A sustained-release preparation and a method for producing the same

Abstract

Provided are a sustained-release preparation and a preparation method thereof. The sustained-release preparation comprises a pharmaceutically active ingredient, a triacylglycerol, a phosphatidylcholine, a solvent, a solubilizer, and a pH adjustor. The preparation method comprises: uniformly mixing the pharmaceutically active ingredient, the triacylglycerol, the phosphatidylcholine, the solvent, the solubilizer, and the pH adjustor.

Description

A sustained-release formulation and its preparation method

[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 sustained-release formulation and its preparation method. Background Technology

[0004] Long-acting injectables have always been a hot topic in dosage form improvement, with typical sustained-release times ranging from 3 days to 6 months, greatly improving patient compliance. Currently marketed long-acting injectables can be broadly categorized into oil solutions, microspheres, in-situ gels, and nanocrystal suspensions.

[0005] The aforementioned long-acting formulations can extend the dosing cycle, greatly improving the convenience of clinical medication compared to ordinary injections. However, some drawbacks also require attention. For example, microsphere injections typically use high molecular weight polymers such as polylactic acid (PLA) and polylactic-glycolic acid copolymer (PLGA) as delivery carriers. Due to the significant batch-to-batch variability of these polymers, product quality may be directly affected. Polymer microparticles are difficult to filter and sterilize, and they melt above 40°C, requiring highly sterile conditions for production, posing a significant challenge to aseptic assurance. Acidic degradation products of polymer microparticles can easily induce inflammation and reduce cell growth rates, leading to pain or tissue damage at the injection site. To ensure the microsphere structure is not destroyed, the injection needle specification is 22G, further increasing injection site pain and reducing patient compliance. Furthermore, the microsphere preparation process is complex, time-consuming, and has poor reproducibility, and requires the use of Class II toxic reagents (such as dichloromethane), posing risks of environmental pollution and harm to the health of operators. While in-situ gels have solved the problems of complex microsphere manufacturing processes and the use of toxic reagents, some products still use high molecular polymers as the main excipients, and the products have high viscosity, requiring the use of 18-20G needles. Patient compliance and the problems caused by high molecular polymer excipients have not been improved.

[0006] The Swedish company Camurus developed preparation. Based on a special combination of endogenous polar lipids, it is an autoadaptive drug delivery system that combines ease of manufacture, processing and injection with long-acting release. Upon contact with tissue fluid, the injection solution transforms into a gel-like crystal, forming a drug reservoir and exerting a sustained release effect. CN101014319B discloses... The composition of the formulation. The company utilizes... It achieved long-acting delivery of buprenorphine, becoming the first marketed product of this dosage form. The key excipients are diacyl esters and phospholipids. These excipients are characterized by high safety but are easily degraded, resulting in relatively poor formulation stability.

[0007] There is an urgent need in this field for research and development of sustained-release formulation technology.

[0008] Invention Overview

[0009] In a first aspect, this application provides a sustained-release formulation comprising: a pharmaceutical active ingredient, triacylglycerol, phosphatidylcholine, a solvent, a solubilizer, and a pH adjuster.

[0010] Secondly, this application provides a method for preparing a sustained-release formulation, the method comprising: mixing the active pharmaceutical ingredient, triacylglycerol, phosphatidylcholine, solvent, solubilizer, and pH adjuster evenly.

[0011] Thirdly, this application provides the use of the sustained-release formulation described in the first aspect or the sustained-release formulation prepared according to the method described in the second aspect in the preparation of a medicament.

[0012] Fourthly, this application provides a method for treating a disease using the sustained-release formulation described in the first aspect or a sustained-release formulation prepared according to the method described in the second aspect, comprising: administering a therapeutically effective amount of the sustained-release formulation to a subject or patient in need.

[0013] Fifthly, this application provides the sustained-release formulation described in the first aspect or the sustained-release formulation prepared according to the method described in the second aspect for the treatment of diseases.

[0014] In other respects, this application also specifically provides a semaglutide sustained-release formulation, its preparation method, and its uses.

[0015] Brief description of the attached diagram

[0016] Figure 1 shows a comparison of the rat pharmacokinetic curves of smegglutide formulations 1-4 sustained-release formulation and Novogene.

[0017] Figure 2 shows a comparison of the PK curves of rats using prescription 10-2 and prescription 10-1.

[0018] Figure 3 shows a comparison of the PK curves of rats using prescription 21-1 and prescription 21-2.

[0019] Detailed description of the invention

[0020] Terminology Definition

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art.

[0022] Smegglutide

[0023] 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.

[0024] Phosphatidylcholine

[0025] 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.

[0026] neutral lipids

[0027] 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).

[0028] Triacylglycerol

[0029] 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).

[0030] Solubilizer

[0031] 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.).

[0032] bile salts

[0033] 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.

[0034] water

[0035] The water used in this application is purified water or water for injection that meets GMP requirements.

[0036] "basically composed of..." or "composed of..."

[0037] 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".

[0038] Unless otherwise stated, the amount or dosage of the API described in this application is calculated in the amount of pure API molecules.

[0039] 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.

[0040] Unless otherwise stated, percentages and parts as described in this application are by weight.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] In general, this application provides a sustained-release formulation, a method for its preparation, and its use. This formulation system exhibits excellent properties in one or more of the following: stability, stable blood drug concentration, duration of sustained release, and patient compliance.

[0046] This application found in its research that active pharmaceutical ingredients such as semaglutide are insoluble in neutral lipid (GDO or MCT) / SPC / ethanol formulation systems, requiring the addition of solubilizers. Further research showed that in formulation systems using GDO as the neutral lipid, the stability of active pharmaceutical ingredients such as semaglutide is poor, failing to meet formulation requirements. This application, through screening, found that using MCT as the neutral lipid helps improve the stability of active pharmaceutical ingredients such as semaglutide in formulations.

[0047] Taking smegglutide as an example, the sustained-release formulations provided in this application possess excellent properties in one or more of the following: stability, stable blood drug concentration, and sustained-release duration. For instance, 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 drug concentrations and a sustained-release duration of up to one month, improving patient compliance. The pharmacokinetic study results 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 sustained-release formulation provided in this application are described below and illustrated in the results of the embodiments of this application.

[0048] In a first aspect, this application provides a sustained-release formulation comprising: a pharmaceutical active ingredient, triacylglycerol, phosphatidylcholine, a solvent, a solubilizer, and a pH adjuster.

[0049] Secondly, this application provides a method for preparing a sustained-release formulation, the method comprising: mixing the active pharmaceutical ingredient, triacylglycerol, phosphatidylcholine, solvent, solubilizer and pH adjuster evenly.

[0050] Thirdly, this application provides the use of the sustained-release formulation described in the first aspect or the sustained-release formulation prepared according to the method described in the second aspect in the preparation of a medicament.

[0051] Fourthly, this application provides a method for treating a disease using the sustained-release formulation described in the first aspect or a sustained-release formulation prepared according to the method described in the second aspect, comprising: administering a therapeutically effective amount of the sustained-release formulation to a subject or patient in need.

[0052] Fifthly, this application provides the sustained-release formulation described in the first aspect or the sustained-release formulation prepared according to the method described in the second aspect for the treatment of diseases.

[0053] The following section first describes some common implementation schemes and technical features shared by aspects one through five.

