposed to the tissue fluid of the individual, such as the subcutaneous fluid of a rat. Therefore, in animal studies, the release of a GLP-1 receptor agonist from a depot is evaluated by recording the pharmacokinetic curve of the GLP-1 receptor agonist after injection administration.

[0089] Instead, as used herein, the terms “release in vitro” and “in-vitro release” refer to the release of a GLP-1 receptor agonist from a depot located in an artificial aqueous solution under simulated physiological conditions (hereinafter referred to as the “elution medium”), including those under which the GLP-1 receptor agonist is expected to be exposed. Examples include physiological saline or phosphate buffer (with or without surfactants and / or enzymes). Accordingly, the extracorporeal release of the GLP-1 receptor agonist from the depot is evaluated by immersing the depot in an artificial aqueous solution under simulated physiological conditions for a predetermined time and measuring the residual rate of semaglutide remaining in the depot.

[0090] As used herein, the term "extended release" means that a GLP-1 receptor agonist is continuously released from a depot, either in vivo or extracorporeally, for at least 20 days.

[0091] In some examples of the lipid matrix composition, phosphatidylcholine (PC) may be obtained from natural sources. Examples of suitable sources of phosphatidylcholine include animal and plant sources such as egg yolk, bovine heart, or soybean. Either a single phosphatidylcholine or a mixture of phosphatidylcholines from these other sources may be used. Preferably, the injectable formulation uses soybean phosphatidyl choline (SPC) to extend the release time of the GLP-1 receptor agonist. In another example, the injectable formulation of the present invention does not contain dioleoyl phosphatidyl ethanolamine (DOPE).

[0092] In preferred embodiments, phosphatidylcholine (PC) is a phospholipid having a glycerol backbone, two fatty acid chains, and one phosphocholine head group. In some embodiments, the chemical structure of PC preferably includes two fatty acid chains containing 16 to 20 carbon atoms. These fatty acid chains may be saturated or unsaturated. These fatty acid chains independently contain 17 to 19 carbon atoms and 0 to 2 double bonds. In other embodiments, the injectable preparation may be dodecyl phosphatidylcholine (DPC).

[0093] For example, the phosphatidylcholine concentration may be 160-300 mg / mL, 160-380 mg / mL, 160-220 mg / mL, 170-250 mg / mL, 175-220 mg / mL, 180-200 mg / mL, 180-250 mg / mL, 180-230 mg / mL, 180-340 mg / mL, 190-220 mg / mL, 200-260 mg / mL, 200-360 mg / mL, 200-340 mg / mL, 195-280 mg / mL, 220-260 mg / mL, 220-380 mg / mL, 220-330 mg / mL, 300-380 mg / mL, or any value within the above range. When the phosphatidylcholine concentration is within the above range, gel formation is more likely, and the release time of GLP-1 receptor agonists is prolonged.

[0094] Diacyllipids are lipids in which one glycerol molecule is linked to two fatty acid molecules via an ester bond. In some examples, these two fatty acid molecules may be saturated or unsaturated and may independently contain C16-C20 alkyl and / or alkenyl groups. Preferably, as an injectable preparation, glycerol dioleate (GDO) is used to prolong the release time of the GLP-1 receptor agonist.

[0095] In some examples, the weight ratio of diacyl lipid to phosphatidylcholine is 0.5 to 1.8, and may be, for example, 0.6 to 1.8, 0.9 to 1.6, 0.5 to 0.8, or any value within the above range. When the weight ratio of diacyl lipid to phosphatidylcholine is 0.5 to 1.8, gel formation is facilitated and the release time of the GLP-1 receptor agonist is extended.

[0096] At least one biocompatible organic solvent is selected from the group consisting of propylene glycol (PG), N-methyl-2-pyrrolidone (NMP), ethanol, and glycerol. In some examples, with the weight percentage of the injectable preparation being 100 wt.%, the concentration of at least one biocompatible organic solvent is 10 wt.% to 35 wt.%, for example, 10 wt.%, 15 wt.%, 20 wt.%, 25 wt.%, 30 wt.%, 35 wt.%, or any value within the above range.

[0097] In other examples, with N-methyl-2-pyrrolidone at a weight percentage of 100 wt.%, the concentration of propylene glycol is 2 wt.% to 10 wt.%, for example, 2 wt.%, 4 wt.%, 6 wt.%, 8 wt.%, 10 wt.%, or any value within the above range. In yet another example, with ethanol at a weight percentage of 100 wt.%, the concentration of propylene glycol is 80 wt.% to 120 wt.%, for example, 80 wt.%, 90 wt.%, 100 wt.%, 110 wt.%, 120 wt.%, or any value within the above range. When at least one biocompatible organic solvent satisfies the above conditions, gel formation is facilitated and the release time of the GLP-1 receptor agonist is extended.

[0098] In another example, with the weight percentage of the injectable agent being 100 wt.%, the concentration of glycerol is 0.1 wt.% to 8 wt.%, preferably 0.5 wt.% to 5 wt.%. When the glycerol concentration satisfies the above conditions, gel formation is facilitated, and the release time of the GLP-1 receptor agonist is extended.

[0099] Furthermore, the injectable preparation of the present invention contains 1.0 mg to 20 mg (mg) of GLP-1 receptor agonist. If the GLP-1 receptor agonist content is less than 1.0 mg, the release time of the GLP-1 receptor agonist is shortened. Conversely, if the GLP-1 receptor agonist content exceeds 20 mg, the initial burst release of the GLP-1 receptor agonist from the gel increases, causing toxicity to the individual. In preferred examples, the GLP-1 receptor agonist content is 10 mg to 20 mg, more preferably 10 mg to 15 mg.

