A sustained-release formulation of semaglutide

Abstract

Disclosed is a sustained-release formulation of semaglutide, which comprises semaglutide or a pharmaceutically acceptable salt thereof, triacylglycerol, phosphatidylcholine, absolute ethyl alcohol, a solubilizing agent, and a pH adjusting agent.

Description

A sustained-release formulation of semaglutide

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese Patent Application No. 202411179154.1, filed on August 27, 2024, and Chinese Patent Application No. 202411783130.7, filed on December 6, 2024, the entire contents of which are incorporated herein by reference and for all purposes. Technical Field

[0003] This application generally relates to the pharmaceutical field, and specifically to a semaglutide sustained-release formulation and its use. Background Technology

[0004] Smegglutide is a human glucagon-like peptide-1 (GLP-1) analog. By optimizing the amino acid sequence of the natural GLP-1 polypeptide chain and adding side chains, it effectively blocks the dipeptidyl peptidase-4 (DPP-4) cleavage site and increases its affinity for albumin, thus achieving long circulation and allowing dosing intervals to be extended to one week. Smegglutide can lower blood glucose by stimulating insulin secretion through its action on GLP-1 receptors on pancreatic β-cells. It can also act on the central nervous system to increase satiety and slow gastric emptying, thereby achieving weight control.

[0005] Currently, there are two types of semaglutide formulations available globally: one is semaglutide injection (ordinary water injection) administered subcutaneously once a week, with the main excipients being disodium hydrogen phosphate dihydrate, phenol, and propylene glycol; the other is semaglutide tablets administered orally once a day, with the main excipients being magnesium stearate, microcrystalline cellulose, povidone, and sodium 8-(2-hydroxybenzamido)octanoate (SNAC).

[0006] Although clinical studies have demonstrated that the marketed semaglutide formulations are effective in lowering blood sugar, reducing weight, and providing cardiovascular benefits, the longest dosing interval is only one week, which still cannot meet the clinical needs of patients with chronic diseases such as diabetes for longer-acting products.

[0007] To address the aforementioned clinical needs, the Swedish company Camurus has proposed a GLP-1 analog formulation (related technology see CN101217940B), utilizing fluid crystals... Technology delivery of GLP-1 and its analogues. The key excipients include phospholipids, glycoglycerols (GDO), and solvents. The pre-injection formulation is a homogeneous oily solution. After subcutaneous injection, the solvent exchanges with the tissue fluid, and the pre-injection formulation transforms into a gel at the injection site, forming an in-situ reservoir. The drug is slowly and continuously released as the reservoir degrades. CN101217940B does not disclose or test a fluid crystal formulation containing semaglutide.

[0008] Therefore, there is an urgent need in the field for improved semaglutide formulations with sustained-release effects.

[0009] Invention Overview

[0010] In a first aspect, this application provides a semaglutide sustained-release formulation, said formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0011] (1) 0.001-70 parts by weight of smegglutinin or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, 0.001-50 parts by weight or 0.001-40 parts by weight;

[0012] (2) Triacylglycerol 100-500 parts by weight;

[0013] (3) Phosphatidylcholine 400-800 parts by weight;

[0014] (4) 50-200 parts by weight of anhydrous ethanol;

[0015] (5) Solubilizer 1-100 parts by weight; and

[0016] (6) pH adjuster, wherein the weight part of the pH adjuster is selected to adjust the pH value of the smegglutinin sustained-release formulation to a predetermined range.

[0017] Secondly, this application provides a semaglutide sustained-release formulation, said formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0018] (1) 0.001-70 parts by weight of smegglutinin or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, 0.001-50 parts by weight or 0.001-40 parts by weight;

[0019] (2) 1000 parts by weight of a lipid mixture, wherein the lipid mixture comprises triacylglycerol, phosphatidylcholine and anhydrous ethanol, or is substantially composed of triacylglycerol, phosphatidylcholine and anhydrous ethanol, or is composed of triacylglycerol, phosphatidylcholine and anhydrous ethanol, wherein:

[0020] a) Triacylglycerols constitute 10%-50% of the weight of the lipid mixture;

[0021] b) Phosphatidylcholine constitutes 40%-80% of the weight of the lipid mixture;

[0022] c) Anhydrous ethanol accounts for 5%-20% of the weight of the lipid mixture;

[0023] (3) Solubilizer 1-100 parts by weight; and

[0024] (4) pH adjuster, wherein the weight part of the pH adjuster is selected to adjust the pH value of the smegglutide sustained-release formulation to a predetermined range.

[0025] Thirdly, this application provides a semaglutide sustained-release formulation, said formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0026] (1) 0.001-70 parts by weight of smegglutinin or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, 0.001-50 parts by weight or 0.001-40 parts by weight;

[0027] (2) Triacylglycerol 100-500 parts by weight;

[0028] (3) Phosphatidylcholine 400-800 parts by weight;

[0029] (4) Ethanol, wherein the amount of anhydrous ethanol is 50-200 parts by weight; and

[0030] (5) Solubilizer 1-100 parts by weight; and

[0031] The pH value of the smegglutide sustained-release formulation is 4.5-7.0.

[0032] Fourthly, this application provides a semaglutide sustained-release formulation, said formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0033] (1) 0.001-70 parts by weight of smegglutinin or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, 0.001-50 parts by weight or 0.001-40 parts by weight;

[0034] (2) 1000 parts by weight of a lipid mixture, wherein the lipid mixture comprises triacylglycerol, phosphatidylcholine and ethanol, or is substantially composed of triacylglycerol, phosphatidylcholine and ethanol, or is composed of triacylglycerol, phosphatidylcholine and ethanol, wherein:

[0035] a) Triacylglycerols constitute 10%-50% of the weight of the lipid mixture;

[0036] b) Phosphatidylcholine constitutes 40%-80% of the weight of the lipid mixture;

[0037] c) The weight percentage of ethanol in the lipid mixture is 5%-20% based on anhydrous ethanol; and

[0038] (3) Solubilizer 1-100 parts by weight; and

[0039] The pH value of the smegglutide sustained-release formulation is 4.5-7.0.

[0040] Fifthly, this application provides the use of the semaglutide sustained-release formulations described in the first to fourth aspects for the treatment of GLP-1R-related diseases.

[0041] Sixthly, this application provides a method for preparing the semaglutide sustained-release formulation using water as a solubilizer as described in the first to fourth aspects, the preparation method comprising the following steps:

[0042] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain the aqueous phase;

[0043] Step 2: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0044] Step 3: Add the aqueous phase obtained in Step 1 to the lipid mixture obtained in Step 2, and stir to mix well;

[0045] Step 4: Add pH adjuster to adjust the pH value to the predetermined pH value of the smegglutinin sustained-release formulation, then filter and fill.

[0046] In a seventh aspect, this application provides a method for preparing the semaglutide sustained-release formulation using bile salts (e.g., sodium deoxycholate) as a solubilizer, as described in the first to fourth aspects, the method comprising the following steps:

[0047] Step a: Smegglutide or its pharmaceutically acceptable salts are dissolved and mixed with bile salts (e.g., sodium deoxycholate) in water and then freeze-dried to form a freeze-dried complex.

[0048] Step b: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0049] Step c: Add the lyophilized complex obtained in step a to the lipid mixture obtained in step b, and stir to dissolve;

[0050] Step d: Add pH adjuster to adjust the pH value to the predetermined pH value of the smegglutinin sustained-release formulation, then filter and fill.

[0051] Eighthly, this application provides the use of the semaglutide sustained-release formulation described in the first to fourth aspects in the preparation of a medicament for treating GLP-1R-related diseases.

[0052] Ninthly, this application provides a method for treating GLP-1R-related diseases in an individual, the method comprising administering a therapeutically effective amount of the semaglutide extended-release formulation described in the first to fourth aspects to the individual in need.

[0053] In a tenth aspect, this application provides a sustained-release formulation of semaglutide as described in the first to fourth aspects for the treatment of GLP-1R-related diseases.

[0054] Brief description of the attached diagram

[0055] Figure 1 shows a comparison of the rat pharmacokinetic curves of smegglutide formulations 1-4 sustained-release formulation and Novogene.

[0056] Figure 2 shows a comparison of the PK curves of rats using prescription 10-2 and prescription 10-1.

[0057] Detailed description of the invention

[0058] Terminology Definition

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art.

[0060] Smegglutide

[0061] Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) with the molecular formula C. 187 H 291 N 45 O 59 Its chemical name is N ε26 [(S)-(22,40-dicarboxylic acid-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetrazane-1-acyl)][Aib 8 Arg 34 GLP-1-(7-37) peptide.

[0062] Phosphatidylcholine

[0063] Phosphatidylcholine (PC) is an amphipathic molecule consisting of a hydrophilic head and a hydrophobic tail. It is a type of phospholipid with a choline group inserted into the head. PC can be derived from natural sources, including animal sources such as eggs, hearts (e.g., bovine hearts), brains, and livers (e.g., bovine livers), as well as plant sources such as soybeans. The formulations of this application may use any single PC or mixture of PCs from these or other sources, preferably soybean PC (SPC), egg PC, or a mixture containing soybean PC (SPC) or egg PC. The PC component preferably contains at least 50% soybean PC or egg PC, more preferably at least 75% soybean PC or egg PC, and most preferably substantially pure soybean PC or egg PC. The PC component can be a commercially available product, such as FDA or CDE-registered phosphatidylcholine, preferably soybean phosphatidylcholine and egg yolk phosphatidylcholine with a purity of 94% or higher.

[0064] neutral lipids

[0065] Neutral lipids are esters obtained by the esterification reaction of glycerol and fatty acids. Based on carbon chain length, fatty acids are classified into short-chain, medium-chain (such as caprylic acid, capric acid, etc.) and long-chain fatty acids (such as oleic acid, linoleic acid, etc.). Based on the site where glycerol is attached to fatty acids, they can be classified into 1-substituted, 2-substituted (i.e., diacylglycerol esters, containing 1,2 and 1,3 forms) and 3-substituted (i.e., triacylglycerol esters).

[0066] Triacylglycerol

[0067] In this application, triacylglycerol, triacylglycerol ester, trisubstituted triglyceride, triglyceride ester, and triglyceride acid ester are used interchangeably and have the same meaning. Triacylglycerol is a major component of animal and vegetable oils and is an ester organic compound composed of one glycerol molecule and three fatty acid molecules. Fatty acids are classified into short-chain, medium-chain, and long-chain according to carbon chain length. Fatty acids containing 6-12 carbon atoms in their carbon chain are generally called medium-chain fatty acids (MCFA). When esterified with glycerol, they produce medium-chain fatty acid triglycerides (or medium-chain triglycerides, MCT). Commercially available medium-chain triglycerides generally contain 50%-80% caprylic acid and 20%-50% capric acid. The formulations in this application may select FDA- or CDE-registered medium-chain triglycerides, medium-chain triglycerides (for injection), or medium-chain triglycerides (Captex).

[0068] Solubilizer

[0069] The solubilizers used in this application refer to substances that can increase the solubility of smegglutide in the present composition, including certain amphiphilic molecules (such as sodium deoxycholate, sodium oleate, etc.) and certain solvents (such as water, propylene glycol, dimethyl sulfoxide, etc.).

[0070] bile salts

[0071] Bile salts are sodium or potassium salts formed from bile acids secreted by hepatocytes, as well as various derivatives formed by structural modifications based on these salts. Commonly used bile salts include sodium glycocholate, sodium ursodeoxycholate, sodium ursodeoxycholate, sodium cholate, sodium chenodeoxycholate, sodium obeticholate, sodium porcine deoxycholate, and sodium deoxycholate.

[0072] water

[0073] The water used in this application is purified water or water for injection that meets GMP requirements.

[0074] "basically composed of..." or "composed of..."

[0075] In this document, when the expression "composed of A, B, and C" is used to describe a formulation, composition, mixture, or other system, it indicates that A, B, and C are all the constituent components of the formulation, composition, mixture, or system. When the expression "essentially composed of A, B, and C" is used to describe a formulation, composition, mixture, or other system, it indicates that A, B, and C are the core constituent components of the formulation, composition, mixture, or system, which may contain other components (e.g., D, E, etc.), but the type or amount of these other components should not have a material effect on the formulation, composition, mixture, or system. For example, the introduction of these other components would not have a significant negative impact compared to the pharmacological or pharmaceutical properties of a formulation, composition, mixture, or system "composed of A, B, and C".

[0076] Unless otherwise stated, the amount or dosage of the API (semaglutide or its pharmaceutically acceptable salt) described in this application is calculated based on semaglutide.