[0054] There are no particular limitations on the types of pharmaceutical active ingredients (“APIs”) used in this application; for example, they can be small molecule compounds, peptides, proteins, and nucleic acids. Suitable pharmaceutical active ingredients include active agents suitable for systemic administration, particularly those active agents that typically have a short retention time in the body due to rapid degradation or excretion, active agents with low oral bioavailability, and / or active agents that require long-term administration for the treatment of chronic diseases. In some embodiments, the active pharmaceutical ingredient is selected from the following human or veterinary drugs: adrenocorticotropic hormone (ACTH) and its fragments, angiotensin and its related peptides, antibodies and their fragments, antigens and their fragments, atrial natriuretic peptide, bioadhesive peptides, bradykinin and its related peptides, calcitonin and its related peptides, cell surface receptor protein fragments, chemokines, cyclosporine, cytokines, dynorphin and its related peptides, endorphin and P-lidotropin fragments, enkephalin and its related proteins, enzyme inhibitors, immunostimulatory peptides and polyamino acids, fibronectin fragments and their related peptides, gastrointestinal peptides, gonadotropin-releasing hormone (GnRH) agonists and antagonists, glucagon-like protein, growth hormone-releasing peptide, immunostimulatory peptides, insulin and insulin-like growth factor, interleukin, luteinizing hormone-releasing hormone (LHRH) and its related peptides, melanocyte-stimulating hormone and its related peptides, peptides associated with nuclear localization signaling regions, neurotensin-lowering peptides and their related peptides, neurotransmitter peptides, opioid-like active peptides, oxytocin. Phosphokinin, vasopressin and its related peptides, parathyroid hormone and its fragments, protein kinases and their related peptides, somatostatin and its related peptides, substance P and its related peptides, transforming growth factor (TGF) and its related peptides, tumor necrosis factor fragments, toxins and toxoids and functional peptides such as anticancer peptides including angiostatin, antihypertensive peptides, anticoagulant peptides, and antimicrobial peptides; proteins selected from the following groups, such as immunoglobulins, angiogenic factors, bone morphogenetic proteins, chemoactivators, colony-stimulating factor (CSF), cytokines, growth factors, interferons (types I and II), interleukins, transforming growth factor and tumor necrosis factor, glucagon-like peptide-1 receptor (GLP-1R) agonists, glucagon-like peptide-1 receptor / glucose-dependent insulinotropic peptide receptor (GLP-1R / GIPR) dual agonists, local and general anesthetics, NSAIDs, Cox1 or Cox2 inhibitors, antipsychotics, drugs for treating neurodegenerative diseases, anti-osteoporosis drugs, etc.

[0055] In some embodiments, the active pharmaceutical ingredient is selected from GLP-1R agonists (e.g., exenatide, liraglutide, dulaglutide, lixisenatide, abiglutide, benaglutide, loxenatide, smegglutide, noliglutide, or enogglutide), GLP-1R / GIPR dual agonists (e.g., telpoitide, HRS-9531, GMA106, HS-20094, AMG-133, CT-868, HRS9531, RAY1225, SCO-094, BGM0504, CT-388, L... Y3493269 or VK-2735), gonadotropin-releasing hormone (GnRH) analogs (e.g., buserreline, leuproreline, gosereline, triptoreline, avoreline, or diloreline), medications for treating neurodegenerative diseases (e.g., donepezil, rivastigmine, huperzine A, memantine, levodopa, amantadine, or entacapone), medications for treating osteoporosis (e.g., bisphosphonates, calcitonin, strontium ranelate, or teriparatide), and local anesthetics (e.g., ropivacaine, procaine, lidocaine, tetracaine, or bupivacaine).

[0056] The aforementioned active pharmaceutical ingredient includes the free form of the drug or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt of the drug is selected from methanesulfonate, hydrochloride, acetate, bis(hydroxynaphthyl)ate, benzoate, maleate, sodium salt, etc. Those skilled in the art can select a suitable form based on its solubility in the formulation system.

[0057] In some embodiments, triacylglycerol may be a single trisubstituted glyceride or a mixture of multiple trisubstituted glycerides. As a non-limiting example, the trisubstituted glyceride may be trioleic acid glyceride, tridecanoic acid glyceride, or tricaprylic acid glyceride. In some embodiments, triacylglycerol is a medium-chain triglyceride (MCT).

[0058] In some embodiments, phosphatidylcholine may be natural or synthetic phosphatidylcholine. As a non-limiting example, phosphatidylcholine may be soybean phosphatidylcholine, egg yolk phosphatidylcholine, or a combination thereof. In some embodiments, the phosphatidylcholine is soybean phosphatidylcholine.

[0059] 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.

[0060] 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.

[0061] 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 value of the sustained-release formulation to a predetermined value or range.

[0062] In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is ethanol (preferably anhydrous ethanol), N-methylpyrrolidone (NMP), or an NMP-ethanol mixture. Preferably, the weight ratio of NMP to ethanol in the NMP-ethanol mixture is (1-5):(5-1), more preferably (1-4):(4-1), (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.

[0063] In some embodiments, the sustained-release formulation is an injection. The quality requirements for triacylglycerol and phosphatidylcholine, as well as the types and quality requirements for solvents, solubilizers, and pH adjusters, can be selected appropriately based on the injection dosage form.

[0064] In some embodiments, the 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:

[0065] (1) 0.001-70 parts by weight of the active pharmaceutical ingredient;

[0066] (2) Triacylglycerol 100-500 parts by weight;

[0067] (3) Phosphatidylcholine 300-800 parts by weight;

[0068] (4) 50-200 parts by weight of anhydrous ethanol;

[0069] (5) Solubilizer 1-150 parts by weight;

[0070] (6) pH adjuster, wherein the weight part of the pH adjuster is selected to adjust the pH value of the sustained-release preparation to a predetermined range.

[0071] In some embodiments, the pH value of the sustained-release formulation is in a predetermined range of 4.0-8.0.

[0072] In some embodiments, 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:

[0073] (1) 0.001-70 parts by weight of the active pharmaceutical ingredient;

[0074] (2) Triacylglycerol 100-500 parts by weight;

[0075] (3) Phosphatidylcholine 300-800 parts by weight;

[0076] (4) Ethanol, wherein the amount of anhydrous ethanol is 50-200 parts by weight; and

[0077] (5) Solubilizer 1-150 parts by weight;

[0078] The sustained-release formulation has a pH value of 4.0-8.0.

[0079] In some embodiments, the active pharmaceutical ingredient is present in amounts of 0.001-60 parts by weight, 0.001-50 parts by weight, or 0.001-40 parts by weight. In some embodiments, the active pharmaceutical ingredient is present in amounts 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, the active pharmaceutical ingredient is present in amounts 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] In some embodiments, the solubilizer has 1-120 parts by weight or 1-100 parts by weight. In some embodiments, the solubilizer has 5-100 parts by weight or 10-90 parts by weight or 10-80 parts by weight or 10-70 parts by weight or 10-60 parts by weight or 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: 1, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 parts by weight.

[0084] In some embodiments, the pH value or predetermined pH range of the sustained-release formulation is 4.5-8.0. In some embodiments, the pH value or predetermined pH range of the sustained-release formulation is 4.5-7.0. In some embodiments, the pH value or predetermined pH range of the sustained-release formulation is 5.0-6.6. In some embodiments, the pH value or predetermined pH range of the sustained-release formulation is 5.3-6.6, 5.4-6.6, or 5.5-6.6. In some embodiments, the pH value or predetermined pH range of the 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 value of the sustained-release formulation is a predetermined value or range of 4.0, 4.1, 4.2, 4.3, 4.4, 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, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0 or a range between any two of the above values.