[0100] In some embodiments, the isoelectric point of the GLP-1 receptor agonist is greater than 3 and less than 7, preferably between 4 and 6. When the isoelectric point of the GLP-1 receptor agonist is within this range, the release time of the GLP-1 receptor agonist is prolonged.

[0101] Generally, GLP-1 receptor agonists have a peptide backbone and side chains connected to it. In some examples, the peptide backbone consists of 28 to 40 amino acids. The side chain has the structure shown in formula I below. [ka]

[0102] In formula I, n is an integer between 16 and 24, m is an integer between 0 and 3, and * is a connection point, which connects the carbonyl group of the side chain to one amino group among the 28 to 40 amino acids in the peptide backbone.

[0103] Preferably, n is an integer between 16 and 20, and / or m is an integer between 0 and 2. When n and / or m are one of the above integers, the release time of the GLP-1 receptor agonist is prolonged.

[0104] In some examples, the amino acid having an amino group to which the side chain is attached is lysine. When the amino acid having an amino group to which the side chain is attached satisfies the above conditions, the release time of the GLP-1 receptor agonist is prolonged.

[0105] In preferred embodiments, the GLP-1 receptor agonist is liraglutide, semaglutide, bofunglutide, tilzepatide, or echnoglutide. When the GLP-1 receptor agonist satisfies the above conditions, the release time of the GLP-1 receptor agonist is prolonged. Preferably, the critical micelle concentration of the GLP-1 receptor agonist in aqueous solution is 0.06 wt.%.

[0106] In specific examples, the semaglutide concentration is between 10 micrograms / microliter (mg / mL) and 35 mg / mL, for example, 15 mg / mL to 25 mg / mL, 15 mg / mL to 20 mg / mL, 20 mg / mL to 25 mg / mL, or any value within the above range. In alternative examples, the semaglutide concentration can be 10, 15, 20, 25, 35 mg / mL, or any value within the above range. Alternatively, the semaglutide concentration may be between 1.5 wt.% and 4.5 wt.%, or any value within the above range.

[0107] In other specific examples, the concentration of semaglutide may be 0.5 mg / mL to 25 mg / mL, for example, 2 to 20 mg / mL, 3 to 15 mg / mL, 4 to 10 mg / mL, or any value within the above range. In alternative examples, the concentration of semaglutide may be 0.5, 2, 3, 4, 10, 15, 20, 25 mg / mL, or any value within the above range. Alternatively, with the weight percentage of the injectable preparation being 100 wt.%, the concentration of semaglutide may be 0.08 wt.% to 5.0 wt.%, for example, 0.1 wt.% to 4.0 wt.%, 0.2 wt.% to 3.0 wt.%, 0.3 wt.% to 2.5 wt.%, 0.4 wt.% to 2.0 wt.%, or any value within the above range. For example, the semaglutide concentration may be 0.08 wt.%, 0.1 wt.%, 0.2 wt.%, 0.3 wt.%, 0.4 wt.%, 0.5 wt.%, 0.6 wt.%, 0.7 wt.%, 0.8 wt.%, 0.9 wt.%, 1.0 wt.%, 2.0 wt.%, 3.0 wt.%, 4.0 wt.%, 5.0 wt.%, or any value within the above range.

[0108] GLP-1 receptor agonists can promote glucose-stimulated insulin secretion and biosynthesis, suppress glucagon secretion, delay gastric emptying, and reduce food intake and appetite. The synergistic effect of these actions may contribute to blood glucose regulation and lead to weight loss. Therefore, GLP-1 receptor agonists can reduce cardiovascular risk, reduce weight, and improve lipid levels in patients with type 2 diabetes.

[0109] In some embodiments, the GLP-1 receptor agonists of the present invention also function as glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, specifically referred to as GLP-1 / GIP receptor dual agonists. In some embodiments, the GLP-1 / GIP receptor dual agonists may contain tirzepatide. In relevant embodiments, the tirzepatide content of the injectable preparation is greater than 15 mg but less than 60 mg, 20-55 mg, 25-50 mg, or 30-90 mg.

[0110] At least one pharmaceutically acceptable ion is selected from the group consisting of alkali metal ions and phosphate ions. In some examples, the alkali metal ion is selected from the group consisting of sodium ions, potassium ions, and lithium ions. Preferably, the injectable preparation uses sodium ions. When sodium ions, potassium ions, or lithium ions are present in the injectable preparation, the release time of the GLP-1 receptor agonist from the gel is prolonged.

[0111] Alkali metal ions can be introduced into injectable preparations by using the corresponding alkali metal salts or alkali metal hydroxides. The corresponding alkali metal salts may include, but are not limited to, alkali metal halides or alkali metal salts of weak organic or weak inorganic acids. Preferably, weak organic and weak inorganic acids have good buffering capacity to resist changes in pH.

[0112] In alternative embodiments, the hydrogen atoms in the carboxylic acid group of the GLP-1 acceptor agonist can be partially or completely replaced with alkali metal ions by ion exchange techniques (e.g., using ion exchange resins). In the relevant embodiments, the alkali metal ions are derived from buffer solutions of the corresponding alkali metal salts dissolved in a polar solvent (e.g., water).

[0113] Furthermore, in a preferred example, the molar ratio of alkali metal ions to GLP-1 receptor agonists is greater than 0 and less than or equal to 25, preferably 1 to 22, and more preferably 1 to 11. For example, the molar ratio of alkali metal ions to GLP-1 receptor agonists is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or any number within the above range. When the molar ratio of alkali metal ions to GLP-1 receptor agonists satisfies the above conditions, the release time of the GLP-1 receptor agonist is extended.