[0077] Unless otherwise stated, the ethanol described in this application is anhydrous ethanol. All statements in this document referring to the weight of anhydrous ethanol, such as parts by weight and weight percentages, are based on the weight of ethanol molecules.

[0078] Unless otherwise stated, percentages and parts as described in this application are by weight.

[0079] For the sake of brevity, the term "about" is not used for some quantitative data herein. It should be understood that, whether the term "about" is explicitly used or not, every numerical value given herein includes not only the actual given value (the given value), but also an approximation of such a given value based on reasonable deduction by one of ordinary skill in the art, including equivalents and approximations of such a given value due to experimental and / or measurement conditions. These approximations are preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, or ±1% of the given value. In some embodiments, the approximations are obtained by rounding.

[0080] As used herein, the terms "comprising" or "including" mean including the stated elements, structures, or steps, but do not exclude any other elements, structures, or steps. In this application, when the terms "comprising" or "including" are used, unless otherwise specified, they also cover situations consisting of the stated elements, structures, or steps.

[0081] As used in this article, the term "treatment" refers to a clinical intervention aimed at altering the natural course of disease in the individual or cells receiving the treatment during the clinicopathological process. Ideal outcomes of treatment include slowing or reducing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis.

[0082] In this application, the terms "effective amount" or "therapeutic effective amount" are used interchangeably and refer to an amount that has a therapeutic effect on a subject, such as: in subjects who have been given the amount, the symptoms or state of the disease are alleviated, reduced, or eliminated, or the development of the symptoms or state of the disease is delayed or suppressed compared to subjects who have not been given the amount.

[0083] Currently marketed semaglutide formulations have a maximum dosing interval of one week. As discussed above, there is an urgent need in the art for improved semaglutide formulations with good sustained-release effects to reduce dosing frequency and improve patient compliance. CN101217940B proposes a method utilizing fluid crystals... The company has provided formulation solutions for GLP-1 and its analogues, but has not disclosed or tested fluidic crystal formulations containing semaglutide. Given the inherently poor stability of the semaglutide molecule, and the fact that formulation stability is a crucial factor in formulation performance, sustained-release formulations suitable for semaglutide require independent research and evaluation.

[0084] This application found that semaglutide is insoluble in neutral lipid (GDO or MCT) / SPC / ethanol formulation systems, requiring the addition of a solubilizer. Further research showed that semaglutide exhibits poor stability in formulation systems using GDO as the neutral lipid, failing to meet formulation requirements. This application, through screening, found that using MCT as the neutral lipid helps improve the stability of semaglutide in formulations.

[0085] The semaglutide sustained-release formulations provided in this application possess excellent properties in one or more of the following: stability, stable blood concentration, and duration of sustained release. For example, one or more formulations prepared and tested in the embodiments of this application achieve high stability during long-term storage at 2-8°C, providing stable blood concentrations and a sustained-release duration of up to one month, improving patient compliance. Pharmacokinetic studies disclosed in CN101217940B show that its GLP-1 composition (using GDO as a neutral lipid), while claiming a certain sustained-release effect, exhibits significant burst release and large fluctuations in the PK curve. One or more formulations prepared and tested in the embodiments of this application (using MCT as a neutral lipid) show a more stable release rate throughout the sustained-release period. max / C 23d The PK curve is significantly lower, more stable, and safer. Further advantages of the semaglutide sustained-release formulation provided in this application are described below and illustrated in the results of the embodiments of this application.

[0086] In a first aspect, this application provides a semaglutide sustained-release formulation, the formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0087] (1) 0.001-70 parts by weight of smegglutinin or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, 0.001-50 parts by weight or 0.001-40 parts by weight;

[0088] (2) Triacylglycerol 100-500 parts by weight;

[0089] (3) Phosphatidylcholine 400-800 parts by weight;

[0090] (4) 50-200 parts by weight of anhydrous ethanol;

[0091] (5) Solubilizer 1-100 parts by weight; and

[0092] (6) pH adjuster, wherein the weight part of the pH adjuster is selected to adjust the pH value of the smegglutinin sustained-release formulation to a predetermined range.

[0093] In some embodiments, semaglutide or its pharmaceutically acceptable salt has a concentration of 0.01-30 parts by weight, 0.1-20 parts by weight, 1-15 parts by weight, 3-15 parts by weight, 5-15 parts by weight, 7-14 parts by weight, or 8-12 parts by weight. In some embodiments, semaglutide or its pharmaceutically acceptable salt has a concentration of 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 parts by weight or a range between any two of the above values.

[0094] In some embodiments, the triacylglycerol has 100-450 parts by weight, 100-400 parts by weight, 100-300 parts by weight, 120-280 parts by weight, or 150-250 parts by weight. In some embodiments, the triacylglycerol has a range between any two of the following values: 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 parts by weight.

[0095] In some embodiments, phosphatidylcholine has a weight of 400-700 parts by weight, 450-650 parts by weight, 500-650 parts by weight, or 550-650 parts by weight. In some embodiments, phosphatidylcholine has a range between any two of the following values: 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, or 800 parts by weight.

[0096] In some embodiments, anhydrous ethanol has 50-180 parts by weight, or 70-180 parts by weight, or 90-180 parts by weight, or 100-170 parts by weight, or 120-170 parts by weight. In some embodiments, anhydrous ethanol 50-200 has a range between any two of the following values: 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 180, 190, or 200 parts by weight.

[0097] In some embodiments, the solubilizer has a range of 5-100 parts by weight, 10-90 parts by weight, 10-80 parts by weight, 10-70 parts by weight, 10-60 parts by weight, 10-50 parts by weight, or 10-40 parts by weight. In some embodiments, the solubilizer has a range between any two of the following values: 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 parts by weight.

[0098] In some embodiments, the pH range of the semaglutide sustained-release formulation is predetermined to be 4.5-7.0. In some embodiments, the pH range of the semaglutide sustained-release formulation is predetermined to be 5.0-6.6. In some embodiments, the pH range of the semaglutide sustained-release formulation is predetermined to be 5.3-6.6, 5.4-6.6, or 5.5-6.6. In some embodiments, the pH range of the semaglutide sustained-release formulation is predetermined to be 5.6-6.5, 5.6-6.4, 5.6-6.3, or 5.6-6.2. In some embodiments, the pH value of the semaglutide sustained-release formulation is a predetermined value or range between any two points of 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 or above.

[0099] Secondly, this application provides a semaglutide sustained-release formulation, the formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0100] (1) 0.001-70 parts by weight of smegglutinin or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, 0.001-50 parts by weight or 0.001-40 parts by weight;

[0101] (2) 1000 parts by weight of a lipid mixture, wherein the lipid mixture comprises triacylglycerol, phosphatidylcholine and anhydrous ethanol, or is substantially composed of triacylglycerol, phosphatidylcholine and anhydrous ethanol, or is composed of triacylglycerol, phosphatidylcholine and anhydrous ethanol, wherein:

[0102] a) Triacylglycerols constitute 10%-50% of the weight of the lipid mixture;

[0103] b) Phosphatidylcholine constitutes 40%-80% of the weight of the lipid mixture;

[0104] c) Anhydrous ethanol accounts for 5%-20% of the weight of the lipid mixture;

[0105] (3) Solubilizer 1-100 parts by weight; and

[0106] (4) pH adjuster, wherein the weight part of the pH adjuster is selected to adjust the pH value of the smegglutide sustained-release formulation to a predetermined range.

[0107] In some embodiments, semaglutide or its pharmaceutically acceptable salt has a concentration of 0.01-30 parts by weight, 0.1-20 parts by weight, 1-15 parts by weight, 3-15 parts by weight, 5-15 parts by weight, 7-14 parts by weight, or 8-12 parts by weight. In some embodiments, semaglutide or its pharmaceutically acceptable salt has a concentration of 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 parts by weight or a range between any two of the above values.

[0108] In some embodiments, the triacylglycerol constitutes a weight percentage of the lipid mixture of 10%-45%, 10%-40%, 10%-30%, 12%-28%, or 15%-25%. In some embodiments, the triacylglycerol constitutes a weight percentage of the lipid mixture within a range of any two point values ​​of 10%, 12%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 28%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, or 47.5%, or 50% or more.

[0109] In some embodiments, the weight percentage of phosphatidylcholine in the lipid mixture is 40%-70%, 45%-65%, or 50%-65%. In some embodiments, the weight percentage of phosphatidylcholine in the lipid mixture is within any two point values ​​of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% or more.

[0110] In some embodiments, the weight percentage of anhydrous ethanol in the lipid mixture is 5%-18%, 7%-18%, or 9%-18%. In some embodiments, the weight percentage of anhydrous ethanol in the lipid mixture is a range between any two point values ​​of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or more.

[0111] In some embodiments, the solubilizer has a range of 5-100 parts by weight, 10-90 parts by weight, 10-80 parts by weight, 10-70 parts by weight, 10-60 parts by weight, 10-50 parts by weight, or 10-40 parts by weight. In some embodiments, the solubilizer has a range between any two of the following values: 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 parts by weight.

[0112] In some embodiments, the pH range of the semaglutide sustained-release formulation is predetermined to be 4.5-7.0. In some embodiments, the pH range of the semaglutide sustained-release formulation is predetermined to be 5.0-6.6. In some embodiments, the pH range of the semaglutide sustained-release formulation is predetermined to be 5.3-6.6, 5.4-6.6, or 5.5-6.6. In some embodiments, the pH range of the semaglutide sustained-release formulation is predetermined to be 5.6-6.5, 5.6-6.4, 5.6-6.3, or 5.6-6.2. In some embodiments, the pH value of the semaglutide sustained-release formulation is a predetermined value or range between any two points of 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 or above.

[0113] Thirdly, this application provides a semaglutide sustained-release formulation, said formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0114] (1) 0.001-70 parts by weight of smegglutinin or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, 0.001-50 parts by weight or 0.001-40 parts by weight;

[0115] (2) Triacylglycerol 100-500 parts by weight;

[0116] (3) Phosphatidylcholine 400-800 parts by weight;

[0117] (4) Ethanol, wherein the amount of anhydrous ethanol is 50-200 parts by weight; and

[0118] (5) Solubilizer 1-100 parts by weight; and

[0119] The pH value of the smegglutide sustained-release formulation is 4.5-7.0.

[0120] In some embodiments, semaglutide or its pharmaceutically acceptable salt has a concentration of 0.01-30 parts by weight, 0.1-20 parts by weight, 1-15 parts by weight, 3-15 parts by weight, 5-15 parts by weight, 7-14 parts by weight, or 8-12 parts by weight. In some embodiments, semaglutide or its pharmaceutically acceptable salt has a concentration of 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 parts by weight or a range between any two of the above values.

[0121] In some embodiments, the triacylglycerol has 100-450 parts by weight, 100-400 parts by weight, 100-300 parts by weight, 120-280 parts by weight, or 150-250 parts by weight. In some embodiments, the triacylglycerol has a range between any two of the following values: 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 parts by weight.

[0122] In some embodiments, phosphatidylcholine has a weight of 400-700 parts by weight, 450-650 parts by weight, 500-650 parts by weight, or 550-650 parts by weight. In some embodiments, phosphatidylcholine has a range between any two of the following values: 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, or 800 parts by weight.

[0123] In some embodiments, the ethanol comprises 50-180 parts by weight, 70-180 parts by weight, 90-180 parts by weight, 100-170 parts by weight, or 120-170 parts by weight. In some embodiments, the ethanol 50-200 comprises a range between any two of the following values: 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 180, 190, or 200 parts by weight.

[0124] In some embodiments, the solubilizer has a range of 5-100 parts by weight, 10-90 parts by weight, 10-80 parts by weight, 10-70 parts by weight, 10-60 parts by weight, 10-50 parts by weight, or 10-40 parts by weight. In some embodiments, the solubilizer has a range between any two of the following values: 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 parts by weight.

[0125] In some embodiments, the pH of the semaglutide sustained-release formulation is 5.0-6.6. In some embodiments, the pH of the semaglutide sustained-release formulation is 5.3-6.6, 5.4-6.6, or 5.5-6.6. In some embodiments, the pH of the semaglutide sustained-release formulation is 5.6-6.5, 5.6-6.4, 5.6-6.3, or 5.6-6.2. In some embodiments, the pH of the semaglutide sustained-release formulation is a range between any two values ​​of 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 or higher.