[0085] In some embodiments, the 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:

[0086] (1) 0.001-70 parts by weight of the active pharmaceutical ingredient;

[0087] (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:

[0088] a) Triacylglycerols constitute 10%-50% of the weight of the lipid mixture;

[0089] b) Phosphatidylcholine constitutes 40%-80% of the weight of the lipid mixture;

[0090] c) Anhydrous ethanol accounts for 5%-20% of the weight of the lipid mixture;

[0091] (3) Solubilizer 1-150 parts by weight;

[0092] (4) pH adjuster, wherein the weight part of the pH adjuster is selected to adjust the pH value of the sustained-release preparation to a predetermined range.

[0093] In some embodiments, 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:

[0094] (1) 0.001-70 parts by weight of the active pharmaceutical ingredient;

[0095] (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:

[0096] a) Triacylglycerols constitute 10%-50% of the weight of the lipid mixture;

[0097] b) Phosphatidylcholine constitutes 40%-80% of the weight of the lipid mixture;

[0098] c) The weight percentage of ethanol in the lipid mixture is 5%-20% based on anhydrous ethanol; and

[0099] (3) Solubilizer 1-150 parts by weight; and

[0100] The sustained-release formulation has a pH value of 4.0-8.0.

[0101] In some embodiments, the active pharmaceutical ingredient is present in amounts of 0.001-60 parts by weight, 0.001-50 parts by weight, or 0.001-40 parts by weight. In some embodiments, the active pharmaceutical ingredient is present in amounts 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, the active pharmaceutical ingredient is present in amounts 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] In some embodiments, the solubilizer has 1-120 parts by weight or 1-100 parts by weight. In some embodiments, the solubilizer has 5-100 parts by weight or 10-90 parts by weight or 10-80 parts by weight or 10-70 parts by weight or 10-60 parts by weight or 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: 1, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 parts by weight.

[0106] In some embodiments, the pH value or predetermined pH range of the sustained-release formulation is 4.5-8.0. In some embodiments, the pH value or predetermined pH range of the sustained-release formulation is 4.5-7.0. In some embodiments, the pH value or predetermined pH range of the sustained-release formulation is 5.0-6.6. In some embodiments, the pH value or predetermined pH range of the sustained-release formulation is 5.3-6.6, 5.4-6.6, or 5.5-6.6. In some embodiments, the pH value or predetermined pH range of the 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 value of the sustained-release formulation is a predetermined value or range of 4.0, 4.1, 4.2, 4.3, 4.4, 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, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0 or a range between any two of the above values.

[0107] In some embodiments, the weight ratio of the solubilizer to the active pharmaceutical ingredient is 15:1 to 1:5. In some embodiments, the weight ratio of the solubilizer to the active pharmaceutical ingredient is 10:1 to 1:5. In some embodiments, the weight ratio of the solubilizer to the active pharmaceutical ingredient is within the range of any two values ​​of 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 or above.

[0108] 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.

[0109] 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.

[0110] In some embodiments, the active pharmaceutical ingredient is liraglutide, and the sustained-release formulation comprises 1-50 parts by weight of liraglutide, 300-800 parts by weight of soybean phosphatidylcholine (SPC), 100-500 parts by weight of medium-chain triglycerides (MCT), 50-200 parts by weight of ethanol, 10-100 parts by weight of water, and the sustained-release formulation has a pH of 4.5-7.0 (e.g., 5.5-6.5 or about 6.0).

[0111] In some embodiments, the active pharmaceutical ingredient is liraglutide, and the sustained-release formulation comprises 1-30 parts by weight of liraglutide, 300-600 parts by weight of soybean phosphatidylcholine (SPC), 150-400 parts by weight of medium-chain triglycerides (MCT), 100-200 parts by weight of ethanol, 30-90 parts by weight of water, and the sustained-release formulation has a pH of 4.5-7.0 (e.g., 5.5-6.5 or about 6.0).

[0112] In some embodiments, the active pharmaceutical ingredient is liraglutide, and the sustained-release formulation comprises 1-30 parts by weight (e.g., about 10 parts by weight) of liraglutide, 300-500 parts by weight (e.g., about 400 parts by weight) of soybean phosphatidylcholine (SPC), 300-500 parts by weight (e.g., about 400 parts by weight) of medium-chain triglycerides (MCT), 120-180 parts by weight (e.g., about 150 parts by weight) of ethanol, 30-50 parts by weight (e.g., about 40 parts by weight) of water, and the sustained-release formulation has a pH of 4.5-7.0 (e.g., 5.5-6.5 or about 6.0).

[0113] In some embodiments, the active pharmaceutical ingredient is liraglutide, and the sustained-release formulation comprises 1-30 parts by weight (e.g., about 20 parts by weight) of liraglutide, 500-600 parts by weight (e.g., 530-580 parts by weight) of soybean phosphatidylcholine (SPC), 150-200 parts by weight (e.g., 170-190 parts by weight) of medium-chain triglycerides (MCT), 120-180 parts by weight (e.g., about 130-160 parts by weight) of ethanol, 70-90 parts by weight (e.g., about 80 parts by weight) of water, and the sustained-release formulation has a pH of 4.5-7.0 (e.g., 5.5-6.5 or about 6.0).

[0114] In some embodiments, the active pharmaceutical ingredient is telpolide, and the sustained-release formulation comprises 1-50 parts by weight of telpolide, 300-800 parts by weight (e.g., 400-700 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 200-400 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 100-200 parts by weight) of ethanol, 10-50 parts by weight of bile salts (e.g., sodium deoxycholate) or water, and the sustained-release formulation has a pH of 6.0-8.0.

[0115] In some embodiments, the active pharmaceutical ingredient is telpolide, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 5-30 parts by weight or about 10 parts by weight) of telpolide, 400-700 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 150-400 parts by weight (e.g., 200-300 parts by weight) of medium-chain triglycerides (MCT), 100-200 parts by weight (e.g., 120-200 parts by weight) of ethanol, 20-50 parts by weight (e.g., 40-50 parts by weight) of water, and the sustained-release formulation has a pH of 6.0-8.0.

[0116] In some embodiments, the active pharmaceutical ingredient is telpolide, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 5-30 parts by weight or about 5 parts by weight) of telpolide, 400-700 parts by weight (e.g., 450-600 parts by weight) of soybean phosphatidylcholine (SPC), 200-500 parts by weight (e.g., 300-400 parts by weight) of medium-chain triglycerides (MCT), 100-200 parts by weight (e.g., 120-200 parts by weight) of ethanol, 10-30 parts by weight (e.g., 10-20 parts by weight) of sodium deoxycholate, and the sustained-release formulation has a pH of 6.0-8.0.

[0117] In some embodiments, the active pharmaceutical ingredient is leuprorelin or leuprorelin acetate, and the sustained-release formulation comprises 1-50 parts by weight (e.g., about 10 parts by weight) of leuprorelin or leuprorelin acetate (calculated as leuprorelin), 300-800 parts by weight (e.g., 350-500 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 350-500 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 100-200 parts by weight) of ethanol, 10-50 parts by weight (e.g., 20-40 parts by weight) of water, and the sustained-release formulation has a pH of 5.0-7.0.

[0118] In some embodiments, the active pharmaceutical ingredient is teriparatide, and the sustained-release formulation comprises 1-10 parts by weight (e.g., about 1 part by weight) of teriparatide, 300-800 parts by weight (e.g., 350-500 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 350-500 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 100-200 parts by weight) of ethanol, 10-50 parts by weight (e.g., 40-50 parts by weight) of water, and the sustained-release formulation has a pH of 6.0-8.0.