[0114] Instead, in other examples, the molar ratio of phosphate ions to GLP-1 receptor agonists is 0.01 to 1.2, preferably 0.01 to 1.0, and more preferably 0.04 to 0.9. For example, the molar ratio of phosphate ions to GLP-1 receptor agonists is 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or any value within the above range. When the molar ratio of phosphate ions to GLP-1 receptor agonists satisfies the above conditions, the release time of the GLP-1 receptor agonist is extended.

[0115] In a preferred example, the pharmaceutically acceptable ions are alkali metal ions (e.g., sodium ions) and phosphate ions, and the molar ratio of alkali metal ions to phosphate ions is 1 to 300, for example, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 130, 150, 170, 190, 200, 210, 230, 250, 270, 290, or any value within the above range. Within the above molar ratio range, the injectable can obtain an appropriate viscosity, and the gel formed by the injectable can have a perfect appearance.

[0116] Organic acid ions and phosphate ions can be introduced into injectable preparations using the corresponding acids or their salts, such as acetic acid, citric acid, phosphoric acid, sodium acetate, sodium citrate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. For example, these ions may be added directly to the injectable preparation as a buffer solution of their salts, or indirectly as the corresponding acids.

[0117] As those skilled in the art will understand, in an aqueous solution, depending on the pH value of the aqueous solution, phosphoric acid can be partially or incompletely ionized, and in such a state, phosphoric acid can produce phosphate ions. Therefore, the phosphate ion of the present invention is an orthophosphate ion (PO4). 3- ), hydrogen phosphate ion (HPO4) 2- ), and dihydrogen phosphate (H2PO4) - ) is included. Accordingly, the phosphate ion content of the present invention is the sum of the contents of the aforementioned plurality of ions.

[0118] In another embodiment, the single-dose injectable preparation may further contain organic acid ions, halogen ions, basic amino acids, or combinations thereof, having a molecular weight of less than 200 g / mol.

[0119] In some examples, organic acid ions with a molecular weight of less than 200 g / mol are selected from the group consisting of acetate ions, tartrate ions, and citrate ions. When the injectable agent uses acetate ions, tartrate ions, or citrate ions, the release time of the GLP-1 receptor agonist is prolonged.

[0120] Specifically, in some examples, the molar ratio of organic acid ions to GLP-1 receptor agonists is 0.1 to 5, preferably 0.1 to 2.5, and more preferably 0.1 to 0.95. For example, the molar ratio of organic acid ions to GLP-1 receptor agonists is 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, or any value within the above range. When the molar ratio of organic acid ions to GLP-1 receptor agonists satisfies the above conditions, the release time of the GLP-1 receptor agonist is extended.

[0121] In some preferred examples, the organic acid ions are tartrate ions, citrate ions, or a combination thereof, and do not contain acetate ions. In some examples, the molar ratio of acetate ions to the GLP-1 receptor agonist is 2.7 or less, for example, 0.01, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 2.6, or any value within the above range.

[0122] In another embodiment, the halogen ion is selected from the group consisting of chloride ions, bromide ions, and iodide ions. Preferably, the halogen ion is a chloride ion or a bromide ion. When chloride ions, bromide ions, or iodide ions are used in the injectable formulation, the release time of the GLP-1 receptor agonist is extended.

[0123] In related examples, the molar ratio of halogen ions to GLP-1 receptor agonists is 0.1 to 20, preferably 0.1 to 17, and more preferably 0.1 to 7. For example, the molar ratio of halogen ions to GLP-1 receptor agonists is 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, or any value within the above range. When the molar ratio of halogen ions to GLP-1 receptor agonists satisfies the above conditions, the release time of the GLP-1 receptor agonist is extended.

[0124] In some cases, chloride ions are removed from the components of the injectable to reduce its viscosity. In some cases, the molar ratio of chloride ions to the GLP-1 receptor agonist is 20 or less, for example, 0.01, 0.1, 0.25, 0.5, 0.75, 1.0, 4.0, 6.0, 7.0, 8.0, 10, 12, 14, 16, 17, 18, 20, or any value within the above range. Within the above molar ratio range, the injectable can achieve an appropriate viscosity, and the gel formed by the injectable can have a perfect appearance.

[0125] Halogen ions can be introduced into injectable preparations using salts of the corresponding halides or aqueous solutions of hydrogen halides. In relevant examples, the halogen ions are derived from aqueous solutions of salts of the corresponding halides, such as sodium chloride, potassium chloride, and sodium bromide.

[0126] As mentioned above, in specific examples, alkali metal ions can be introduced into injectable preparations together with organic acid ions, phosphate ions, or halogen ions. For example, sodium acetate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, or combinations thereof can be dissolved in a polar solvent (e.g., water or ethanol) and then added to the injectable preparation. In these examples, the molar ratio of alkali metal ions to the anions is determined based on the stoichiometrically relationship of their corresponding salts.

[0127] However, in other examples, the molar ratio of alkali metal ions to the anions is not determined based on the stoichiometry of their corresponding salts. In these related examples, the alkali metal ions and the anions are introduced into the injectable formulation independently or partially alone. When the molar ratio of alkali metal ions to the anions is not determined based on the stoichiometry of their corresponding salts, the release time of the GLP-1 receptor agonist is prolonged.