[0126] Fourthly, this application provides a semaglutide sustained-release formulation, said formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0127] (1) 0.001-70 parts by weight of smegglutinin or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, 0.001-50 parts by weight or 0.001-40 parts by weight;

[0128] (2) 1000 parts by weight of a lipid mixture, wherein the lipid mixture comprises triacylglycerol, phosphatidylcholine and ethanol, or is substantially composed of triacylglycerol, phosphatidylcholine and ethanol, or is composed of triacylglycerol, phosphatidylcholine and ethanol, wherein:

[0129] a) Triacylglycerols constitute 10%-50% of the weight of the lipid mixture;

[0130] b) Phosphatidylcholine constitutes 40%-80% of the weight of the lipid mixture;

[0131] c) The weight percentage of ethanol in the lipid mixture is 5%-20% based on anhydrous ethanol; and

[0132] (3) Solubilizer 1-100 parts by weight; and

[0133] The pH value of the smegglutide sustained-release formulation is 4.5-7.0.

[0134] In some embodiments, semaglutide or its pharmaceutically acceptable salt has a concentration of 0.01-30 parts by weight, 0.1-20 parts by weight, 1-15 parts by weight, 3-15 parts by weight, 5-15 parts by weight, 7-14 parts by weight, or 8-12 parts by weight. In some embodiments, semaglutide or its pharmaceutically acceptable salt has a concentration of 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 parts by weight or a range between any two of the above values.

[0135] In some embodiments, the triacylglycerol constitutes a weight percentage of the lipid mixture of 10%-45%, 10%-40%, 10%-30%, 12%-28%, or 15%-25%. In some embodiments, the triacylglycerol constitutes a weight percentage of the lipid mixture within a range of any two point values ​​of 10%, 12%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 28%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, or 47.5%, or 50% or more.

[0136] In some embodiments, the weight percentage of phosphatidylcholine in the lipid mixture is 40%-70%, 45%-65%, or 50%-65%. In some embodiments, the weight percentage of phosphatidylcholine in the lipid mixture is within any two point values ​​of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% or more.

[0137] In some embodiments, the weight percentage of ethanol in the lipid mixture, calculated as anhydrous ethanol, is 5%-18%, 7%-18%, or 9%-18%. In some embodiments, the weight percentage of ethanol in the lipid mixture is within the range of any two point values ​​of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or more.

[0138] In some embodiments, the solubilizer has a range of 5-100 parts by weight, 10-90 parts by weight, 10-80 parts by weight, 10-70 parts by weight, 10-60 parts by weight, 10-50 parts by weight, or 10-40 parts by weight. In some embodiments, the solubilizer has a range between any two of the following values: 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 parts by weight.

[0139] In some embodiments, the pH of the semaglutide sustained-release formulation is 5.0-6.6. In some embodiments, the pH of the semaglutide sustained-release formulation is 5.3-6.6, 5.4-6.6, or 5.5-6.6. In some embodiments, the pH of the semaglutide sustained-release formulation is 5.6-6.5, 5.6-6.4, 5.6-6.3, or 5.6-6.2. In some embodiments, the pH of the semaglutide sustained-release formulation is a range between any two values ​​of 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 or higher.

[0140] The following details specific embodiments or technical features of the inventions in the first to fourth aspects described above. Generally, unless there is a contradiction or conflict, the specific embodiments or technical features described below apply to the inventions in the first to fourth aspects described above.

[0141] In some embodiments, the semaglutide extended-release formulation is an injectable.

[0142] In some embodiments, the solubilizer is selected from water, bile salts, sodium oleate, dimethyl sulfoxide (DMSO), or propylene glycol. In some embodiments, the solubilizer is selected from water or bile salts.

[0143] In some embodiments, the bile salt is selected from sodium glycocholate, sodium ursodeoxycholate, sodium ursodeoxycholate (from bovine ursodeoxycholate), sodium cholate, sodium chenodeoxycholate, sodium obeticholate, sodium porcine deoxycholate, and sodium deoxycholate. In some embodiments, the bile salt is sodium glycocholate, sodium ursodeoxycholate, or sodium deoxycholate. In some embodiments, the bile salt is sodium glycocholate or sodium deoxycholate. In some embodiments, the bile salt is sodium deoxycholate.

[0144] In some embodiments, the weight ratio of the solubilizer to semaglutide or a pharmaceutically acceptable salt thereof is 15:1 to 1:5. In some embodiments, the weight ratio of the solubilizer to semaglutide or a pharmaceutically acceptable salt thereof is 10:1 to 1:5. In some embodiments, the weight ratio of the solubilizer to semaglutide or a pharmaceutically acceptable salt thereof is within the range of any two of the following values: 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, or 1:5.

[0145] In some embodiments, the solubilizer is water, and the weight ratio of water to semaglutide or its pharmaceutically acceptable salt is 15:1 to 1:5. In some embodiments, the weight ratio of water to semaglutide or its pharmaceutically acceptable salt is 10:1 to 1:5. In some embodiments, the weight ratio of water to semaglutide or its pharmaceutically acceptable salt is 10:1 to 1:2, 8:1 to 1:1, 6:1 to 2:1, or 5:1 to 3:1. In some embodiments, the weight ratio of water to semaglutide or its pharmaceutically acceptable salt is 4:1. In some embodiments, the solubilizer is bile salt, and the weight ratio of bile salt to semaglutide or its pharmaceutically acceptable salt is 15:1 to 1:5. In some embodiments, the weight ratio of bile salt to semaglutide or its pharmaceutically acceptable salt is 10:1 to 1:5. In some embodiments, the weight ratio of bile salts to smegglutide or its pharmaceutically acceptable salt is 15:1, 14:1, 13:1, 12:1, 11:1, 10:1-1:2, 8:1-1:2, 6:1-1:1, 4:1-1:1, 3:1-1:1, or 2:1-1:1. In some embodiments, the weight ratio of bile salts to smegglutide or its pharmaceutically acceptable salt is 1.5:1.

[0146] In some embodiments, the pharmaceutically acceptable salt of semaglutide is selected from mesylate, hydrochloride, acetate, dihydroxynaphthyl salt, benzoate, maleate, and sodium salt. In some embodiments, the pharmaceutically acceptable salt of semaglutide is semaglutide acetate or semaglutide sodium salt. In some embodiments, the pharmaceutically acceptable salt of semaglutide is semaglutide sodium salt.

[0147] In some embodiments, the pH adjuster is selected from benzoic acid, citric acid, sulfuric acid, phosphoric acid, maleic acid, hydrohalic acid, sulfonic acid, methanesulfonic acid, hydrochloric acid, and acetic acid. In some embodiments, the pH adjuster is methanesulfonic acid or hydrochloric acid. In some embodiments, the pH adjuster is hydrochloric acid. The amount of pH adjuster can be adjusted by those skilled in the art of pharmaceutical formulation based on the acid strength and the strength of the acid solution to adjust the pH of the semaglutide sustained-release formulation to a predetermined value or range.

[0148] Triacylglycerol can be a single trisubstituted glyceride or a mixture of multiple trisubstituted glycerides. As a non-limiting example, the trisubstituted glyceride can be trioleic acid glyceride, tridecanoic acid glyceride, or tricaprylic acid glyceride. In some embodiments, the triacylglycerol is a medium-chain triglyceride (MCT).

[0149] Phosphatidylcholine can be natural or synthetic. As a non-limiting example, phosphatidylcholine can be soybean phosphatidylcholine, egg yolk phosphatidylcholine, or a combination thereof. In some embodiments, the phosphatidylcholine is soybean phosphatidylcholine.

[0150] In some embodiments, the weight ratio of triacylglycerol to phosphatidylcholine is 15:85 to 50:50. In some embodiments, the weight ratio of triacylglycerol to phosphatidylcholine is 15:85 to 45:55. In some embodiments, the weight ratio of triacylglycerol to phosphatidylcholine is 15:85 to 35:65. In some embodiments, the weight ratio of triacylglycerol to phosphatidylcholine is 15:85 to 40:60, or 17:83 to 40:60, or 20:80 to 40:60, or 15:85 to 35:65, or 20:80 to 30:70. In some embodiments, the weight ratio of triacylglycerol to phosphatidylcholine is 25:75. In some implementations, the weight ratio of triacylglycerol to phosphatidylcholine is a range between any two point values ​​of 15:85, 18:82, 17:83, 20:80, 22:78, 25:75, 28:72, 30:70, 35:65, 40:60, 45:55, or 50:50 or above.

[0151] In some embodiments, the triacylglycerol is a medium-chain triglyceride, and the phosphatidylcholine is soybean phosphatidylcholine. In some embodiments, the weight ratio of medium-chain triglyceride to soybean phosphatidylcholine is from 15:85 to 50:50. In some embodiments, the weight ratio of medium-chain triglyceride to soybean phosphatidylcholine is from 15:85 to 45:55. In some embodiments, the weight ratio of medium-chain triglyceride to soybean phosphatidylcholine is from 15:85 to 40:60. In some embodiments, the weight ratio of medium-chain triglyceride to soybean phosphatidylcholine is from 17:83 to 40:60. In some embodiments, the weight ratio of medium-chain triglyceride to soybean phosphatidylcholine is from 15:85 to 35:65. In some embodiments, the weight ratio of medium-chain triglyceride to soybean phosphatidylcholine is from 20:80 to 40:60. In some embodiments, the weight ratio of medium-chain triglycerides to soybean phosphatidylcholine is 20:80 to 30:70. In some embodiments, the weight ratio of medium-chain triglycerides to soybean phosphatidylcholine is 25:75. In some embodiments, the weight ratio of medium-chain triglycerides to soybean phosphatidylcholine is within the range of any two of the following values: 15:85, 18:82, 17:83, 20:80, 22:78, 25:75, 28:72, 30:70, 35:65, 40:60, 45:55, or 50:50.

[0152] In some embodiments of the first or third aspect, the semaglutide sustained-release formulation comprises, or is substantially composed of, the following components in parts by weight, or is composed of, the following components in parts by weight:

[0153] (a) 0.01-30 parts by weight of semaglutide or its pharmaceutically acceptable salt, 100-450 parts by weight of triacylglycerol, 400-800 parts by weight of phosphatidylcholine, 50-180 parts by weight of anhydrous ethanol or ethanol, and 10-80 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.0-6.6; or

[0154] (b) 0.1-20 parts by weight of semaglutide or its pharmaceutically acceptable salt, 100-400 parts by weight of triacylglycerol, 400-700 parts by weight of phosphatidylcholine, 70-180 parts by weight of anhydrous ethanol or ethanol, and 10-70 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.6; or

[0155] (c) 1-15 parts by weight of semaglutide or its pharmaceutically acceptable salt, 100-300 parts by weight of triacylglycerol, 450-650 parts by weight of phosphatidylcholine, 90-180 parts by weight of anhydrous ethanol or ethanol, and 10-60 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.6; or

[0156] (d) 5-15 parts by weight of semaglutide or its pharmaceutically acceptable salt, 120-280 parts by weight of triacylglycerol, 500-650 parts by weight of phosphatidylcholine, 100-170 parts by weight of anhydrous ethanol or ethanol, and 10-50 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.6; or

[0157] (e) 7-14 parts by weight of semaglutide or its pharmaceutically acceptable salt, 150-250 parts by weight of triacylglycerol, 550-650 parts by weight of phosphatidylcholine, 120-170 parts by weight of anhydrous ethanol or ethanol, and 10-40 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.5; or

[0158] (f) 8-12 parts by weight of semaglutide or its pharmaceutically acceptable salt, 150-250 parts by weight of triacylglycerol, 550-650 parts by weight of phosphatidylcholine, 120-170 parts by weight of anhydrous ethanol or ethanol, and 10-40 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.6-6.2.