[0119] In some embodiments, the active pharmaceutical ingredient is donepezil, and the sustained-release formulation comprises 1-50 parts by weight (e.g., about 10 parts by weight) of donepezil, 300-800 parts by weight (e.g., 350-500 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 350-500 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 100-200 parts by weight) of ethanol, 50-100 parts by weight (e.g., about 60-80 parts by weight) of water, and the sustained-release formulation has a pH of 5.0-7.0.

[0120] In some embodiments, the active pharmaceutical ingredient is exenatide acetate, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 1-20 parts by weight) of exenatide acetate (calculated as exenatide), 300-800 parts by weight (e.g., 500-800 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 100-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, 50-150 parts by weight (e.g., about 70-130 parts by weight) of water or bile salts, and the sustained-release formulation has a pH of 4.0-5.0 (e.g., about 4.0).

[0121] In some embodiments, the active pharmaceutical ingredient is exenatide acetate, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 1-20 parts by weight or about 8 parts by weight) of exenatide acetate (calculated as exenatide), 300-800 parts by weight (e.g., about 600-800 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., about 100-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., about 120-180 parts by weight) of ethanol, 100-150 parts by weight (e.g., about 110-130 parts by weight) of bile salts, and the sustained-release formulation has a pH of 4.0-5.0 (e.g., about 4.0).

[0122] In some embodiments, the active pharmaceutical ingredient is exenatide acetate, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 1-20 parts by weight or about 10 parts by weight) of exenatide acetate (calculated as exenatide), 300-800 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 150-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, 50-100 parts by weight (e.g., about 70-90 parts by weight) of water, and the sustained-release formulation has a pH of 4.0-5.0 (e.g., about 4.0).

[0123] In some embodiments, the active pharmaceutical ingredient is goserelin acetate, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 1-20 parts by weight or about 10 parts by weight) of goserelin acetate (calculated as goserelin), 300-800 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 150-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, 50-100 parts by weight (e.g., about 70-90 parts by weight) of water, and the sustained-release formulation has a pH of 4.0-8.0.

[0124] In some embodiments, the active pharmaceutical ingredient is ropivacaine hydrochloride, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 5-40 parts by weight or about 30 parts by weight) of ropivacaine hydrochloride (calculated as ropivacaine), 300-800 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 150-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, 50-100 parts by weight (e.g., about 70-90 parts by weight) of water, and the sustained-release formulation has a pH of 4.0-8.0.

[0125] In some embodiments, the active pharmaceutical ingredient is semaglutide, and the sustained-release formulation comprises 1-70 parts by weight (e.g., 10-60 parts by weight or about 60 parts by weight) of semaglutide, 300-800 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 150-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, and 50-100 parts by weight (e.g., about 70-90 parts by weight) of water; and the sustained-release formulation has a pH of 5.0-6.6 (e.g., 5.3-6.6, 5.4-6.6, or 5.5-6.6).

[0126] In some embodiments of the second aspect, the mixing of the active pharmaceutical ingredient, triacylglycerol, phosphatidylcholine, solvent, solubilizer, and pH adjuster is carried out in multiple steps.

[0127] In some embodiments, the preparation method includes:

[0128] Step 1: Prepare a drug mixture containing the active pharmaceutical ingredient and a solubilizer;

[0129] Step 2: Prepare a lipid mixture containing triacylglycerol, phosphatidylcholine, and a solvent;

[0130] Step 3: Mix the drug mixture and the lipid mixture thoroughly to obtain the final mixture;

[0131] The pH adjuster is added in step 1, step 2, or step 3.

[0132] In some embodiments, the preparation method further includes step 4: filtration and filling.

[0133] In some embodiments, step 2 includes: a) mixing phosphatidylcholine, triacylglycerol and a solvent, stirring and dissolving to obtain a lipid mixture; or b) mixing phosphatidylcholine and a solvent, stirring and dissolving to obtain a phosphatidylcholine solution, and then mixing the triacylglycerol and the phosphatidylcholine solution evenly to obtain a lipid mixture.

[0134] In some embodiments, the preparation method includes:

[0135] Step 1: Prepare a drug mixture containing the active pharmaceutical ingredient and a solubilizer;

[0136] Step 2: Prepare a phosphatidylcholine solution containing phosphatidylcholine and a solvent;

[0137] Step 3: Mix the drug mixture with the phosphatidylcholine solution until homogeneous, then add triacylglycerol and mix until homogeneous to obtain the final mixture;

[0138] The pH adjuster is added in step 1, step 2, or step 3.

[0139] In some embodiments, the preparation method further includes step 4: filtration and filling.

[0140] In some embodiments, the sustained-release formulation uses water as a solubilizer, and step 1 includes: mixing the active pharmaceutical ingredient with water, stirring to dissolve it, to obtain a pharmaceutical mixture (also referred to as an aqueous phase).

[0141] In some embodiments, the sustained-release formulation uses bile salts (e.g., sodium deoxycholate) as a solubilizer, and step 1 includes: dissolving and mixing the active pharmaceutical ingredient with bile salts (e.g., sodium deoxycholate) in water and then lyophilizing it to form a drug mixture in the form of a lyophilized complex.

[0142] In some embodiments of the preparation method, in step 2, the temperature is controlled to be less than or equal to 60°C, preferably less than or equal to 50°C, more preferably less than or equal to 45°C or 40°C, for example, room temperature.

[0143] In some embodiments, in step 3, before mixing with the drug mixture, the temperature of the phosphatidylcholine solution or lipid mixture is below 40°C, below 35°C, or below 30°C, for example, room temperature.

[0144] In some embodiments, the preparation method includes:

[0145] Step 1: Mix the active pharmaceutical ingredient, solubilizer, phosphatidylcholine, and solvent, and stir to dissolve;

[0146] Step 2: Add triacylglycerol and mix well to obtain the final mixture;

[0147] The pH adjuster is added in step 1 or step 2.

[0148] In some embodiments, the preparation method further includes step 3: filtration and filling.

[0149] In a third aspect, this application also provides the use of the sustained-release formulation described in the first aspect or the sustained-release formulation prepared according to the method described in the second aspect in the preparation of a medicament. The disease treated by the medicament is related to the therapeutic effect of the active pharmaceutical ingredient.

[0150] In some embodiments, the active pharmaceutical ingredient of the sustained-release formulation is a gonadotropin-releasing hormone (GnRH) analog (e.g., buserreline, leuproreline, gosereline, triptoreline, avoreline, diloreline), and the sustained-release formulation can be used to prepare drugs for treating diseases such as prostate cancer, breast cancer, uterine fibroids, endometriosis, central precocious puberty, and polycystic ovary syndrome.

[0151] In some embodiments, the sustained-release formulation comprises a pharmaceutically active ingredient selected from GLP-1R agonists or GLP-1R / GIPR dual agonists (e.g., exenatide, liraglutide, dulaglutide, lixisenatide, abiglutide, benaglutide, loxenatide, smegglutide, noliglutide, enogglutide, telpoglutide, HRS-9531, GMA106, HS-20094, AMG-133, CT-868, HRS9531, RAY1225, SCO-094, BGM). 0504, CT-388, LY3493269 or VK-2735), the sustained-release formulation can be used to prepare medicines for treating diseases related to GLP-1R and / or GIPR, such as 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, uterine diseases, etc.