[0128] In another embodiment, the single-dose injectable preparation of the present invention further comprises a basic amino acid. Specifically, the basic amino acid is selected from the group consisting of histidine, lysine, and arginine. When at least one of the basic amino acids is present in the injectable preparation, the release time of the GLP-1 receptor agonist from the gel is extended.

[0129] In some cases, the molar ratio of basic amino acids to GLP-1 receptor agonists is 0.1 to 2.0, preferably 0.1 to 1.5, and more preferably 0.5 to 0.8. For example, the molar ratio of basic amino acids to GLP-1 receptor agonists is 0.1, 0.5, 1.0, 1.5, 2.0, or any value within the above range. When the molar ratio of basic amino acids to GLP-1 receptor agonists is within the above range, the release time of the GLP-1 receptor agonist from the gel is extended.

[0130] In preferred examples, the injectable formulation of the present invention does not contain somatostatin receptor agonists, octreotide, setmelanotide, leuprolide, pasireotide, granisetron, gonadotropin-releasing hormone (GnRH) agonists, goserelin, buprenorphine, opioids, prostacyclin, 5-HT3 antagonists, or any combination thereof. When the active ingredient of the injectable formulation does not contain the above-mentioned active ingredients, the injectable formulation can provide a good therapeutic effect.

[0131] In preferred examples, the injectable formulation of the present invention does not contain polyethylene glycosylated fatty acid, polyethylene glycosylated phospholipid, polyethylene glycosylated glyceryl fatty acid ester, ester of sugar, or any combination thereof. When the injectable formulation of the present invention does not contain the above excipients, the release time of the GLP-1 receptor agonist from the gel can be extended, or the thermal stability or injectability of the injectable formulation can be improved. In other examples, the injectable preparation of the present invention does not contain polysorbate 80, polysorbate 20, sugars, sugar derivatives such as sorbitan monooleate, sorbitan dioleate, sorbitan trioleate, or sorbitan tetraoleate.

[0132] In some embodiments, the injectable preparation of the present invention may further contain water, with the water concentration being 0-1.5 wt.%, for example, 0.1-1.5 wt.%, 0.5-1.5 wt.%, 0.5-1.0 wt.%, or 1.0-1.5 wt.%, with the weight percentage of the injectable preparation being 100 wt.%. When the water concentration in the injectable preparation is within the above range, a small amount of water extends the release time of the GLP-1 receptor agonist. Specifically, the water concentration in the injectable preparation of the present invention can be determined by measuring the water content of the injectable preparation using a Karl-Fischer titrator.

[0133] In an extracorporeal release test, the injectable drug is placed in an elution medium and then allowed to stand for 20-30 minutes to form a gel. The gel, placed in a rotating elution basket, is immersed in the elution medium until a predetermined time point. Next, the amount of GLP-1 receptor agonist remaining in the gel is measured by liquid chromatography, and the residual rate of the GLP-1 receptor agonist is calculated based on 100 wt.% of the original weight of the GLP-1 receptor agonist in the injectable drug. Assuming that the sum of the residual rate and the release rate of the GLP-1 receptor agonist is equal to 100 wt.%, the release rate can be calculated.

[0134] If the remaining percentage of GLP-1 receptor agonists in the gel exceeds 0%, it indicates that the time it takes for the GLP-1 receptor agonists to be released from the gel exceeds a predetermined time point corresponding to the measurement of their remaining amount. In some examples, after 20 days in the elution medium, the remaining percentage of GLP-1 receptor agonists in the gel exceeds 24%, preferably exceeds 50%, and more preferably exceeds 60%. In other examples, after 31 days in the elution medium, the remaining percentage of GLP-1 receptor agonists in the gel exceeds 23.5%, preferably exceeds 40%, and more preferably exceeds 55%.

[0135] On the other hand, in endogenous release tests, the injectable agent is subcutaneously injected into the animal body, and then the pharmacokinetic curve of the GLP-1 receptor agonist in the blood is recorded to evaluate the time it takes for the GLP-1 receptor agonist to be released from the gel into the animal's tissue fluid. In some examples, the GLP-1 receptor agonist is released from the gel in the body for 20 days, more than 20 days, preferably more than 30 days, and more preferably more than 40 days. In some examples, the GLP-1 receptor agonist is released from the gel in the body for 25 to 30 days. In other examples, the GLP-1 receptor agonist is released from the gel in the body for 21 to 42 days, 21 to 35 days, 28 to 42 days, 28 to 35 days, or 35 to 42 days.

[0136] The sustained release of the GLP-1 receptor agonist of the present invention extends the duration of action in the body, thereby reducing the frequency of administration of the injectable drug. This allows the injectable drug to be designed for single use. Since the unit dose of the injectable drug can be used up in one go, there is no need to store the injectable drug until the next administration. Therefore, the injectable drug of the present invention can provide greater convenience to patients and improve patient compliance and adherence.

[0137] In addition to reducing the frequency of administration, the injectable formulation of the present invention has excellent thermal stability. Therefore, it does not need to be maintained at 2°C to 8°C like conventional injectable formulations, and can be stored and transported at room temperature. The thermal stability of the injectable formulation is evaluated by its appearance and its GLP-1 receptor agonist content (assay).

[0138] In some examples, no precipitate or gel formed in the injectable agent after six consecutive cycles of freezing at -20°C and thawing at 25°C. Preferably, after six consecutive cycles of freezing at -20°C and thawing at 25°C, the GLP-1 receptor agonist content of the injectable agent decreased by less than 17%.