[0159] In some embodiments of the second or fourth aspect, the semaglutide sustained-release formulation comprises, or is substantially composed of, the following components in parts by weight, or is composed of, the following components in parts by weight:

[0160] (a) 0.01-30 parts by weight of semaglutide or its pharmaceutically acceptable salt, 1000 parts by weight of the lipid mixture, and 10-80 parts by weight of the solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.0-6.6; wherein triacylglycerol accounts for 10%-45% by weight of the lipid mixture, phosphatidylcholine accounts for 40%-70% by weight of the lipid mixture, and ethanol accounts for 5%-20% by weight of the lipid mixture; or

[0161] (b) 0.1-20 parts by weight of semaglutide or a pharmaceutically acceptable salt thereof, 1000 parts by weight of a lipid mixture, and 10-70 parts by weight of a solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or has a pH value of 5.3-6.6; wherein triacylglycerol accounts for 10%-40% by weight of the lipid mixture, phosphatidylcholine accounts for 45%-65% by weight of the lipid mixture, and ethanol accounts for 5%-18% by weight of the lipid mixture; or

[0162] (c) Smegglutide or its pharmaceutically acceptable salt comprises 1-15 parts by weight, a lipid mixture comprises 1000 parts by weight, and a solubilizer comprises 10-60 parts by weight, wherein the pH of the smegglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.6; wherein triacylglycerol comprises 10%-30% by weight of the lipid mixture, phosphatidylcholine comprises 45%-65% by weight of the lipid mixture, and ethanol comprises 7%-18% by weight of the lipid mixture; or

[0163] (d) 5-15 parts by weight of semaglutide or its pharmaceutically acceptable salt, 1000 parts by weight of the lipid mixture, and 10-50 parts by weight of the solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or has a pH value of 5.3-6.6; wherein triacylglycerol accounts for 12%-28% by weight of the lipid mixture, phosphatidylcholine accounts for 50%-65% by weight of the lipid mixture, and ethanol accounts for 9%-18% by weight of the lipid mixture; or

[0164] (e) 7-14 parts by weight of semaglutide or its pharmaceutically acceptable salt, 1000 parts by weight of the lipid mixture, and 10-40 parts by weight of the solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or has a pH value of 5.3-6.5; wherein triacylglycerol accounts for 12%-28% by weight of the lipid mixture, phosphatidylcholine accounts for 50%-65% by weight of the lipid mixture, and ethanol accounts for 9%-18% by weight of the lipid mixture; or

[0165] (f) 8-12 parts by weight of semaglutide or its pharmaceutically acceptable salt, 1000 parts by weight of the lipid mixture, 10-40 parts by weight of the solubilizer, and the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.6-6.2; wherein, triacylglycerol accounts for 12%-28% by weight of the lipid mixture, phosphatidylcholine accounts for 50%-65% by weight of the lipid mixture, and ethanol accounts for 9%-18% by weight of the lipid mixture.

[0166] In some embodiments, the sustained-release formulation of semaglutide described in the first to fourth aspects uses NMP or an NMP-ethanol mixture instead of ethanol; preferably, the weight ratio of NMP to ethanol in the NMP-ethanol mixture is (1-5):(5-1), more preferably (1-4):(4-1) or (1-3):(3-1) or (1-2):(2-1); for example, the weight ratio of NMP to ethanol is 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1 or any two of the above values.

[0167] Fifthly, this application provides the use of the semaglutide sustained-release formulations described in the first to fourth aspects for the treatment of GLP-1R-related diseases.

[0168] Sixthly, this application provides a method for preparing the semaglutide sustained-release formulation using water as a solubilizer as described in the first to fourth aspects, the preparation method comprising the following steps:

[0169] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain the aqueous phase;

[0170] Step 2: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0171] Step 3: Add the aqueous phase obtained in Step 1 to the lipid mixture obtained in Step 2, and stir to mix well;

[0172] Step 4: Add pH adjuster to adjust the pH value to the predetermined pH value of the smegglutinin sustained-release formulation, then filter and fill.

[0173] In a seventh aspect, this application provides a method for preparing the semaglutide sustained-release formulation using bile salts (e.g., sodium deoxycholate) as a solubilizer, as described in the first to fourth aspects, the method comprising the following steps:

[0174] Step a: Smegglutide or its pharmaceutically acceptable salts are dissolved and mixed with bile salts (e.g., sodium deoxycholate) in water and then freeze-dried to form a freeze-dried complex.

[0175] Step b: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0176] Step c: Add the lyophilized complex obtained in step a to the lipid mixture obtained in step b, and stir to dissolve;

[0177] Step d: Add pH adjuster to adjust the pH value to the predetermined pH value of the smegglutinin sustained-release formulation, then filter and fill.

[0178] In some embodiments of aspects six and seven, step 2 or step b controls the temperature to be less than or equal to 45°C. In some embodiments, step 2 or step b controls the temperature to be less than or equal to 40°C, for example, room temperature.

[0179] Those skilled in the art, based on the disclosure of this application and knowledge of pharmaceutical formulation, should understand that some steps or processes in the methods of aspects six and seven of this application can be varied or adjusted, and equivalent preparation methods can be obtained by adjusting the order of some steps or replacing conventional processes. These applicable solutions obtained by adjusting the order of some steps or replacing conventional processes also fall within the protection scope of this application. Specific examples of the methods of aspects six and seven can be found in the descriptions of the embodiments of this application. Where there are no contradictions or conflicts, the operating parameters in the embodiments of this application can be considered as independent features in the methods of aspects six and seven.

[0180] Eighthly, this application provides the use of the semaglutide sustained-release formulation described in the first to fourth aspects in the preparation of a medicament for treating GLP-1R-related diseases.

[0181] Ninthly, this application provides a method for treating GLP-1R-related diseases in an individual, the method comprising administering a therapeutically effective amount of the semaglutide extended-release formulation described in the first to fourth aspects to the individual in need.

[0182] In a tenth aspect, this application provides a sustained-release formulation of semaglutide as described in the first to fourth aspects for the treatment of GLP-1R-related diseases.

[0183] In some implementation schemes of aspects five, eight, nine, or ten, GLP-1R-related diseases are selected from type 2 diabetes, overweight, obesity, cardiovascular disease, non-alcoholic steatohepatitis, Alzheimer's disease, diabetic nephropathy, intermittent claudication, stroke, myocardial infarction, polycystic ovary syndrome, heart failure, type 1 diabetes, peripheral artery disease, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, and uterine diseases.

[0184] In some embodiments of aspects five, eight, nine, or ten, the semaglutide extended-release formulation is administered to individuals every 2-8 weeks. In some embodiments, the semaglutide extended-release formulation is administered to individuals every 3-6 weeks. In some embodiments, the semaglutide extended-release formulation is administered to individuals every 4-5 weeks, every 4 weeks, or monthly.

[0185] In some implementations of aspects five, eight, nine, or ten, the individual is a mammal. In some implementations, the individual is a human patient. Example

[0186] The inventions of this application are further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of this application. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Furthermore, any methods and materials similar to or equivalent to those described herein can be applied to the methods of this application. The preferred embodiments and materials described herein are for illustrative purposes only.

[0187] 1. Visual inspection: Use the visual method. Hold the test sample under the light inspection instrument and rotate it in three steps: vertical, horizontal, and upside down. Visually inspect it against both black and white backgrounds. Repeat the observation. The total inspection time is 20 seconds.

[0188] 2. Determination of content and total impurities

[0189] Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0190] Chromatographic conditions: Octylsilane-bonded silica gel was used as the stationary phase; mobile phase A was 0.05 mol / L sodium dihydrogen phosphate (pH adjusted to 3.0 with phosphoric acid)-acetonitrile (65:35), and mobile phase B was 0.05 mol / L sodium dihydrogen phosphate (pH adjusted to 3.0 with phosphoric acid)-acetonitrile (50:50), with gradient elution as shown in Table 1 below; the flow rate was 0.6 mL / min; the detection wavelength was 215 nm; and the column temperature was 40 °C.

[0191] Table 1. Gradient elution protocols

[0192] 3. Oligomer determination

[0193] Determined according to size exclusion chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0194] The chromatographic conditions were as follows: hydrophilic modified silica gel was used as the stationary phase; isopropanol-glacial acetic acid-water (150:200:150) was used as the mobile phase; the flow rate was 0.3 ml per minute; the detection wavelength was 276 nm; and the column temperature was 50 °C.

[0195] 4. Thrust (Injectability) Measurement Method

[0196] Equipment: HAK-3132WJ push-pull force testing machine;

[0197] Push rate: 100 mm / min;

[0198] Pushing distance: 1cm;

[0199] Measurement temperature: 20℃.

[0200] The main raw and auxiliary materials used in the embodiments of this application are as follows:

[0201] Smegglutinin was prepared by the inventor team using the technology disclosed in WO2006 / 097537, with a purity of 94.2%.

[0202] Soybean phosphatidylcholine (SPC): purchased from LIPOID GMBH, purity 94%.

[0203] Medium-chain triglycerides (MCT): Purchased from Liaoning Xinxing Pharmaceutical Co., Ltd., with the main fatty acid composition being 50.0%–80.0% caprylic acid and 20.0%–50.0% capric acid.

[0204] Example 1. Preparation of smegglutide sustained-release formulation

[0205] Prepare a semaglutide sustained-release formulation according to the following prescription:

[0206] Table 2. Formulation of Smegglutide sustained-release formulation

[0207] 1. The preparation method of prescription 1-1 or 1-2 is as follows (hereinafter referred to as preparation method 1):

[0208] Step 1: Smegglutide and sodium deoxycholate are dissolved and mixed in water and then freeze-dried to form a freeze-dried complex (SMBS).

[0209] Step 2: Mix soybean phosphatidylcholine (SPC), medium-chain triglycerides (MCT), and anhydrous ethanol, stir to dissolve, and obtain a lipid mixture;

[0210] Step 3: Add the lyophilized complex obtained in Step 1 to the lipid mixture obtained in Step 2 and stir to dissolve;

[0211] Step 4: Add a pH adjuster (such as hydrochloric acid) to adjust the pH value to the target value, then filter and fill.

[0212] 2. The preparation methods for prescriptions 1-3, 1-4, or 1-5 are as follows (hereinafter referred to as preparation method 2):

[0213] Step 1: Mix smegglutinin with water, stir to dissolve, and obtain the aqueous phase;

[0214] Step 2: Mix soybean phosphatidylcholine (SPC), medium-chain triglycerides (MCT), and anhydrous ethanol, stir to dissolve, and obtain a lipid mixture;

[0215] Step 3: Add the aqueous phase obtained in Step 1 to the lipid mixture obtained in Step 2, and stir to mix well;

[0216] Step 4: Add a pH adjuster (such as hydrochloric acid) to adjust the pH value to the target value, then filter and fill.

[0217] Example 2. Effect of the type of neutral lipid on formulation performance

[0218] Referring to Formulations 1-2 of Example 1, the effect of the type of neutral lipid on the performance of the formulation was investigated. The different types of neutral lipids tested are shown in Table 3. All other raw materials and amounts were the same as in Formulations 1-2. Preparation was carried out according to Preparation Method 1 of Example 1 (excluding step 4, which involves adding a pH adjuster to adjust the pH). After preparation, the stability was monitored by placing the product at 40°C and 25°C for different times. The results are shown in Table 3.

[0219] Table 3. Effect of a single type of neutral lipid on formulation performance Note: *Content refers to the content of smegglutinin, calculated at each stability point with D0 content as 100%.

[0220] The results showed that, under the above experimental conditions, the stability of the MCT formulation was significantly better than that of the GDO and GMO formulations.

[0221] Example 3. Effects of different pH adjusters on formulation performance

[0222] Referring to Formulation 1-1 of Example 1, the effect of different pH adjusters on the performance of the formulation was investigated. The different pH adjusters tested are shown in Table 4; the remaining raw materials and dosages were the same as in Formulation 1-1. Preparation was carried out according to Preparation Method 1 described in Example 1, with different types of acid used for pH adjustment in step 4. After preparation, the formulation was placed at 40°C for 5 days and at 25°C for 14 days to monitor stability. The results are shown in Table 4.

[0223] Table 4. Effects of different pH adjusters on formulation performance Note: *Content refers to the content of smegglutinin, and the stability point content is calculated with D0 content as 100%.

[0224] The results showed that when the pH of the formulations was basically the same, the formulations using maleic acid as a pH adjuster had significantly worse stability, while the groups using mesylic acid and hydrochloric acid had relatively better stability.

[0225] Example 4. Effects of different solubilizers on formulation performance

[0226] Considering that the preparation method 1 is relatively complex, water is used as a solubilizer in the study to test and develop a simpler formulation and process (preparation method 2).

[0227] The effects of bile salts (sodium deoxycholate) and water as solubilizers on the performance of the formulations were investigated. Formulation information is shown in Table 5. Formulations 4-1 and 4-2 were prepared according to preparation methods 1 and 2 described in Example 1, respectively. After preparation, the formulations were stored at 5°C for 6 months to monitor stability. The results are shown in Table 5.

[0228] Table 5. Effects of different solubilization methods on formulation performance Note: *Content refers to the content of smegglutinin, calculated with D0 content as 100% for 6 months.

[0229] The results showed that under the above experimental conditions, both bile salts and water could achieve complete dissolution of API (semaglutide) in the composition system. The mixture remained a clear liquid throughout the observation period, and after being placed at 5°C for 6 minutes, there was no significant difference in API content between the two methods. Water was even slightly better as a solubilizer. Therefore, using water as a solubilizer is a feasible approach.