[0152] In some embodiments, the sustained-release formulation contains donepezil as the active pharmaceutical ingredient, and the sustained-release formulation can be used to prepare a drug for treating Alzheimer's disease.

[0153] In some embodiments, the sustained-release formulation contains teriparatide as the active pharmaceutical ingredient, and the sustained-release formulation can be used to prepare a drug for treating osteoporosis.

[0154] In some embodiments, the sustained-release formulation contains ropivacaine as the active pharmaceutical ingredient, and the sustained-release formulation can be used to prepare a local anesthetic.

[0155] In a fourth aspect, this application also provides a method for treating a disease using the sustained-release formulation described in the first aspect or the sustained-release formulation prepared according to the method described in the second aspect, comprising: administering a therapeutically effective amount of the sustained-release formulation to a subject or patient in need.

[0156] For the correspondence between active pharmaceutical ingredients and indications, please refer to the description in section three above.

[0157] In some implementations, the application is performed once every 1-8 weeks, preferably once every 1-6 weeks (e.g., once every 1 week, once every 2 weeks, once every 2 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks), once every 1-6 months (e.g., once a month, once every 2 months, once every 3 months, once every 4 months, once every 6 months), once every 10 days, once every 15 days, once every 20 days, once every 30 days, once every 45 days, or once every 60 days.

[0158] In a fifth aspect, this application also provides the sustained-release formulation described in the first aspect or prepared according to the method described in the second aspect for the treatment of diseases. The correspondence between the active pharmaceutical ingredient and the indication can be found in the description of the third aspect above.

[0159] In other aspects, this application provides a method for preparing a semaglutide sustained-release formulation, the semaglutide sustained-release formulation comprising: semaglutide or a pharmaceutically acceptable salt thereof, triacylglycerol, phosphatidylcholine, solvent, solubilizer and pH adjuster;

[0160] The preparation method includes: mixing smegglutinin or its pharmaceutically acceptable salt, triacylglycerol, phosphatidylcholine, solvent, solubilizer, and pH adjuster evenly.

[0161] In some embodiments, the preparation method includes:

[0162] Step 1: Prepare a pharmaceutical mixture comprising smegglutinin or its pharmaceutically acceptable salt and a solubilizer;

[0163] Step 2: Prepare a lipid mixture containing triacylglycerol, phosphatidylcholine, and a solvent;

[0164] Step 3: Mix the drug mixture and the lipid mixture thoroughly to obtain the final mixture;

[0165] The pH adjuster is added in step 2 or step 3.

[0166] In some embodiments, the preparation method includes step 4: filtration and filling.

[0167] In some embodiments, step 2 includes: a) mixing phosphatidylcholine, triacylglycerol and a solvent, stirring and dissolving to obtain a lipid mixture, or b) mixing phosphatidylcholine and a solvent, stirring and dissolving to obtain a phosphatidylcholine solution, and then mixing the triacylglycerol and the phosphatidylcholine solution evenly to obtain a lipid mixture.

[0168] In some embodiments, the preparation method includes:

[0169] Step 1: Prepare a pharmaceutical mixture comprising smegglutinin or its pharmaceutically acceptable salt and a solubilizer;

[0170] Step 2: Prepare a phosphatidylcholine solution containing phosphatidylcholine and a solvent;

[0171] Step 3: Mix the drug mixture with the phosphatidylcholine solution until homogeneous, then add triacylglycerol and mix until homogeneous to obtain the final mixture;

[0172] The pH adjuster is added in step 2 or step 3.

[0173] In some embodiments, the preparation method further includes step 4: filtration and filling.

[0174] In some embodiments, the semaglutide sustained-release formulation uses water as a solubilizer, and step 1 includes: mixing semaglutide or its pharmaceutically acceptable salt with water, stirring to dissolve, to obtain a drug mixture (also referred to as an aqueous phase).

[0175] In some embodiments, the semaglutide sustained-release formulation uses bile salts (e.g., sodium deoxycholate) as a solubilizer, and step 1 includes: dissolving and mixing semaglutide or its pharmaceutically acceptable salt with bile salts (e.g., sodium deoxycholate) in water and then lyophilizing to form a drug mixture in the form of a lyophilized complex.

[0176] In some embodiments of the above preparation method, in step 2, the temperature is controlled to be less than or equal to 60°C, preferably less than or equal to 50°C, more preferably less than or equal to 45°C or 40°C, for example, room temperature.

[0177] In some embodiments, in step 3, before mixing with the drug mixture, the temperature of the phosphatidylcholine solution or lipid mixture is below 40°C, below 35°C, or below 30°C, for example, room temperature.

[0178] In some embodiments, the preparation method includes:

[0179] Step 1: Mix smegglutide or its pharmaceutically acceptable salt, solubilizer, phosphatidylcholine and the solvent of phosphatidylcholine, and stir to dissolve;

[0180] Step 2: Add triacylglycerol and mix well;

[0181] Optionally, step 3: filtration and filling.

[0182] The pH adjuster is added in step 1 or step 2.

[0183] In other aspects, this application provides a semaglutide sustained-release formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0184] (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;

[0185] (2) Triacylglycerol 100-500 parts by weight;

[0186] (3) Phosphatidylcholine 400-800 parts by weight;

[0187] (4) 50-200 parts by weight of anhydrous ethanol;

[0188] (5) Solubilizer 1-100 parts by weight; and

[0189] (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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] In other aspects, this application provides a semaglutide sustained-release formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0197] (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;

[0198] (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:

[0199] a) Triacylglycerols constitute 10%-50% of the weight of the lipid mixture;

[0200] b) Phosphatidylcholine constitutes 40%-80% of the weight of the lipid mixture;

[0201] c) Anhydrous ethanol accounts for 5%-20% of the weight of the lipid mixture;

[0202] (3) Solubilizer 1-100 parts by weight; and

[0203] (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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] In other respects, this application provides a semaglutide sustained-release formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0211] (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;

[0212] (2) Triacylglycerol 100-500 parts by weight;

[0213] (3) Phosphatidylcholine 400-800 parts by weight;

[0214] (4) Ethanol, wherein the amount of anhydrous ethanol is 50-200 parts by weight; and

[0215] (5) Solubilizer 1-100 parts by weight; and

[0216] The pH value of the smegglutide sustained-release formulation is 4.5-7.0.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] In other respects, this application provides a semaglutide sustained-release formulation comprising, or substantially consisting of, the following components in parts by weight, or consisting of, the following components in parts by weight:

[0224] (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;

[0225] (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:

[0226] a) Triacylglycerols constitute 10%-50% of the weight of the lipid mixture;

[0227] b) Phosphatidylcholine constitutes 40%-80% of the weight of the lipid mixture;

[0228] c) The weight percentage of ethanol in the lipid mixture is 5%-20% based on anhydrous ethanol; and

[0229] (3) Solubilizer 1-100 parts by weight; and

[0230] The pH value of the smegglutide sustained-release formulation is 4.5-7.0.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] The following details specific embodiments or technical features of the inventions described in other aspects. Generally, unless there is a contradiction or conflict, the specific embodiments or technical features described below apply to the inventions described in other aspects.

[0238] In some embodiments, the semaglutide extended-release formulation is an injectable.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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).

[0246] 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.

[0247] 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.

[0248] 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.

[0249] In some embodiments, 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:

[0250] (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

[0251] (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

[0252] (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

[0253] (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

[0254] (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

[0255] (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.

[0256] In some embodiments, 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:

[0257] (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

[0258] (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

[0259] (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

[0260] (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

[0261] (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

[0262] (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.