[0139] Furthermore, the injectable agent of the present invention has rheological properties and can improve syringeablility. Specifically, the injectable agent can be easily administered through a thin needle, and unlike the puncture pain or dull ache caused by the thick needles of conventional injectable agents, it provides comfort to the patient during the administration process. In some examples, at 20°C, the injectable agent was 0.1 to 0.5 s -1 Viscosity measured at shear rates of 100-1000 s -1 It is greater than the viscosity measured at the shear rate. In a specific example, the 1s of the injectable drug -1 The viscosity measured at a shear rate of 1s is less than 1000 millipascal seconds (mPa·s), which improves the injectability of the injectable drug. For example, at a shear rate of 1s -1In this case, the viscosity of the injectable solution is 50 mPa·s, 100 mPa·s, 200 mPa·s, 300 mPa·s, 400 mPa·s, 500 mPa·s, 600 mPa·s, 700 mPa·s, 800 mPa·s, 900 mPa·s, 950 mPa·s, or any value within the above range.

[0140] Another aspect of the present invention provides an administration device. The administration device includes a vial, a pre-filled syringe, or a pre-filled cartridge. The vial, pre-filled syringe, and pre-filled cartridge are all filled with a single-dose injectable agent. The injectable agent comprises a lipid matrix composition, a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion. The at least one pharmaceutically acceptable ion is selected from the group consisting of alkali metal ions and phosphate ions. In some examples, with the weight percentage of the injectable agent being 100 wt.%, the concentration of the GLP-1 receptor agonist is 0.08 wt.% to 5.0 wt.%, and a single-dose dose of 1.0 mg to 20 mg of the GLP-1 receptor agonist is provided. In other examples, with the weight percentage of the injectable drug set to 100 wt.%, the concentration of the GLP-1 receptor agonist is 0.08 wt.% to 5.0 wt.%, providing a single dose of 15 mg to 90 mg of GLP-1 receptor agonist.

[0141] In some embodiments, the administration device is a device well known to those skilled in the art, and the vials, pre-filled syringes, and pre-filled cartridges may be manufactured from materials used by those skilled in the art. In other embodiments, the vials, pre-filled syringes, and pre-filled cartridges are manufactured from glass or plastic materials. Glass materials can improve the biocompatibility of the vials, pre-filled syringes, and pre-filled cartridges.

[0142] On the other hand, the injection molding process for vials, pre-filled syringes, and pre-filled cartridges allows plastic materials to be provided with precise dimensions for these items. Therefore, the dead volume within the vials, pre-filled syringes, and pre-filled cartridges can be minimized.

[0143] Preferably, the plastic material includes, but is not limited to, cycloolefin polymers (COP), cycloolefin copolymers (COC), polypropylene (PP), polyethylene (PE), or mixtures thereof. Cycloolefin polymers and cycloolefin copolymers have particularly excellent solvent resistance to biocompatible organic solvents (e.g., ethanol). When vials, pre-filled syringes, and pre-filled cartridges are manufactured using these plastic materials, the vials, pre-filled syringes, and pre-filled cartridges have accurate dimensions and good biocompatibility.

[0144] Another aspect of the present invention provides a method for treating metabolic diseases. In this method for treating metabolic diseases, a single-dose injectable agent is administered to the individual every 20 to 45 days. For example, it may be administered every 20 days, every 25 days, every 30 days, every 35 days, every 40 days, every 45 days, or at any number of days within the above range. In some examples, the injectable agent is administered to the individual every 20 to 30 days, every 30 to 40 days, every 25 to 35 days, or every 35 to 45 days. In other examples, the injectable agent is administered to the individual every 21 to 42 days, every 21 to 35 days, every 28 to 42 days, every 28 to 35 days, or every 35 to 42 days.

[0145] As used herein, the term “subject” refers to mammals such as humans, dogs, monkeys, rabbits, rats, mice, and pigs. In some examples, the subjects do not have medullary thyroid carcinoma, multiple endocrine neoplasia type 2 syndrome, or pancreatitis.

[0146] In the treatment of metabolic diseases, the frequency or interval of administration of injectable drugs is determined by the duration of action of the GLP-1 receptor agonist in the body, and the duration of action may be evaluated by the release of the GLP-1 receptor agonist from the depot, such as the extracorporeal and intracorporeal release of the GLP-1 receptor agonist described above.

[0147] In some embodiments, the injectable drug may be administered to the individual in a manner that sequentially increases the dose of the GLP-1 receptor agonist. For example, the dose of the GLP-1 receptor agonist may be increased by 1 to 20 mg with each subsequent administration. In these embodiments, the individual is first administered a small volume of the injectable drug, followed by a larger volume of another injectable drug. The injectable drug may be administered to the individual in a manner that sequentially increases the dose of the GLP-1 receptor agonist by changing the volume of the injectable drug.

[0148] Generally, the route of administration for injectable drugs may be one that is well known to those skilled in the art. For example, injectable drugs may be administered by subcutaneous injection, intramuscular injection, or intradermal injection.

[0149] In a treatment method for metabolic diseases, it is preferable to administer a titration dose of GLP-1 receptor agonist to the individual before administering the injectable drug. The titration dose is less than the amount of GLP-1 receptor agonist contained in the injectable drug. The titration dose of GLP-1 receptor agonist may be administered orally or by other routes of administration well known to those skilled in the art. On the other hand, the amount of GLP-1 receptor agonist contained in the injectable drug is called the maintenance dose.