[0230] Example 5. Effect of different endpoint pH values ​​on formulation performance

[0231] Referring to formulations 1-4 of Example 1, the effect of different endpoint pH values ​​on the performance of the formulation was investigated. Formulations for different endpoint pH values ​​are shown in Table 6. Preparation was carried out according to preparation method 2 described in Example 1 (step 4 involves adding an appropriate amount of hydrochloric acid to adjust the pH value). After preparation, the formulation was stored at 5°C for 12 months, and its stability was monitored. The results are shown in Table 6.

[0232] Table 6. Effects of different pH values ​​on formulation performance Note: Oligomers and total impurities were not detected in any of the D0 formulations; *content refers to the content of semaglutide, calculated as 100% of the D0 content for 12 months.

[0233] The results showed that under the above experimental conditions, a higher endpoint pH led to an increase in oligomer content, but a decrease in total impurity content. Based on comprehensive analysis, an endpoint pH between 5.6 and 6.2 is more favorable for the stability of the formulation.

[0234] Example 6. Effect of neutral lipid mixtures on formulation performance

[0235] Referring to Formulations 1-4 of Examples 1, the effect of the type of neutral lipid mixture (corresponding to the MCT component in Formulations 1-4) on the formulation performance was investigated. In each formulation, the amounts of smegglutinin, water, and anhydrous ethanol remained constant, as did the amounts of SPC and neutral lipids. The types of neutral lipid mixtures and their ratio to SPC were adjusted according to Table 7.

[0236] The preparation was carried out according to method 2 described in Example 1 (step 4 involves adding hydrochloric acid to adjust the pH to approximately 5.7). After preparation, the sample was placed at 25°C for one month to monitor its stability. The results are shown in Table 7.

[0237] Table 7. Effect of neutral lipid mixture type on formulation performance Note: *Content refers to the content of smegglutinin, calculated with D0 content as 100%. SMO: Span 80; SAIB: sucrose diacetate; TA: ethyl tocopherol; IPP: isopropyl palmitate.

[0238] The results showed that, for neutral lipid mixture formulations, those containing MCT generally exhibited better stability than those without MCT. Considering both neutral lipid mixture formulations and MCT-only formulations, the results indicated that the MCT-only formulations demonstrated the best stability.

[0239] Example 7. Effect of API concentration on formulation performance

[0240] Referring to formulations 1-4 in Examples 1, the effect of API (semaglutide) concentration on formulation performance was investigated. Formulations with different API concentrations are shown in Table 8; the remaining excipients and their amounts were the same as in formulations 1-4. Preparation was carried out according to preparation method 2 described in Example 1 (step 4 involves adjusting the pH to 5.6 with hydrochloric acid). After preparation, the formulation was stored at 25°C for one month, and its stability was monitored. The results are shown in Table 8.

[0241] Table 8. Effect of API concentration on formulation performance Note: *Content refers to the content of smegglutinin, and the API concentration in the table refers to the amount of API relative to the lipid mixture (the mixture of SPC+MCT+anhydrous ethanol in step 2).

[0242] The results showed that under the above experimental conditions, API concentrations between 8-12 mg / g had no significant difference in effect on stability, but were significantly better than 4 mg / g. Therefore, the results of this experiment suggest that appropriately increasing the API concentration can help improve the stability of the formulation.

[0243] Example 8. Effect of water dosage on formulation performance

[0244] Referring to Formulations 1-3 of Examples 1, the effect of water dosage on the performance of the formulation was investigated. The water dosage is shown in Table 9; the dosages of other raw materials and excipients were the same as in Formulations 1-3. Preparation was carried out according to Preparation Method 2 described in Example 1 (step 4 involves adjusting the pH to 5.7 with hydrochloric acid). After preparation, the formulation was stored at 25°C for 3 months, and its stability was monitored. The results are shown in Table 9.

[0245] Table 9. Effect of water dosage on formulation performance Note: The amount of water used in the table refers to the amount of water relative to the lipid mixture (the mixture of SPC+MCT+anhydrous ethanol in step 2).

[0246] The results showed that, under the above experimental conditions, the amount of water used, ranging from 20 to 60 mg / g, had no significant effect on the product's properties, thrust, and stability.

[0247] Example 9. Effect of different SPC / MCT ratios on formulation performance 1

[0248] The effect of the SPC / MCT ratio on the formulation performance was investigated according to Tables 10-1 and 10-2. The overall formulation of this example is shown in Table 10-1, and different SPC / MCT ratios are shown in Table 10-2. Preparation was carried out according to preparation method 2 described in Example 1. After preparation, the product was stored at 25°C for 2 months, and its stability was monitored. The results are shown in Table 10-2.

[0249] Table 10-1. Pharmaceutical Formulation

[0250] Table 10-2. Effects of different SPC / MCT ratios on formulation performance Note: *Content refers to the content of smegglutinin, and the stability point content is calculated with D0 content as 100%.

[0251] The results show that, under the above test conditions, the stability of SPC / MCT between 70 / 15 and 50 / 35 is better than that at 30 / 55.

[0252] Example 10. Stability of the formulation of this application

[0253] Samples were prepared according to formulations 1-3 in Example 1, and their stability under different conditions was determined. The results are shown in Table 11.

[0254] Table 11. Formulation stability results Note: *Content refers to the content of smegglutinin, calculated with D0 content as 100% for stability point content. M1, M2, M3, M6, M12, M18, and M24 represent storage periods of 1, 2, 3, 6, 12, 18, and 24 months, respectively.

[0255] When formulations 1-3 are stored at 25°C for 3 months, the API content decreases by approximately 10%; when stored at 5°C for 12 months, the API content decreases by 6%; and when stored at 5°C for 24 months, the API content decreases by approximately 8%. However, the content changes are clearly stabilizing, indicating the potential for long-term storage under refrigeration conditions.

[0256] Example 11. In vivo release characteristics of the formulation of this application

[0257] This embodiment compares the pharmacokinetic characteristics of formulations 1-4 of Example 1 of this application with those of Smegglutide injection (Novogene) already marketed in China in rats.

[0258] The experimental methods are as follows: Male SD rats, weighing 200-220g, were randomly divided into two groups of 6 rats each: (1) Novogene group: Smegglutide injection (Novogene, commercially available), subcutaneous injection, dose 0.123mg / kg (based on smegglutide), blood was collected before administration and at 0.5h, 1h, 3h, 6h, 9h, 12h, 24h, 36h, 3d, and 4d after administration; (2) The group of this application: according to Samples prepared according to Formulations 1-4 of Examples 1 (API concentration of 4 mg / g lipid mixture) were administered subcutaneously at a dose of 7 mg / kg (based on semaglutide). Approximately 0.2 mL blood samples were collected before administration and at 0.5 h, 1 h, 3 h, 6 h, 9 h, 12 h, 24 h, 36 h, 3 d, 4 d, 5 d, 7 d, 10 d, 14 d, 18 d, 21 d, 24 d, 27 d, and 30 d after administration. Immediately after collection, the blood samples were mixed in pre-chilled K2EDTA tubes containing 10 μL of aprotinin and placed on an ice pack. Plasma was centrifuged within 1 h of collection. The plasma was placed in labeled polypropylene tubes and stored at -60°C or lower for LC-MS / MS analysis. Protein precipitation was used to process the plasma samples, and the concentration of semaglutide in the samples was determined using LC-MS / MS.

[0259] The PK results are shown in Figure 1. It can be seen that formulations 1-4 provide a slow and sustained release of semaglutide, with a single injection providing sustained release for more than 28 days, demonstrating a significantly better sustained-release effect compared to the commercially available formulation Novogene.

[0260] Example 12. Comparison of in vivo release characteristics of medium-chain triglycerides (MCT) and dioleoglycerides (GDO) formulations.

[0261] Formulas 10-1 and 10-2 were prepared according to preparation method 1 described in Example 1 (see Table 12-1), and their pharmacokinetic characteristics in rats were compared.

[0262] The experimental method is as follows: Male SD rats, weighing 200-220g, were randomly divided into two groups of 6 rats each. They were subcutaneously injected with a dose of 2.4 mg / kg (based on semaglutide). Blood samples of approximately 0.2 mL were collected before administration and at 0.5h, 1h, 3h, 6h, 9h, 12h, 24h, 36h, 3d, 4d, 5d, 7d, 10d, 14d, 18d, 21d, 23d, and 26d after administration. Immediately after collection, the blood samples were mixed in pre-chilled K2EDTA tubes containing 10 μL of aprotinin and placed on an ice pack. Plasma was centrifuged within 1 hour of collection. The plasma was placed in labeled polypropylene tubes and stored at -60℃ or lower for LC-MS / MS analysis. Protein precipitation was used to process the plasma samples, and the concentration of semaglutide in the samples was detected using LC-MS / MS.

[0263] Table 12-1. Formulation Information

[0264] Table 12-2. Different Prescriptions C max / C 23d contrast Note: Data were collected for 26 days in this experiment, but the blood drug concentration of rats treated with prescription 10-2 was below the detection limit on day 26, so data from day 23 were used as the tail point data.

[0265] The PK results are shown in Table 12-2 and Figure 2. It can be seen that, at the same dosage, the PK curves of formulations 10-2 and 10-1 basically overlapped between approximately 336h and 576h. However, the Cmax of formulation 10-2 in the early release phase was significantly higher than that of formulation 10-1, and the Cmax / C23d ratio of formulation 10-2 was also significantly higher than that of formulation 10-1. Therefore, the PK curve of formulation 10-1 was generally more stable, indicating that the MCT-based formulation has more favorable sustained-release properties.

[0266] Comparative Example 1

[0267] Comparative Example 1 was prepared according to the composition of the lipid mixture in Example 6 of patent CN101217940B. The proportions of SPC, GDO, and anhydrous ethanol in Comparative Example 1 were consistent with those in CN101217940B (SPC / GDO / EtOH = 42.5 / 42.5 / 15wt%). To facilitate comparison with the formulation of this application, the proportion of ethanol in the lipid mixture was adjusted to 15%, smegglutinin was adjusted to 4 mg / g (relative to the amount of lipid mixture), and bile salts were selected as a solubilizer. The specific formulation is shown in Table 13. The preparation method was the same as preparation method 1 in Example 1.

[0268] Table 13. Prescription information for Comparative Example 1

[0269] Test Example 1: Stability Comparison of GDO and MCT Prescriptions

[0270] The stability of the sample from Formulation 1-1 of Example 1 (with pH adjusted to 5.6 by appropriate amount of hydrochloric acid) and the sample from Comparative Example 1 at different temperatures was investigated. The results are shown in Table 14.

[0271] Table 14. Stability results of Formulation 1-1 and Comparative Example 1 (%) Note: *Content refers to the content of smegglutinin, calculated with D0 content as 100% for stability point content. The pH of the formulation is 5.6-5.7.

[0272] Comparative Example 2

[0273] Comparative Example 2 was prepared according to the composition of the lipid mixture in Example 6 of patent CN101217940B. The proportions of SPC, GDO, and anhydrous ethanol in Comparative Example 2 were consistent with those in CN101217940B (SPC / GDO / EtOH = 42.5 / 42.5 / 15wt%). To facilitate comparison with the formulation of this application, the proportion of ethanol in the lipid mixture was adjusted to 15%, smegglutinin was adjusted to 10 mg / g (relative to the amount of lipid mixture), and water was selected as the solubilizer. The specific formulation is shown in Table 15. The preparation method was the same as preparation method 2 in Example 1.

[0274] Table 15. Prescription information for Comparative Example 2

[0275] Test Example 2: Stability Comparison of GDO and MCT Prescriptions

[0276] Samples of formulations 1-3 from Example 1 (with pH adjusted to 6.0 by appropriate amount of hydrochloric acid) and sample of Comparative Example 2 were taken and their stability at different temperatures was investigated. The results are shown in Table 16.

[0277] Table 16 Stability results of the formulation of this application and Comparative Example 2 (content %*) Note: *Content refers to the content of smegglutinin, and the stability point content is calculated with D0 content as 100%.

[0278] CN101217940B uses GDO as the core neutral lipid. Combined with the comparative examples above and Examples 2 and 6, it can be seen that using MCT as the core neutral lipid can significantly improve the stability of the semaglutide sustained-release formulation. The results of Test Examples 1 and 2 directly demonstrate that the stability of the representative formulation of this application is significantly better than that of the comparative examples.

[0279] Example 13. Process testing for the preparation of lipid mixtures

[0280] Referring to formulations 1-3 of Example 1 and taking preparation method 2 of Example 1 as an example, the effects of temperature and heating time in step 2 on the stability of the lipid mixture were investigated.