[0263] In some embodiments, the sustained-release formulation of semaglutide 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), (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.

[0264] In other respects, this application provides the use of the semaglutide extended-release formulation for the treatment of GLP-1R-related diseases.

[0265] In other aspects, this application provides a method for preparing a semaglutide sustained-release formulation using water as a solubilizer, the method comprising the following steps:

[0266] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain the aqueous phase;

[0267] Step 2: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0268] Step 3: Add the aqueous phase obtained in Step 1 to the lipid mixture obtained in Step 2, and stir to mix well;

[0269] 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.

[0270] In other aspects, this application provides a method for preparing a semaglutide sustained-release formulation using bile salts (e.g., sodium deoxycholate) as a solubilizer, the method comprising the following steps:

[0271] 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.

[0272] Step b: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0273] Step c: Add the lyophilized complex obtained in step a to the lipid mixture obtained in step b, and stir to dissolve;

[0274] 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.

[0275] In some embodiments, 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.

[0276] 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 method of this application can be changed 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 method 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 of the method.

[0277] In other respects, this application provides the use of the semaglutide sustained-release formulation in the preparation of a medicament for treating GLP-1R-related diseases.

[0278] In other respects, 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 to the individual in need.

[0279] In other respects, this application provides a sustained-release formulation of the semaglutide for the treatment of GLP-1R-related diseases.

[0280] In some implementation schemes, 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.

[0281] In some implementations, the semaglutide extended-release formulation is administered to individuals every 2-8 weeks. In some implementations, the semaglutide extended-release formulation is administered to individuals every 3-6 weeks. In some implementations, the semaglutide extended-release formulation is administered to individuals every 4-5 weeks, every 4 weeks, or monthly.

[0282] In some implementations, the individual is a mammal. In some implementations, the individual is a human patient. Example

[0283] 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 without specific conditions 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. In the specific embodiments of this application, unless otherwise specified, the temperature is room temperature (25±5℃).

[0284] 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.

[0285] 2. Smegglutide sustained-release formulation - content and total impurity determination

[0286] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0287] 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 according to the table below; the flow rate was 0.6 mL / min; the detection wavelength was 215 nm; and the column temperature was 40 °C.

[0288] 3. Smegglutide sustained-release formulation - oligomer determination

[0289] The determination was performed according to size exclusion chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0290] 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.

[0291] 4. Thrust (Injectability) Measurement Method

[0292] Equipment: HAK-3132WJ push-pull force testing machine;

[0293] Push rate: 100 mm / min;

[0294] Pushing distance: 1cm;

[0295] Measurement temperature: 20℃.

[0296] The main raw and auxiliary materials used in the embodiments of this application are as follows:

[0297] Smegglutinin was prepared independently by the inventor team using the technology disclosed in WO2006 / 097537, with a purity of 94.2%.

[0298] Soybean phosphatidylcholine (SPC): purchased from LIPOID GMBH, purity 94%.

[0299] 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.

[0300] Other drug components were prepared by the inventors' team using methods disclosed in existing technologies or purchased from commercially available products.

[0301] Example 1. Preparation of smegglutide sustained-release formulation

[0302] Prepare a semaglutide sustained-release formulation according to the following prescription:

[0303] Table 2. Formulation of Smegglutide sustained-release formulation

[0304] 1. The preparation method of prescription 1-1 or 1-2 is as follows (hereinafter referred to as preparation method 1):

[0305] Step 1: Smegglutide and sodium deoxycholate are dissolved and mixed in water and then freeze-dried to form a freeze-dried complex (SMBS).

[0306] Step 2: Mix soybean phosphatidylcholine (SPC), medium-chain triglycerides (MCT), and anhydrous ethanol, stir to dissolve, and obtain a lipid mixture;

[0307] Step 3: Add the lyophilized complex obtained in Step 1 to the lipid mixture obtained in Step 2 and stir to dissolve;

[0308] Step 4: Add a pH adjuster (such as hydrochloric acid) to adjust the pH value to the target value, then filter and fill.

[0309] 2. The preparation methods for prescriptions 1-3, 1-4, or 1-5 are as follows (hereinafter referred to as preparation method 2):

[0310] Step 1: Mix smegglutinin with water, stir to dissolve, and obtain the aqueous phase;

[0311] Step 2: Mix soybean phosphatidylcholine (SPC), medium-chain triglycerides (MCT), and anhydrous ethanol, stir to dissolve, and obtain a lipid mixture;

[0312] Step 3: Add the aqueous phase obtained in Step 1 to the lipid mixture obtained in Step 2, and stir to mix well;

[0313] Step 4: Add a pH adjuster (such as hydrochloric acid) to adjust the pH value to the target value, then filter and fill.

[0314] Example 2. Effect of the type of neutral lipid on formulation performance

[0315] 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.

[0316] 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%.

[0317] 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.

[0318] Example 3. Effects of different pH adjusters on formulation performance

[0319] 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.

[0320] 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%.

[0321] 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.

[0322] Example 4. Effects of different solubilizers on formulation performance

[0323] 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).

[0324] 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.

[0325] 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.

[0326] 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.

[0327] Example 5. Effect of different endpoint pH values ​​on formulation performance

[0328] 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.

[0329] 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.

[0330] 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.

[0331] Example 6. Effect of neutral lipid mixtures on formulation performance

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] Example 7. Effect of API concentration on formulation performance

[0337] 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.

[0338] 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).

[0339] 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.

[0340] Example 8. Effect of water dosage on formulation performance

[0341] 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.

[0342] 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).

[0343] 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.

[0344] Example 9. Effect of different SPC / MCT ratios on formulation performance 1

[0345] 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.

[0346] Table 10-1. Pharmaceutical Formulation

[0347] 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%.

[0348] 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.

[0349] Example 10. Stability of the formulation of this application

[0350] 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.

[0351] Table 11. Formulation stability results Note: *Content refers to the content of smegglutinin, calculated with D0 content as 100% for the 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.

[0352] 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.

[0353] Example 11. In vivo release characteristics of the formulation of this application

[0354] 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.

[0355] 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 in 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.

[0356] 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.

[0357] Example 12. Comparison of in vivo release characteristics of medium-chain triglycerides (MCT) and dioleoglycerides (GDO) formulations.

[0358] 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.

[0359] 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.

[0360] Table 12-1. Formulation Information

[0361] 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.

[0362] 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 formulation 10-2 and formulation 10-1 basically overlapped between approximately 336h and 576h, but the Ck of formulation 10-2 in the early release phase was different. max The C value was significantly higher than that of prescriptions 10⁻¹ and 10⁻². max / C 23d The ratio of [prescription 10-1] was also significantly higher than that of prescription 10-1. Therefore, the overall PK curve of prescription 10-1 was more stable, indicating that the MCT-based prescription had more favorable sustained-release properties.

[0363] Comparative Example 1

[0364] 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.

[0365] Table 13. Prescription information for Comparative Example 1

[0366] Test Example 1: Stability Comparison of GDO and MCT Prescriptions

[0367] 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.

[0368] 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.

[0369] Comparative Example 2

[0370] 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.

[0371] Table 15. Prescription information for Comparative Example 2

[0372] Test Example 2: Stability Comparison of GDO and MCT Prescriptions

[0373] 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.

[0374] 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%.

[0375] 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.

[0376] Example 13. Process testing for the preparation of lipid mixtures

[0377] 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.

[0378] 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.

[0379] 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.