[0150] In some embodiments, the titration dose is 1.0 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.25 mg, 4.5 mg or 4.75 mg less than the maintenance dose. In other embodiments, the weight ratio of the titration dose to the maintenance dose is 0.01 to 0.7, 0.02 to 0.5, 0.3 to 0.7 or 0.25 to 0.5. When the above-described method further includes administration of a GLP-1 receptor agonist at a titration dose, the therapeutic effect can be improved.

[0151] In related examples, the GLP-1 receptor agonist at the titration dose may be administered once a week, and after continuing for 1 to 4 weeks, may shift to a subsequent dosing schedule of administering the GLP-1 receptor agonist at the maintenance dose once a month. In a specific example, the GLP-1 receptor agonist at the titration dose may be administered once every 7 to 21 days, once every 10 to 18 days, once every 21 to 35 days or once every 24 to 31 days. Specifically, the GLP-1 receptor agonist at the titration dose may be continuously administered until the concentration of the GLP-1 receptor agonist in the individual's blood reaches 3 nanograms / milliliter (ng / mL) to 6 ng / mL.

[0152] Furthermore, the GLP-1 receptor agonist at the titration dose may be administered 1 to 3 times, and the dosing interval is 1 to 3 weeks. In related examples, the GLP-1 receptor agonist at the titration dose may be incremented sequentially. Also, the GLP-1 receptor agonist at the maintenance dose may be incremented sequentially. As an example, the GLP-1 receptor agonist at the maintenance dose may be incremented by 1 to 10 mg, and preferably by 5 to 10 mg, at each subsequent administration.

[0153] Regarding the pharmacokinetic curve, in some embodiments, the maximum blood concentration (C max ) of the GLP-1 receptor agonist in the individual's blood is the minimum blood concentration (C min) is 15 times or less, preferably 12 times or less, and more preferably 9 times or less. For example, the C of a GLP-1 receptor agonist in the blood of an individual. max This refers to the C of GLP-1 receptor agonists in the blood of an individual. min It is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times or less.

[0154] In preferred embodiments, the peak blood concentration of the GLP-1 receptor agonist in the individual's blood (C max ) is the lowest blood concentration (C) of the GLP-1 receptor agonist in the individual's blood. min ) is 9 times or less, preferably 5 times or less, and more preferably 3 times or less. In a specific example, the C of semaglutide in the blood of an individual. max This refers to the C of semaglutide in the blood of an individual. min It is 9 times or less, preferably 5 times or less, and more preferably 3 times or less. max and C min If the above conditions are met, individual compliance and adherence can be improved.

[0155] In specific examples, metabolic diseases may be selected from the group consisting of type 1 diabetes, type 2 diabetes, obesity, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases. Preferably, the content of the GLP-1 receptor agonist in the injectable drug can be optimized based on the indication for the metabolic disease.

[0156] Furthermore, the above metabolic diseases can be treated or alleviated by lowering blood glucose levels, suppressing glucagon secretion from pancreatic α-cells, lowering blood HbA1c levels, and / or delaying gastric emptying. In some examples, after at least 3 months of treatment, the individual's HbA1c level decreased by at least 1.0%, for example, by 1.0-3.0%. In related examples, after at least 3 months of treatment, the body weight of individuals without type 2 diabetes decreased by at least 5%, for example, by 5-23%. In related examples, after at least 3 months of treatment, the individual's food intake decreased by at least 20%, for example, by 20-40%. In related examples, several metabolic parameters of the individual, such as cholesterol levels and blood glucose levels, can be improved.

[0157] Examples 1 to 15 and Comparative Examples 1 to 3

[0158] Preparation of injectable drugs

[0159] According to Tables 1 to 4, in each example, soy phosphatidylcholine and glycerol dioleate were dissolved in the required solvent at room temperature (approximately 25°C) to prepare a non-aqueous solution. Then, under a nitrogen atmosphere at room temperature, semaglutide and other components were added to the non-aqueous solution and dissolved to obtain the prepared injectable formulation. The prepared injectable formulation was filled into syringes made of glass or cycloolefin polymer (COP). In Tables 1 to 4, the term "NA" indicates that the corresponding component was not used in the injectable formulation. N-methyl-2-pyrrolidone or ethanol was used as a solvent, and the amount added was adjusted so that the weight of the corresponding prepared injectable formulation was 100 wt.%. In all examples and all comparative examples, with the weight percentage of the corresponding prepared injectable formulation being 100 wt.%, the concentration of at least one biocompatible organic solvent was between 10 wt.% and 35 wt.%. Furthermore, in all examples and comparative examples, the volume of the prepared injectable solution ranged from 0.4 milliliters (mL) to 2 milliliters. Unless otherwise specified, in Tables 1 to 4, the concentration of each component is expressed based on 100 wt.% of the weight of the corresponding prepared injectable solution.

[0160] [Table 1]

[0161] [Table 2]

[0162] [Table 3]

[0163] [Table 4]

[0164] Method for measuring the viscosity of injectable drugs

[0165] Using an Anton-Paar rheometer (MCR 92) at 20°C, and with a cone-plate geometry (CP25-1), the measurement time was 0.001s. -1 ~1000s -1 The viscosity of the injectable agent was measured at the shear rate and recorded in Figures 1 and 2. Compared with all examples, 1s -1 At the shear rate, the viscosity of the injectable formulation of Comparative Example 3 exceeded 1000 mPa·s, which was higher than the viscosity of the injectable formulations of Examples 1 to 15. Compared to the dioleoyl phosphatidylethanolamine used in Comparative Example 3, the soy phosphatidylcholine used in Examples 1 to 14 showed superior injectability.