[0281] A lipid mixture was prepared by mixing soybean phosphatidylcholine (SPC), medium-chain triglycerides (MCT), and anhydrous ethanol and heating. The effects of different temperatures on the lipid dissolution rate and stability were investigated. The resulting lipid mixture was cooled to room temperature, and the drug mixture (the aqueous phase from step 1) was mixed with the lipid mixture according to preparation method 2 in Example 1. The stability of the final product was then tested.

[0282] Specifically, the peroxide value and methoxyaniline value of this project were determined in accordance with the determination methods for peroxide value and methoxyaniline value in Chapter 0713, General Chapter 4, Fats and Fatty Oils, of the 2020 edition of the Chinese Pharmacopoeia.

[0283] V1 is the volume of sodium thiosulfate titrant consumed by the test sample, in ml;

[0284] V0 represents the volume of sodium thiosulfate titrant consumed in the blank test, in ml;

[0285] C represents the concentration of sodium thiosulfate titrant, in mol / L;

[0286] m is the sample weight, in grams;

[0287] L represents the labeled amount of soybean phosphatidylcholine, in mg / g.

[0288] m is the sample weight, in grams;

[0289] L represents the labeled amount of soybean phosphatidylcholine in the test sample in the formulation, in g / g;

[0290] 1.2 represents the dilution factor of the solution after adding 4-methoxyaniline glacial acetic acid solution;

[0291] A1 is the absorbance value of the solution in the stoppered test tube A;

[0292] A2 is the absorbance value of the solution in the stoppered test tube B;

[0293] A0 is the absorbance value of the test solution without the addition of 4-methoxyaniline glacial acetic acid solution.

[0294] As shown in Tables 17-1 and 17-2, heating helps accelerate SPC dissolution and shorten process time, but higher temperatures may lead to the degradation of SPC and MCT. Heating at 60℃ for 4 or 8 hours resulted in decreased stability of SPC and MCT, a significant increase in the peroxide value of the lipid mixture, and a significant increase in the peroxide value and methoxyaniline value of the finished product. Heating at 40℃ for 4 hours showed better stability of both the lipid mixture and the finished product. This suggests that excessively high heating temperatures and prolonged heating times in step 2 will affect the stability of the lipid mixture and the finished product. Therefore, the recommended temperature for step 2 is less than or equal to 45℃ or 40℃, and the heating time should not exceed 4 hours.

[0295] Table 17-1 Effect of temperature on the dissolution time of lipid mixture in step 2.

[0296] Table 17-2 Effects of Step 2 Temperature and Heating Time on the Stability of Lipid Mixtures and Finished Products

[0297] Example 14. Formulation preparation process testing

[0298] Referring to formulations 1-4 in Examples 1, semaglutide long-acting injection was prepared according to methods A, B, C, and D respectively. The only difference between the four methods was the order of the steps; the process parameters remained the same. In step 2, the temperature was 40°C, and step 3 was performed after the product cooled to room temperature.

[0299] Method A includes the following steps:

[0300] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain an aqueous phase, i.e., a drug mixture;

[0301] Step 2: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0302] Step 3: Mix the aqueous phase obtained in Step 1 and the lipid mixture obtained in Step 2 thoroughly, add the pH adjuster, and mix thoroughly.

[0303] Step 4: Filtering and filling.

[0304] Method B includes the following steps:

[0305] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain an aqueous phase, i.e., a drug mixture;

[0306] Step 2: Mix phosphatidylcholine and ethanol, stir and dissolve to obtain phosphatidylcholine solution; mix triacylglycerol ester with phosphatidylcholine solution evenly, add pH adjuster, mix evenly to obtain lipid mixture;

[0307] Step 3: Mix the aqueous phase obtained in Step 1 with the lipid mixture obtained in Step 2 until homogeneous;

[0308] Step 4: Filtering and filling.

[0309] Method C includes the following steps:

[0310] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain an aqueous phase, i.e., a drug mixture;

[0311] Step 2: Mix phosphatidylcholine and ethanol, stir to dissolve, and obtain a phosphatidylcholine solution;

[0312] Step 3: Mix the aqueous phase obtained in Step 1 with the phosphatidylcholine solution obtained in Step 2 until homogeneous; then add triacylglycerol and mix until homogeneous; add pH adjuster and mix until homogeneous.

[0313] Step 4: Filtering and filling.

[0314] Method D includes the following steps:

[0315] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain an aqueous phase, i.e., a drug mixture;

[0316] Step 2: Mix phosphatidylcholine and ethanol, stir to dissolve, and obtain a phosphatidylcholine solution;

[0317] Step 3: Mix the aqueous phase obtained in Step 1 with the phosphatidylcholine solution obtained in Step 2 until homogeneous, add the pH adjuster and mix until homogeneous; add the triacylglycerol and mix until homogeneous.

[0318] Step 4: Filtering and filling.

[0319] After comprehensive evaluation, the results showed that the formulations obtained by the above methods had no significant differences in appearance, stability, and in vitro and in vivo release behavior.

[0320] Example 15

[0321] Referring to Formulation 1-1 in Example 1, semaglutide long-acting injection was prepared according to methods E, F, G, and H below. The four methods only adjusted the order of steps; the process parameters remained the same. Step 2 was performed at 40°C, and then step 3 was carried out after cooling to room temperature.

[0322] The method E includes the following steps:

[0323] Step 1: Dissolve and mix smegglutide or its pharmaceutically acceptable salt with bile salt (sodium deoxycholate) in water, then freeze-dry to form a freeze-dried complex, i.e., a drug mixture.

[0324] Step 2: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0325] Step 3: Add the lyophilized complex obtained in Step 1 to the lipid mixture obtained in Step 2, stir to dissolve; add pH adjuster, mix well;

[0326] Step 4: Filtering and filling.

[0327] The method F includes the following steps:

[0328] Step 1: Dissolve and mix smegglutide or its pharmaceutically acceptable salt with bile salt (sodium deoxycholate) in water, then freeze-dry to form a freeze-dried complex, i.e., a drug mixture.

[0329] Step 2: Mix phosphatidylcholine and ethanol, stir and dissolve to obtain phosphatidylcholine solution; mix the phosphatidylcholine solution with triacylglycerol ester evenly, add pH adjuster, mix evenly to obtain lipid mixture;

[0330] Step 3: Add the lyophilized complex obtained in Step 1 to the lipid mixture obtained in Step 3, and stir to dissolve;

[0331] Step 4: Filtering and filling.

[0332] The method G includes the following steps:

[0333] Step 1: Dissolve and mix smegglutide or its pharmaceutically acceptable salt with bile salt (sodium deoxycholate) in water, then freeze-dry to form a freeze-dried complex, i.e., a drug mixture.

[0334] Step 2: Mix phosphatidylcholine and ethanol, stir to dissolve, and obtain phosphatidylcholine solution;

[0335] Step 3: Add the lyophilized complex obtained in Step 1 to the phosphatidylcholine solution obtained in Step 2, stir to dissolve, add triacylglycerol, and mix well; add pH adjuster and mix well.

[0336] Step 4: Filtering and filling.

[0337] The method H includes the following steps:

[0338] Step 1: Dissolve and mix smegglutide or its pharmaceutically acceptable salt with bile salt (sodium deoxycholate) in water, then freeze-dry to form a freeze-dried complex, i.e., a drug mixture.

[0339] Step 2: Mix phosphatidylcholine and ethanol, stir to dissolve, and obtain phosphatidylcholine solution;

[0340] Step 3: Add the lyophilized complex obtained in Step 1 to the phosphatidylcholine solution obtained in Step 2, stir to dissolve, add pH adjuster, and mix well; add triacylglycerol ester and mix well.

[0341] Step 4: Filtering and filling.

[0342] After comprehensive evaluation, the results showed that the formulations obtained by the above methods had no significant differences in appearance, stability, and in vitro and in vivo release behavior.

[0343] Example 16. Effects of different esters on formulation performance

[0344] 16.1 Effect of Span 20 on the stability of MCT-containing prescriptions

[0345] Referring to Formulation 1-1 of Example 1, the effect of introducing Span 20 on the formulation performance was investigated. In each formulation, the amounts of smegglutide, sodium deoxycholate, and anhydrous ethanol remained unchanged, as did the amounts of SPC + Span 20 + MCT. The component ratios were adjusted according to Table 18-1.

[0346] The preparation was carried out according to preparation method 1 described in Example 1. After preparation, the samples were placed at 25°C for 28 days or at 5°C for 3 months to monitor stability. The results are shown in Table 18-2.

[0347] Table 18-1. Formulation Information (Unit: mg)

[0348] Table 18-2. Stability Results Note: *Content refers to the content of smegglutinin.

[0349] The results showed that the introduction of Span 20 had a negative impact on stability for all prescriptions.

[0350] 16.2 Effects of Span 80, Ethyl Tocopherol (TA), and Ethyl Oleate (EO) on the Stability of MCT-Containing Formulations

[0351] Referring to Formulation 1-1 of Example 1, the effects of introducing Span 80, ethyl tocopherol, or ethyl oleate on the formulation performance were investigated. In each formulation, the amounts of smegglutide, sodium deoxycholate, and anhydrous ethanol remained unchanged, as did the amounts of SPC + Span 80 + ethyl tocopherol + ethyl oleate + MCT. The component ratios were adjusted according to Table 18-3.

[0352] The preparation was carried out according to preparation method 1 described in Example 1. After preparation, the samples were placed at 40°C for 8 days, at 25°C for 28 days, or at 5°C for 1 month to monitor stability. The results are shown in Table 18-4.

[0353] Table 18-3. Formulation Information (Unit: mg)

[0354] Table 18-4. Stability Results Note: *Content refers to the content of smegglutinin.

[0355] Comparing formulations 11-5 to 11-7, it is evident that replacing MCT with TA or EO significantly worsens the stability of semaglutide in the formulation. Comparing formulations 11-7 and 11-8, it is clear that introducing Span 80 into MCT-containing formulations leads to decreased stability of semaglutide in the formulation. Therefore, MCT formulations are more beneficial for the stability of semaglutide in the formulation.

[0356] Example 17. Solubilization Test 1

[0357] This example compares the solubilizing ability and the effect on formulation stability when sodium deoxycholate (BS), sodium glycocholate, sodium ursodeoxycholate, and sodium oleate (SO) are used as solubilizers.

[0358] Referring to Formulation 1-1 of Example 1, the effects of introducing different types and amounts of solubilizers on solubilization capacity (dissolution time in step 3) and formulation performance were investigated. The component ratios were adjusted as shown in Table 19-1, and preparation was carried out according to Preparation Method 1 of Example 1. The dissolution time in step 3 was recorded during the preparation process. After preparation, the products were stored at 25°C for 28 days or at 30°C for 8 days to monitor stability. The results are shown in Table 19-2.

[0359] Table 19-1. Pharmaceutical Formulation Information

[0360] Table 19-2. Results of Solubilizer Test Note: *Content refers to the content of smegglutinin.

[0361] The results showed that the effects of different solubilizers on formulation stability were not significantly different. Relatively speaking, the three bile salts showed better solubilizing effects.

[0362] Example 18. Effect of solvent on formulation performance

[0363] Referring to Formulation 1-1 of Example 1, the effect of replacing part of the ethanol with N-methylpyrrolidone (NMP) on the performance of the formulation was investigated. The component ratios were set as shown in Table 20-1, and the preparation was carried out according to Preparation Method 1 of Example 1. After preparation, the stability was monitored by placing the product at 25°C for 7, 14, or 28 days. The results are shown in Table 20-2.

[0364] Table 20-1. Formulation Information (Unit: mg)

[0365] Table 20-2. Stability Results Note: *Content refers to the content of smegglutinin.

[0366] The results showed that replacing 1 / 3 to 2 / 3 of ethanol with NMP had no significant effect on the stability of the formulation, therefore NMP is also a suitable solvent for the formulation of this application.

[0367] Example 19. Solubilization Test 2

[0368] This embodiment investigates the effect of using water, dimethyl sulfoxide (DMSO), or propylene glycol as solubilizers on the performance of the formulation. The component ratios were set as shown in Table 21-1, and the preparation was carried out according to preparation method 2 described in Example 1 (with appropriate amounts of hydrochloric acid added to adjust the pH). After preparation, the mixture was placed at 40°C for 7 or 14 days, and its stability and viscosity were monitored, and its appearance was evaluated. The results are shown in Tables 21-2 and 21-3.