[0380] V1 is the volume of sodium thiosulfate titrant consumed by the test sample, in ml;

[0381] V0 represents the volume of sodium thiosulfate titrant consumed in the blank test, in ml;

[0382] C represents the concentration of the sodium thiosulfate titrant, in mol / L;

[0383] m is the sample weight, in grams;

[0384] L represents the labeled amount of soybean phosphatidylcholine, in mg / g.

[0385] m is the sample weight, in grams;

[0386] L represents the labeled amount of soybean phosphatidylcholine in the test sample in the formulation, in g / g;

[0387] 1.2 represents the dilution factor of the solution after adding 4-methoxyaniline glacial acetic acid solution;

[0388] A1 is the absorbance value of the solution in the stoppered test tube A;

[0389] A2 is the absorbance value of the solution in the stoppered test tube B;

[0390] A0 is the absorbance value of the test solution without the addition of 4-methoxyaniline glacial acetic acid solution.

[0391] 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.

[0392] Table 17-1 Effect of temperature on the dissolution time of lipid mixture in step 2.

[0393] Table 17-2 Effects of Step 2 Temperature and Heating Time on the Stability of Lipid Mixtures and Finished Products

[0394] Example 14. Formulation preparation process testing

[0395] 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.

[0396] Method A includes the following steps:

[0397] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain an aqueous phase, i.e., a drug mixture;

[0398] Step 2: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0399] 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.

[0400] Step 4: Filtering and filling.

[0401] Method B includes the following steps:

[0402] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain an aqueous phase, i.e., a drug mixture;

[0403] 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;

[0404] Step 3: Mix the aqueous phase obtained in Step 1 with the lipid mixture obtained in Step 2 until homogeneous;

[0405] Step 4: Filtering and filling.

[0406] Method C includes the following steps:

[0407] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain an aqueous phase, i.e., a drug mixture;

[0408] Step 2: Mix phosphatidylcholine and ethanol, stir to dissolve, and obtain a phosphatidylcholine solution;

[0409] 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.

[0410] Step 4: Filtering and filling.

[0411] Method D includes the following steps:

[0412] Step 1: Mix smegglutinin or its pharmaceutically acceptable salt with water, stir to dissolve, and obtain an aqueous phase, i.e., a drug mixture;

[0413] Step 2: Mix phosphatidylcholine and ethanol, stir to dissolve, and obtain a phosphatidylcholine solution;

[0414] 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.

[0415] Step 4: Filtering and filling.

[0416] 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.

[0417] Example 15. Formulation preparation process testing

[0418] 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.

[0419] The method E includes the following steps:

[0420] 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.

[0421] Step 2: Mix phosphatidylcholine, triacylglycerol and ethanol, stir to dissolve, and obtain a lipid mixture;

[0422] 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;

[0423] Step 4: Filtering and filling.

[0424] The method F includes the following steps:

[0425] 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.

[0426] 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;

[0427] Step 3: Add the lyophilized complex obtained in Step 1 to the lipid mixture obtained in Step 3, and stir to dissolve;

[0428] Step 4: Filtering and filling.

[0429] The method G includes the following steps:

[0430] 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.

[0431] Step 2: Mix phosphatidylcholine and ethanol, stir to dissolve, and obtain phosphatidylcholine solution;

[0432] 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.

[0433] Step 4: Filtering and filling.

[0434] The method H includes the following steps:

[0435] 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.

[0436] Step 2: Mix phosphatidylcholine and ethanol, stir to dissolve, and obtain phosphatidylcholine solution;

[0437] 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.

[0438] Step 4: Filtering and filling.

[0439] 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.

[0440] Example 16. Effects of different esters on formulation performance

[0441] 16.1 Effect of Span 20 on the stability of MCT-containing prescriptions

[0442] 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.

[0443] 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.

[0444] Table 18-1. Formulation Information (Unit: mg)

[0445] Table 18-2. Stability Results Note: *Content refers to the content of smegglutinin.

[0446] The results showed that the introduction of Span 20 had a negative impact on stability for all prescriptions.

[0447] 16.2 Effects of Span 80, Ethyl Tocopherol (TA), and Ethyl Oleate (EO) on the Stability of MCT-Containing Formulations

[0448] 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.

[0449] 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.

[0450] Table 18-3. Formulation Information (Unit: mg)

[0451] Table 18-4. Stability Results Note: *Content refers to the content of smegglutinin.

[0452] 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.

[0453] Example 17. Solubilization Test 1

[0454] 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.

[0455] 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.

[0456] Table 19-1. Pharmaceutical Formulation Information

[0457] Table 19-2. Results of Solubilizer Test Note: *Content refers to the content of smegglutinin.

[0458] 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.

[0459] Example 18. Effect of solvent on formulation performance

[0460] 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.

[0461] Table 20-1. Formulation Information (Unit: mg)

[0462] Table 20-2. Stability Results Note: *Content refers to the content of smegglutinin.

[0463] 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.

[0464] Example 19. Solubilization Test 2

[0465] 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.

[0466] Table 21-1. Formulation Information (Component Content Unit: Parts by Weight)

[0467] Table 21-2. Stability Results Note: *Content refers to the content of smegglutinin.

[0468] The results showed that there was no significant difference in formulation stability when using water, DMSO, and propylene glycol as solubilizers.

[0469] 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.

[0470] 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.

[0471] Example 20. Effect of different SPC / MCT ratios on formulation performance (test 2)

[0472] 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.

[0473] Table 22-1. Formulation Information (Component Content Unit: Parts by Weight)

[0474] Table 22-2. Stability Results Note: *Content refers to the content of smegglutinin.

[0475] 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.

[0476] 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.

[0477] 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.

[0478] Example 21. Stability Comparison of GDO and MCT Formulations 3

[0479] 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.

[0480] Table 23-1. Formulation Information (Component Content Unit: Parts by Weight)

[0481] Table 23-2. Stability Results Note: *Content refers to the content of smegglutinin or liraglutinin.

[0482] The results showed that smegglutide and liraglutide had significantly better stability in MCT formulations than in GDO formulations.

[0483] 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.

[0484] 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.

[0485] Example 22. Preparation of telpopril sustained-release formulation

[0486] The telpoeptide sustained-release formulation was prepared according to the formulation shown in Table 24, following preparation method 1 or preparation method 2 of Example 1:

[0487] Table 24. Exemplary telpolide formulation prescription information

[0488] Example 23. Preparation of Leuprorelin Sustained-Release Formulation

[0489] Following the preparation method 2 of Example 1, leuprorelin sustained-release formulations were prepared according to the formulations shown in Table 25:

[0490] Table 25. Exemplary Leuprorelin Formulation Prescription Information

[0491] Example 24. Preparation of Teriparatide sustained-release formulation

[0492] Following the preparation method 2 of Example 1, the teriparatide sustained-release formulation was prepared according to the formulation shown in Table 26:

[0493] Table 26. Exemplary Teriparatide Formulation Prescription Information

[0494] Example 25. Preparation of donepezil sustained-release formulation

[0495] Prepare donepezil sustained-release formulations according to the formulation shown in Table 27, following preparation method 2 of Example 1:

[0496] Table 27. Exemplary donepezil formulation prescription information

[0497] Example 26. MCT and GDO formulation tests of exenatide acetate

[0498] Following the preparation method 1 in Example 1, and according to the component ratios shown in Table 28-1, the MCT and GDO formulations of exenatide acetate were prepared. After preparation, the formulations were stored at 5°C for 28 days, and their stability was monitored. The results are shown in Table 28-2.