[0166] Method for measuring the water content of injectable drugs

[0167] The water content of the injectable drug was measured using a Karl-Fischer titrator (Metrohm). The injectable drug was dissolved in methanol. The dissolved injectable drug was titrated with the Karl-Fischer reagent until the titration endpoint was reached. The results for the water content of the injectable drug are shown in Table 5.

[0168] [Table 5]

[0169] Method for evaluating the appearance of gels formed by injectable drugs

[0170] At 25°C, 200–650 μL of the injectable agent was injected into 4 mL of phosphate buffer (10 mM sodium phosphate, 8.25 mg / mL sodium chloride, pH 7.4) using a pipette tip, and then allowed to stand for 20–30 minutes to form a gel. The appearance of the gel was evaluated by visual observation. As shown in Table 6, the gel formed by the injectable agent of Comparative Example 2 had defects in appearance. Compared to the higher molar ratio of chloride ions to semaglutide (greater than 20) used in Comparative Example 2, the lower molar ratio of chloride ions to semaglutide (less than or equal to 20) used in Examples 1 to 15 all provided gels with a perfect appearance. The perfection of the gel appearance extended the release time of the GLP-1 receptor agonist from the gel.

[0171] [Table 6]

[0172] A method for measuring the remaining semaglutide in a gel after 20 or 31 days in an elution medium at 37°C.

[0173] The injectable agent was introduced into a basket via a 29G needle, and the basket was placed in 500 mL of elution medium (50 mM potassium phosphate buffer, pH 7.4) at 37°C. The introduced injectable agent was allowed to stand at 37°C for 20 minutes to form a gel. After gel formation, the basket was rotated at 100 rpm. After 20 or 31 days, the gel was removed from the basket and completely dissolved in benzyl alcohol under sonication to thoroughly dissolve the semaglutide in the gel. Subsequently, the dissolved semaglutide was analyzed by gradient elution using high-performance liquid chromatography (HPLC) or ultra-high-performance liquid chromatography (UPLC). A protective column (C18, 1.7 μm, 2.1 × 5 mm) and an analytical column (C18, 1.7 μm, 2.1 × 150 mm) were used. The mobile phase consisted of mobile phase A (trifluoroacetic acid, acetonitrile, and water, volume ratio 1.5:10:988.5) and mobile phase B (trifluoroacetic acid and acetonitrile, volume ratio 1.5:998.5). A photodiode array detector was used, and detection was performed at 220 nm. The residual percentage of semaglutide in the gel was calculated, with the original weight of semaglutide in the injectable drug set to 100%.

[0174] According to Table 7, compared to all the examples from Example 1 to Example 12, the injectable formulation of Comparative Example 1 used a smaller amount (0.4 mg) of semaglutide, resulting in a lower residual rate of semaglutide in the gel after 31 days in the elution medium.

[0175] Furthermore, as mentioned above, Table 6 shows that the gel formed from the injectable solution of Comparative Example 2 had defects in its appearance. Therefore, it was expected that semaglutide would be released more easily from the gel in Comparative Example 2, and as a result, the retention rate would also decrease. In addition, according to the results of Examples 6 and 9 (see Table 7 below), the retention rate of semaglutide in the gel increased as the chloride ion content decreased.

[0176] From the data of Examples 7 and 8 in Table 7 below, it was found that, compared to acetate ions, sodium ions and phosphate ions both increased the residual rate of semaglutide in the gel, thereby extending the release time of semaglutide from the gel.

[0177] According to the results of Examples 8 and 11, compared to citrate ions, sodium ions and phosphate ions both increased the residual rate of semaglutide in the gel, thereby extending the release time of semaglutide from the gel.

[0178] Furthermore, the results of Examples 8 and 12 showed that, compared to tartrate ions, sodium ions and phosphate ions both increased the residual rate of semaglutide in the gel, thereby extending the release time of semaglutide from the gel. All components used in Example 16 were the same as in Example 4, but the weight used in Example 16 was 2.8 times that of Example 4. In Example 16, the residual rate of semaglutide retained in the gel after 30 days in the elution medium at 37°C was also measured and was 66.40%.

[0179] [Table 7]

[0180] Note: The notation "NA" in Table 7 indicates that the above conditions have not been tested.

[0181] Method for testing the thermal stability of injectable drugs

[0182] The injectable formulations were subjected to six consecutive cycles of freezing at -20°C and thawing at 25°C (60% relative humidity (RH)). Thermal stability tests of the injectable formulations were performed by gradient high-performance liquid chromatography (HPLC) or ultra-high-performance liquid chromatography (UPLC). A protective column (C18, 1.7 am, 2.1 × 5 mm) and an analytical column (C18, 1.7 μm, 2.1 × 150 mm) were used. The mobile phase consisted of mobile phase A (trifluoroacetic acid, acetonitrile, and water, volume ratio 1.5:10:988.5) and mobile phase B (trifluoroacetic acid and acetonitrile, volume ratio 1.5:998.5). Detection was performed at 220 nm using a photodiode array detector. The appearance of the injectable formulations was visually inspected before the first cycle and after each cycle. In all examples, after six consecutive cycles, the appearance of these injectable formulations was clear and pale yellow, and they exhibited good fluidity. Furthermore, no gelation or layer separation was observed in any of the injectable formulations in the examples. The semaglutide content before and after the continuous cycle was calculated, and the difference in semaglutide content is summarized in Table 8 below, where the content difference (%) = (semaglutide content after continuous cycle (%)) - (semaglutide content before continuous cycle (%)). This content difference is used to evaluate the thermal stability of the injectable formulation.