[0369] Table 21-1. Formulation Information (Component Content Unit: Parts by Weight)

[0370] Table 21-2. Stability Results Note: *Content refers to the content of smegglutinin.

[0371] The results showed that there was no significant difference in formulation stability when using water, DMSO, and propylene glycol as solubilizers.

[0372] Table 21-3. Appearance and viscosity evaluation (viscosity unit: mPa·s) Note: This product is in the form of a pre-filled syringe. The solvent will not be lost during storage and will not affect the viscosity. Therefore, only the viscosity at 0h needs to be tested.

[0373] The results showed that the samples with different solubilizer formulations were all clear and transparent in appearance, and no significant changes occurred after 14 days of storage at 40℃. The viscosity of the samples with different solubilizer formulations differed, and the viscosity was ordered from largest to smallest as follows: water formulation > propylene glycol formulation > DMSO formulation.

[0374] Example 20. Effect of different SPC / MCT ratios on formulation performance (test 2)

[0375] Similar to Example 9, the effect of the SPC / MCT ratio on formulation performance was investigated in another set of formulation systems. The component ratios were set as shown in Table 22-1, and preparation was carried out according to preparation method 2 described in Example 1 (with pH adjusted by adding an appropriate amount of hydrochloric acid). After preparation, the formulations were placed at 40°C for 7 or 14 days, and stability and viscosity were monitored, and appearance was evaluated. The results are shown in Tables 22-2 and 22-3.

[0376] Table 22-1. Formulation Information (Component Content Unit: Parts by Weight)

[0377] Table 22-2. Stability Results Note: *Content refers to the content of smegglutinin.

[0378] The results showed that the stability of the formulation tended to decrease as the SPC / MCT ratio decreased. Based on the content results at 40℃ for 14 days, it was found that the formulation with an SPC / MCT ratio of 70 / 10-40 / 40 had better stability than the formulation with an SPC / MCT ratio of 30 / 50.

[0379] Table 22-3. Appearance and viscosity evaluation (viscosity unit: mPa·s) Note: This product is in the form of a pre-filled syringe. The solvent will not be lost during storage and will not affect the viscosity. Therefore, only the viscosity at 0h needs to be tested.

[0380] The results showed that the samples with different SPC / MCT ratios were all clear and transparent in appearance, and no significant changes occurred after 14 days of storage at 40℃; as the SPC / MCT ratio decreased, the sample viscosity decreased.

[0381] Example 21. Stability Comparison of GDO and MCT Formulations 3

[0382] Similar to Test Example 2, the effects of GDO and MCT formulations on formulation performance were investigated in another set of formulation systems, with liraglutide introduced as another API. The component ratios were set as shown in Table 23-1, and preparation was carried out according to Preparation Method 2 described in Example 1 (with pH adjusted by adding an appropriate amount of hydrochloric acid). After preparation, the formulations were stored at 40°C for 7 or 14 days, and stability and viscosity were monitored, and appearance was evaluated. The results are shown in Tables 23-2 and 23-3.

[0383] Table 23-1. Formulation Information (Component Content Unit: Parts by Weight)

[0384] Table 23-2. Stability Results Note: *Content refers to the content of smegglutinin or liraglutinin.

[0385] The results showed that smegglutide and liraglutide had significantly better stability in MCT formulations than in GDO formulations.

[0386] Table 23-3. Appearance and viscosity evaluation (viscosity unit: mPa·s) Note: This product is in the form of a pre-filled syringe. The solvent will not be lost during storage and will not affect the viscosity. Therefore, only the viscosity at 0h needs to be tested.

[0387] The results showed that both the semaglutide and liraglutide MCT formulations and the GDO formulations were clear and transparent in appearance, and no significant changes occurred after storage at 40°C for 14 days; the viscosity of the semaglutide and liraglutide MCT formulations was lower than that of the GDO formulations.

[0388] Example 22. Preparation of a high-concentration smegglutide sustained-release formulation

[0389] Smegglutide sustained-release formulation was prepared according to the following method:

[0390] (1) Mix 58 parts by weight of SPC, 19 parts by weight of MCT and 10 parts by weight of anhydrous ethanol to prepare a lipid mixture for later use.

[0391] (2) Mix 5 parts by weight of anhydrous ethanol, 8 parts by weight of water and 6 parts by weight of smegglutinin and stir to dissolve to prepare an aqueous solution containing API.

[0392] (3) Take the aqueous solution containing API obtained in step (2) (a total of 19 parts by weight) and mix it with 81 parts by weight of the lipid mixture obtained in step (1) and stir it evenly to obtain 100 parts by weight of the final formulation.

[0393] The final formulation was clear and transparent, with a weight percentage of smegglutide of 6%. After preparation, the formulation remained clear and transparent for 24 hours at room temperature, without turbidity or precipitation, demonstrating good stability.

Claims

A semaglutide sustained-release formulation (e.g., an injection), said formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight: (1) 0.001-70 parts by weight of smegglutide or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, or 0.001-50 parts by weight, or 0.001-40 parts by weight, preferably 0.01-30 parts by weight, or 0.1-20 parts by weight, or 1-15 parts by weight, or 3-15 parts by weight, or 5-15 parts by weight, or 7-14 parts by weight, or 8-12 parts by weight, for example 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 parts by weight or any range between any two of the above points; (2) 100-500 parts by weight of triacylglycerol, preferably 100-450 parts by weight, or 100-400 parts by weight, or 100-300 parts by weight, or 120-280 parts by weight, or 150-250 parts by weight, for example, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 or 500 parts by weight or any two of the above values. (3) Phosphatidylcholine 400-800 parts by weight, preferably 400-700 parts by weight, or 450-650 parts by weight, or 500-650 parts by weight, or 550-650 parts by weight, for example, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775 or 800 parts by weight or the range between any two points above; (4) 50-200 parts by weight of anhydrous ethanol, preferably 50-180 parts by weight, 70-180 parts by weight, 90-180 parts by weight, 100-170 parts by weight, or 120-170 parts by weight, for example, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 180, 190, or 200 parts by weight or any two of the above values. (5) The solubilizer is 1-100 parts by weight, preferably 5-100 parts by weight, 10-90 parts by weight, 10-80 parts by weight, 10-70 parts by weight, 10-60 parts by weight, 10-50 parts by weight, or 10-40 parts by weight, for example, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 parts by weight or more, or any range between any two of these values; and (6) A pH adjuster, wherein the weight part of the pH adjuster is selected to adjust the pH value of the semaglutide sustained-release formulation to a predetermined range, wherein the predetermined pH range of the semaglutide sustained-release formulation is preferably 4.5-7.0, preferably 5.0-6.6, preferably 5.3-6.6 or 5.4-6.6 or 5.5-6.6, more preferably 5.6-6.5 or 5.6-6.4 or 5.6-6.3 or 5.6-6.2, for example, the range between any two points of 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0 or above. A semaglutide sustained-release formulation (e.g., an injection), said formulation comprising, or substantially consisting of, the following components having parts by weight, or consisting of, the following components having parts by weight: (1) 0.001-70 parts by weight of smegglutide or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, or 0.001-50 parts by weight, or 0.001-40 parts by weight, preferably 0.01-30 parts by weight, or 0.1-20 parts by weight, or 1-15 parts by weight, or 3-15 parts by weight, or 5-15 parts by weight, or 7-14 parts by weight, or 8-12 parts by weight, for example 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 parts by weight or any range between any two of the above points; (2) 1000 parts by weight of a lipid mixture, wherein the lipid mixture comprises triacylglycerol, phosphatidylcholine and anhydrous ethanol, or is substantially composed of triacylglycerol, phosphatidylcholine and anhydrous ethanol, or is composed of triacylglycerol, phosphatidylcholine and anhydrous ethanol, wherein: a) The triacylglycerols constitute 10%-50% by weight of the lipid mixture, preferably 10%-45%, 10%-40%, 10%-30%, 12%-28%, or 15%-25%, for example, a range between any two points of 10%, 12%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 28%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, or 50% or more; b) Phosphatidylcholine accounts for 40%-80% of the weight percentage of the lipid mixture, preferably 40%-70%, 45%-65%, or 50%-65%, for example, the range between any two point values ​​of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% or more. c) The weight percentage of anhydrous ethanol in the lipid mixture is 5%-20%, preferably 5%-18%, 7%-18%, or 9%-18%, for example, within any two point values ​​of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or more; (3) The solubilizer is 1-100 parts by weight, preferably 5-100 parts by weight, 10-90 parts by weight, 10-80 parts by weight, 10-70 parts by weight, 10-60 parts by weight, 10-50 parts by weight, or 10-40 parts by weight, for example, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 parts by weight or more, or any range between two of these values; and (4) A pH adjuster, wherein the weight part of the pH adjuster is selected to adjust the pH value of the semaglutide sustained-release formulation to a predetermined range. The predetermined range of pH value of the semaglutide sustained-release formulation is preferably 4.5-7.0, preferably 5.0-6.6, preferably 5.3-6.6 or 5.4-6.6 or 5.5-6.6, more preferably 5.6-6.5 or 5.6-6.4 or 5.6-6.3 or 5.6-6.2, for example, the range between any two points of 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0 or above. A semaglutide sustained-release formulation (e.g., an injection), said formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight: (1) 0.001-70 parts by weight of smegglutide or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, or 0.001-50 parts by weight, or 0.001-40 parts by weight, preferably 0.01-30 parts by weight, or 0.1-20 parts by weight, or 1-15 parts by weight, or 3-15 parts by weight, or 5-15 parts by weight, or 7-14 parts by weight, or 8-12 parts by weight, for example 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 parts by weight or any range between any two of the above points; (2) 100-500 parts by weight of triacylglycerol, preferably 100-450 parts by weight, or 100-400 parts by weight, or 100-300 parts by weight, or 120-280 parts by weight, or 150-250 parts by weight, for example, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 or 500 parts by weight or any two of the above values. (3) Phosphatidylcholine 400-800 parts by weight, preferably 400-700 parts by weight, or 450-650 parts by weight, or 500-650 parts by weight, or 550-650 parts by weight, for example, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775 or 800 parts by weight or the range between any two points above; (4) Ethanol, wherein the weight of anhydrous ethanol is 50-200 parts, preferably 50-180 parts, 70-180 parts, 90-180 parts, 100-170 parts, or 120-170 parts, for example, any two values ​​between 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 180, 190, or 200 parts; and (5) The solubilizer is 1-100 parts by weight, preferably 5-100 parts by weight, 10-90 parts by weight, 10-80 parts by weight, 10-70 parts by weight, 10-60 parts by weight, 10-50 parts by weight, or 10-40 parts by weight, for example, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 parts by weight or a range between any two of the above values; and The pH value of the smegglutide sustained-release formulation is 4.5-7.0, preferably 5.0-6.6, preferably 5.3-6.6, 5.4-6.6, or 5.5-6.6, more preferably 5.6-6.5, 5.6-6.4, 5.6-6.3, or 5.6-6.2, for example, within the range of any two values ​​between 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 or above. A semaglutide sustained-release formulation (e.g., an injection), said formulation comprising, or substantially consisting of, the following components having parts by weight, or consisting of, the following components having parts by weight: (1) 0.001-70 parts by weight of smegglutide or its pharmaceutically acceptable salt, preferably 0.001-60 parts by weight, or 0.001-50 parts by weight, or 0.001-40 parts by weight, preferably 0.01-30 parts by weight, or 0.1-20 parts by weight, or 1-15 parts by weight, or 3-15 parts by weight, or 5-15 parts by weight, or 7-14 parts by weight, or 8-12 parts by weight, for example 0.001, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 12, 14, 15, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 parts by weight or any range between any two of the above points; (2) 1000 parts by weight of a lipid mixture, wherein the lipid mixture comprises triacylglycerol, phosphatidylcholine and ethanol, or is substantially composed of triacylglycerol, phosphatidylcholine and ethanol, or is composed of triacylglycerol, phosphatidylcholine and ethanol, wherein: a) The triacylglycerols constitute 10%-50% by weight of the lipid mixture, preferably 10%-45%, 10%-40%, 10%-30%, 12%-28%, or 15%-25%, for example, a range between any two points of 10%, 12%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 28%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, or 50% or more; b) Phosphatidylcholine accounts for 40%-80% of the weight percentage of the lipid mixture, preferably 40%-70%, 45%-65%, or 50%-65%, for example, the range between any two point values ​​of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% or more. c) The weight percentage of ethanol in the lipid mixture, calculated as anhydrous ethanol, is 5%-20%, preferably 5%-18%, 7%-18%, or 9%-18%, for example, within the range of any two points of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or more; and (3) The solubilizer is 1-100 parts by weight, preferably 5-100 parts by weight, 10-90 parts by weight, 10-80 parts by weight, 10-70 parts by weight, 10-60 parts by weight, 10-50 parts by weight, or 10-40 parts by weight, for example, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 parts by weight or a range between any two of the above values; and The pH value of the smegglutide sustained-release formulation is 4.5-7.0, preferably 5.0-6.6, preferably 5.3-6.6, 5.4-6.6, or 5.5-6.6, more preferably 5.6-6.5, 5.6-6.4, 5.6-6.3, or 5.6-6.2, for example, within the range of any two values ​​between 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0 or above. The smegglutide sustained-release formulation according to any one of claims 1-4, wherein the solubilizer is selected from water, bile salts, sodium oleate, dimethyl sulfoxide (DMSO) or propylene glycol. The smegglutide sustained-release formulation according to claim 5, wherein the bile salt is selected from sodium glycocholate, sodium ursodeoxycholate, sodium ursodeoxycholate, sodium cholate, sodium chenodeoxycholate, sodium obeticholate, sodium porphyrin, and sodium deoxycholate, preferably sodium glycocholate or sodium deoxycholate, and more preferably sodium deoxycholate. The semaglutide sustained-release formulation according to any one of claims 1-6, wherein the weight ratio of the solubilizer to semaglutide or its pharmaceutically acceptable salt is 15:1 to 1:5, preferably 10:1 to 1:5, for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4 or 1:5 or any two of the above ranges. The semaglutide sustained-release formulation according to any one of claims 1-6, wherein the solubilizer is water, and the weight ratio of water to semaglutide or its pharmaceutically acceptable salt is 15:1-1:5, preferably 10:1-1:5, more preferably 10:1-1:2, 8:1-1:1, 6:1-2:1 or 5:1-3:1, and even more preferably 4:1; or, The solubilizer is a bile salt, and the weight ratio of the bile salt to smegglutinin or its pharmaceutically acceptable salt is 15:1-1:5, preferably 10:1-1:5, more preferably 10:1-1:2, 8:1-1:2, 6:1-1:1, 4:1-1:1, 3:1-1:1 or 2:1-1:1, and even more preferably 1.5:

1. The semagrapeptide sustained-release formulation according to any one of claims 1-8, wherein the pharmaceutically acceptable salt of semagrapeptide is selected from mesylate, hydrochloride, acetate, bis(hydroxynaphthyl)ate, benzoate, maleate and sodium salt, preferably semagrapeptide acetate or semagrapeptide sodium salt, more preferably semagrapeptide sodium salt. The smegglutide sustained-release formulation according to claim 1 or 2, wherein the pH adjuster is selected from benzoic acid, citric acid, sulfuric acid, phosphoric acid, maleic acid, hydrohalic acid, sulfonic acid, methanesulfonic acid, hydrochloric acid and acetic acid, preferably methanesulfonic acid or hydrochloric acid, more preferably hydrochloric acid. The smegglutide sustained-release formulation according to any one of claims 1-10, wherein the triacylglycerol is a trisubstituted glyceride or a mixture of multiple trisubstituted glycerides, preferably, the trisubstituted glyceride is selected from trioleic acid glyceride, tridecanoic acid glyceride and tricaprylic acid glyceride, more preferably, the triacylglycerol is a medium-chain triglyceride (MCT). The smegglutide sustained-release formulation according to any one of claims 1-11, wherein the phosphatidylcholine is a natural or synthetic phosphatidylcholine, preferably soybean phosphatidylcholine, egg yolk phosphatidylcholine or a combination thereof, more preferably soybean phosphatidylcholine. The smegglutide sustained-release formulation according to any one of claims 1-12, wherein the weight ratio of triacylglycerol to phosphatidylcholine is 15:85 to 50:50, preferably 15:85 to 45:55, more preferably 15:85 to 35:65, further preferably 15:85 to 40:60, or 17:83 to 40:60, or 20:80 to 40:60, or 15:85 to 35:65, or 20:80 to 30:70, most preferably 25:75, for example, 15:85, 18:82, 17:83, 20:80, 22:78, 25:75, 28:72, 30:70, 35:65, 40:60, 45:55 or 50:50 or any two of the above values. The semaglutide sustained-release formulation according to claim 1 or 3, or any one of claims 5-13 of claim 1 or 3, wherein the formulation comprises, or is substantially composed of, the following components in parts by weight, or is composed of, the following components in parts by weight: (a) 0.01-30 parts by weight of semaglutide or its pharmaceutically acceptable salt, 100-450 parts by weight of triacylglycerol, 400-800 parts by weight of phosphatidylcholine, 50-180 parts by weight of anhydrous ethanol or ethanol, and 10-80 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.0-6.6; or (b) 0.1-20 parts by weight of semaglutide or its pharmaceutically acceptable salt, 100-400 parts by weight of triacylglycerol, 400-700 parts by weight of phosphatidylcholine, 70-180 parts by weight of anhydrous ethanol or ethanol, and 10-70 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.6; or (c) 1-15 parts by weight of semaglutide or its pharmaceutically acceptable salt, 100-300 parts by weight of triacylglycerol, 450-650 parts by weight of phosphatidylcholine, 90-180 parts by weight of anhydrous ethanol or ethanol, and 10-60 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.6; or (d) 5-15 parts by weight of semaglutide or its pharmaceutically acceptable salt, 120-280 parts by weight of triacylglycerol, 500-650 parts by weight of phosphatidylcholine, 100-170 parts by weight of anhydrous ethanol or ethanol, and 10-50 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.6; or (e) 7-14 parts by weight of semaglutide or its pharmaceutically acceptable salt, 150-250 parts by weight of triacylglycerol, 550-650 parts by weight of phosphatidylcholine, 120-170 parts by weight of anhydrous ethanol or ethanol, and 10-40 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.5; or (f) 8-12 parts by weight of semaglutide or its pharmaceutically acceptable salt, 150-250 parts by weight of triacylglycerol, 550-650 parts by weight of phosphatidylcholine, 120-170 parts by weight of anhydrous ethanol or ethanol, and 10-40 parts by weight of solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.6-6.

2. The semaglutide sustained-release formulation according to claim 2 or 4, or any one of claims 5-13 of claim 2 or 4, wherein the formulation comprises, or is substantially composed of, the following components in parts by weight, or is composed of, the following components in parts by weight: (a) 0.01-30 parts by weight of semaglutide or its pharmaceutically acceptable salt, 1000 parts by weight of the lipid mixture, and 10-80 parts by weight of the solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.0-6.6; wherein triacylglycerol accounts for 10%-45% by weight of the lipid mixture, phosphatidylcholine accounts for 40%-70% by weight of the lipid mixture, and ethanol accounts for 5%-20% by weight of the lipid mixture; or (b) 0.1-20 parts by weight of semaglutide or a pharmaceutically acceptable salt thereof, 1000 parts by weight of a lipid mixture, and 10-70 parts by weight of a solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or has a pH value of 5.3-6.6; wherein triacylglycerol accounts for 10%-40% by weight of the lipid mixture, phosphatidylcholine accounts for 45%-65% by weight of the lipid mixture, and ethanol accounts for 5%-18% by weight of the lipid mixture; or (c) Smegglutide or its pharmaceutically acceptable salt comprises 1-15 parts by weight, a lipid mixture comprises 1000 parts by weight, and a solubilizer comprises 10-60 parts by weight, wherein the pH of the smegglutide sustained-release formulation is within a predetermined range or the pH value is 5.3-6.6; wherein triacylglycerol comprises 10%-30% by weight of the lipid mixture, phosphatidylcholine comprises 45%-65% by weight of the lipid mixture, and ethanol comprises 7%-18% by weight of the lipid mixture; or (d) 5-15 parts by weight of semaglutide or its pharmaceutically acceptable salt, 1000 parts by weight of the lipid mixture, and 10-50 parts by weight of the solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or has a pH value of 5.3-6.6; wherein triacylglycerol accounts for 12%-28% by weight of the lipid mixture, phosphatidylcholine accounts for 50%-65% by weight of the lipid mixture, and ethanol accounts for 9%-18% by weight of the lipid mixture; or (e) 7-14 parts by weight of semaglutide or its pharmaceutically acceptable salt, 1000 parts by weight of the lipid mixture, and 10-40 parts by weight of the solubilizer, wherein the pH of the semaglutide sustained-release formulation is within a predetermined range or has a pH value of 5.3-6.5; wherein triacylglycerol accounts for 15%-25% by weight of the lipid mixture, phosphatidylcholine accounts for 50%-65% by weight of the lipid mixture, and ethanol accounts for 9%-18% by weight of the lipid mixture; or (f) 8-12 parts by weight of semaglutide or its pharmaceutically acceptable salt, 1000 parts by weight of the lipid mixture, 9%-18% by weight of ethanol in the lipid mixture, 10-40 parts by weight of the solubilizer, and the pH of the semaglutide sustained-release formulation is within a predetermined range or the pH value is 5.6-6.2; wherein, triacylglycerol accounts for 15%-25% by weight of the lipid mixture, and phosphatidylcholine accounts for 50%-65% by weight of the lipid mixture. The semaglutide sustained-release formulation according to any one of claims 1-15 is used to treat GLP-1R-related diseases; preferably, the GLP-1R-related diseases are selected from type 2 diabetes, overweight, obesity, cardiovascular disease, non-alcoholic steatohepatitis, Alzheimer's disease, diabetic nephropathy, intermittent claudication, stroke, myocardial infarction, polycystic ovary syndrome, heart failure, type 1 diabetes, peripheral artery disease, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, and uterine diseases. In any one of claims 1-16, the sustained-release formulation of semaglutide uses NMP or an NMP-ethanol mixture instead of ethanol; preferably, the final weight ratio of NMP to ethanol in the NMP-ethanol mixture is (1-5):(5-1), more preferably (1-4):(4-1) or (1-3):(3-1) or (1-2):(2-1). The method for preparing the semaglutide sustained-release formulation according to any one of claims 1-17, The semaglutide sustained-release formulation uses water as a solubilizer, and the preparation method includes the following steps: Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain the aqueous phase; Step 2: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture; Step 3: Add the aqueous phase obtained in Step 1 to the lipid mixture obtained in Step 2, and stir to mix well; Step 4: Add pH adjuster to adjust the pH value to the predetermined pH value of the smegglutinin sustained-release formulation, then filter and fill. or, The semaglutide sustained-release formulation uses bile salts (e.g., sodium deoxycholate) as a solubilizer, and the preparation method includes the following steps: Step a: Smegglutide or its pharmaceutically acceptable salts are dissolved and mixed with bile salts (e.g., sodium deoxycholate) in water and then freeze-dried to form a freeze-dried complex. Step b: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture; Step c: Add the lyophilized complex obtained in step a to the lipid mixture obtained in step b, and stir to dissolve; Step d: Add pH adjuster to adjust the pH value to the predetermined pH value of the smegglutinin sustained-release formulation, then filter and fill. The use of the smegglutide sustained-release formulation as described in any one of claims 1-17 in the preparation of a medicament for treating GLP-1R-related diseases; preferably, the GLP-1R-related diseases are selected from type 2 diabetes, overweight, obesity, cardiovascular disease, non-alcoholic steatohepatitis, Alzheimer's disease, diabetic nephropathy, intermittent claudication, stroke, myocardial infarction, polycystic ovary syndrome, heart failure, type 1 diabetes, peripheral artery disease, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, and uterine diseases. A method for treating GLP-1R-related diseases in an individual, the method comprising administering a therapeutically effective amount of the semaglutide extended-release formulation of any one of claims 1-17 to the individual in need; preferably, the GLP-1R-related diseases are selected from type 2 diabetes, overweight, obesity, cardiovascular disease, non-alcoholic steatohepatitis, Alzheimer's disease, diabetic nephropathy, intermittent claudication, stroke, myocardial infarction, polycystic ovary syndrome, heart failure, type 1 diabetes, peripheral artery disease, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, and uterine diseases. The semaglutide sustained-release formulation according to any one of claims 1-17 is used to treat GLP-1R-related diseases; preferably, the GLP-1R-related diseases are selected from type 2 diabetes, overweight, obesity, cardiovascular disease, non-alcoholic steatohepatitis, Alzheimer's disease, diabetic nephropathy, intermittent claudication, stroke, myocardial infarction, polycystic ovary syndrome, heart failure, type 1 diabetes, peripheral artery disease, nicotine addiction (smoking cessation), asthma, alcohol addiction, liver fibrosis, and uterine diseases.

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