[0183] [Table 8]

[0184] According to Table 8, the variation in the content of the injectable agent was smaller in Examples 1 to 14 compared to Comparative Example 1. Therefore, these injectable agents had better thermal stability compared to the injectable agent in Comparative Example 1.

[0185] Pharmacokinetics Test

[0186] The injectable preparations of Examples 8, 13, 14, and Comparative Example 3 (hereinafter referred to as "injection solutions") were administered subcutaneously to Sprague Dawley rats (n=3 in each group) at doses of 3.75 mg / kg and 7.5 mg / kg, respectively.

[0187] Blood samples were collected from Sprague-Dolly rats at predetermined blood sampling points before and after administration and used for pharmacokinetic studies. After blood sample collection, the samples were placed on ice and then centrifuged to obtain plasma. The plasma was stored at -70°C or below. The plasma was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Pharmacokinetic curves for these examples and Comparative Example 3 were recorded.

[0188] In comparison with Comparative Example 3, in Examples 8 and 13, semaglutide was continuously released from the gel for 28 days under in vivo conditions. Specifically, in a rat model, one month after administration, Examples 8 and 13 showed significant effects compared to Comparative Example 3 and the placebo group, with weight loss exceeding 20% ​​and a significant decrease in food intake.

[0189] In Comparative Example 3, the semaglutide concentration in the blood of Sprague-Dorley rats was approximately 0 ng / mL on both day 20 and day 30. In Example 8, the semaglutide concentration in the blood of Sprague-Dorley rats was 259 ng / mL and 230 ng / mL on day 20 and day 30, respectively. In Example 13, the semaglutide concentration in the blood of Sprague-Dorley rats was 182 ng / mL and 169 ng / mL on day 20 and day 30, respectively.

[0190] In Example 14, under in vivo conditions, semaglutide was continuously released from the gel formed from the injection for 20 to 28 days. In Example 14, the semaglutide concentrations in the blood of Sprague-Dorey rats were 154 ng / mL and 73 ng / mL on day 20 and day 30, respectively. Unexpectedly, the peak blood concentration of semaglutide in the blood of Sprague-Dorey rats was (C max ) is its lowest blood concentration (C min The effect was less than 15 times. In the rat model, one month after administration, Example 14 showed a significant effect compared to the placebo group, with a substantial decrease in body weight.

[0191] Although the present invention has been described in the above-described examples, these examples are not intended to limit the present invention, and any person skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the scope of protection of the present invention should be based on the claims appended below.

Claims

1. A single-dose injectable drug, Phosphatidylcholine and Diacyl lipids and At least one biocompatible organic solvent selected from the group consisting of propylene glycol, N-methyl-2-pyrrolidone, ethanol, and glycerol, The aforementioned injectable agent is given a weight percentage of 100 wt.% and a GLP-1 receptor agonist with a concentration of 0.08 wt.% to 5.0 wt.%, At least one pharmaceutically acceptable ion selected from the group consisting of alkali metal ions and phosphate ions, Includes, The aforementioned injectable agent is a single-dose injectable agent that forms a depot upon contact with an aqueous liquid.

2. The single-dose injectable preparation according to claim 1, wherein the weight percentage of the injectable preparation is 100 wt., and the concentration of the GLP-1 receptor agonist is 0.1 wt. to 4.0 wt.

3. The GLP-1 receptor agonist has a peptide skeleton and a side chain connected thereto, the peptide skeleton consists of 28 to 40 amino acids, and the side chain has the structure shown in formula I below. 【Chemistry 4】 The single-dose injectable preparation according to claim 1, wherein n is an integer from 16 to 24, m is an integer from 0 to 3, and * is a connection point, wherein the connection point connects the carbonyl group of the side chain to one amino group among the 28 to 40 amino acids in the peptide skeleton.

4. The single-dose injectable preparation according to claim 1, wherein the molar ratio of the alkali metal ion to the GLP-1 receptor agonist is greater than 0 and 25 or less.

5. The single-dose injectable preparation according to claim 1, wherein the molar ratio of the phosphate ion to the GLP-1 receptor agonist is 0.01 to 1.

2.

6. A single-dose injectable preparation according to claim 1, further comprising organic acid ions, halogen ions, basic amino acids, or combinations thereof, with a molecular weight of less than 200 g / mol.

7. An injectable drug for the treatment of metabolic diseases, An injectable preparation for the treatment of metabolic diseases comprising a lipid matrix composition, a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion, wherein the at least one pharmaceutically acceptable ion is selected from the group consisting of alkali metal ions and phosphate ions, the content of the GLP-1 receptor agonist is 1.0 mg to 20 mg, and the lipid matrix composition consists of phosphatidylcholine, diacyl lipids, and at least one biocompatible organic solvent, wherein the injectable preparation is administered as a single dose to an individual every 20 to 45 days.

8. The injectable agent for treating metabolic diseases according to claim 7, wherein the metabolic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, obesity, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, and cardiovascular disease.

9. In a dispensing device containing a vial, pre-filled syringe, or pre-filled cartridge, which contains a single-dose injectable drug, The injectable preparation comprises a lipid matrix composition, a GLP-1 receptor agonist, and at least one pharmaceutically acceptable ion, wherein the at least one pharmaceutically acceptable ion is selected from the group consisting of alkali metal ions and phosphate ions, and the concentration of the GLP-1 receptor agonist is 0.08 wt.% to 5.0 wt.%, with the weight percentage of the injectable preparation being 100 wt.%.

10. The administration device according to claim 9, wherein the vial, the pre-filled syringe, and the pre-filled cartridge are made of glass or plastic material.

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