[0499] Table 28-1. Formulation Information (Component Content Unit: Parts by Weight) Note: The dosage of exenatide acetate is calculated based on exenatide.

[0500] Table 28-2. Stability Results Note: *Content refers to the content of exenatide.

[0501] The results showed that the stability of exenatide MCT formulation 21-1 was significantly better than that of GDO formulation 21-2, consistent with the results observed in smegglutide formulation.

[0502] The in vivo release characteristics of formulations 21-1 and 21-2 were tested in rats according to the in vivo experiments described in Example 12 (subcutaneous injection of 0.2 ml of formulation 21-1 or 21-2, with blood collection at 0h, 0.5h, 1h, 3h, 9h, 24h, D2, D3, D7, D10, D14, D18, D21, D24, D28, and D32). As shown in Figure 3, the rat PK curves of exenatide MCT formulation 21-1 and GDO formulation 21-2 differed. GDO formulation 21-2 showed a burst release within 2 hours after administration, with the burst peak approximately twice the height of the main peak; a trough occurred from day 3 to day 8 after administration, with a plasma concentration of approximately 10 ng / ml, about 1 / 10 of the main peak; the difference between the burst peak and the trough was approximately 20 times. MCT formulation 21-1 exhibits a burst release peak within 2 hours after administration, slightly lower than the main peak height. A trough occurs from day 1 to day 7 after administration, approximately 10 ng / ml, about 1 / 8 of the main peak height; the burst release peak and trough differ by approximately 8 times. Based on PK curve results, the PK curve of MCT formulation 21-1 is flatter than that of GDO formulation 21-2.

[0503] Example 27. Stability testing of different API formulations

[0504] Referring to formulations 1-3 to 1-5 of Example 1, formulations of goserelin acetate, ropivacaine hydrochloride, exenatide acetate, smegglutide, and liraglutide were prepared according to the component ratios shown in Table 29-1. After preparation, the formulations were placed at room temperature for 24 hours to evaluate their appearance stability; the results are shown in Table 29-2.

[0505] Table 29-1. Formulation Information (by weight %) Note: The dosage of goserelin acetate is calculated as goserelin; the dosage of ropivacaine hydrochloride is calculated as ropivacaine; the dosage of exenatide acetate is calculated as exenatide.

[0506] The preparation method of the above-mentioned prescription preparation (based on 100 parts by weight) is as follows:

[0507] (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.

[0508] (2) Mix 5 parts by weight of anhydrous ethanol, 8 parts by weight of water and API (X parts by weight, i.e. X% of API in Table 29-1) and stir to dissolve to prepare an aqueous solution containing API.

[0509] (3) Take 13+X parts by weight of the aqueous solution containing API obtained in step (2) and 87-X parts by weight of the lipid mixture obtained in step (1) and mix them evenly to obtain 100 parts by weight of the final formulation.

[0510] Table 29-2.24-hour appearance stability evaluation

Claims

1. A sustained-release formulation comprising: a pharmaceutically active ingredient, triacylglycerol, phosphatidylcholine, a solvent (e.g., an organic solvent), a solubilizer, and a pH adjuster.

2. A method for preparing a sustained-release formulation, the method comprising: The active pharmaceutical ingredient, triacylglycerol, phosphatidylcholine, solvent, solubilizer, and pH adjuster are mixed evenly. Preferably, the mixing is completed in multiple steps.

3. The preparation method according to claim 2, comprising: Step 1: Prepare a drug mixture containing the active pharmaceutical ingredient and a solubilizer; Step 2: Prepare a lipid mixture containing triacylglycerol, phosphatidylcholine, and a solvent; Step 3: Mix the drug mixture and the lipid mixture thoroughly to obtain the final mixture; The pH adjuster is added in step 1, step 2, or step 3; Optionally, the preparation method includes step 4: filtration and filling.

4. The preparation method according to claim 3, wherein step 2 includes: a) Mix phosphatidylcholine, triacylglycerol and solvent, stir and dissolve to obtain a lipid mixture; or b) Mix phosphatidylcholine and solvent, stir and dissolve to obtain a phosphatidylcholine solution, then mix triacylglycerol and phosphatidylcholine solution evenly to obtain a lipid mixture.

5. The preparation method according to claim 2, comprising: Step 1: Prepare a drug mixture containing the active pharmaceutical ingredient and a solubilizer; Step 2: Prepare a phosphatidylcholine solution containing phosphatidylcholine and a solvent; Step 3: Mix the drug mixture with the phosphatidylcholine solution until homogeneous, then add triacylglycerol and mix until homogeneous to obtain the final mixture; The pH adjuster is added in step 1, step 2, or step 3; Optionally, the preparation method includes step 4: filtration and filling.

6. The preparation method according to any one of claims 3-5, wherein the sustained-release formulation uses water as a solubilizer, and step 1 comprises: The active pharmaceutical ingredient is mixed with water and stirred to dissolve, resulting in a pharmaceutical mixture. or, The sustained-release formulation uses bile salts (e.g., sodium deoxycholate) as a solubilizer, and step 1 includes: dissolving and mixing the active pharmaceutical ingredient with bile salts (e.g., sodium deoxycholate) in water and then lyophilizing it to form a drug mixture in the form of a lyophilized complex.

7. The preparation method according to any one of claims 3-6, wherein in step 2, the temperature is controlled to be less than or equal to 60°C, preferably less than or equal to 50°C, more preferably less than or equal to 45°C or 40°C, for example, room temperature.

8. The preparation method according to any one of claims 3-7, wherein in step 3, before mixing with the drug mixture, the temperature of the phosphatidylcholine solution or lipid mixture is controlled below 40°C, below 35°C, or below 30°C, for example, room temperature.

9. The preparation method according to claim 2, comprising: Step 1: Mix the active pharmaceutical ingredient, solubilizer, phosphatidylcholine, and solvent, and stir to dissolve; Step 2: Add triacylglycerol and mix well to obtain the final mixture; The pH adjuster is added in step 1 or step 2; Optionally, the preparation method includes step 3: filtration and filling.

10. The sustained-release formulation according to claim 1 or the preparation method according to any one of claims 2-9, wherein the active pharmaceutical ingredient is selected from small molecule compounds, peptides, proteins and nucleic acids.

11. The sustained-release formulation or preparation method of claim 10, wherein the active pharmaceutical ingredient is selected from GLP-1R agonists (e.g., exenatide, liraglutide, dulaglutide, lixisenatide, abiglutide, benaglutide, loxenatide, smegglutide, noliglutide, or enogglutide), GLP-1R / GIPR dual agonists (e.g., telpoitide, HRS-9531, GMA106, HS-20094, AMG-133, CT-868, HRS9531, RAY1225, SCO-094, BGM0504). CT-388, LY3493269, or VK-2735), gonadotropin-releasing hormone (GnRH) analogs (e.g., buserreline, leuproreline, gosereline, triptoreline, avoreline, or diloreline), medications for treating neurodegenerative diseases (e.g., donepezil, rivastigmine, huperzine A, memantine, levodopa, amantadine, or entacapone), medications for treating osteoporosis (e.g., bisphosphonates, calcitonin, strontium ranelate, or teriparatide), and local anesthetics (e.g., ropivacaine, procaine, lidocaine, tetracaine, or bupivacaine).

12. The sustained-release formulation according to claim 1, 10, or 11, or the preparation method according to any one of claims 2-11, 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); and / or The phosphatidylcholine is a natural or synthetic phosphatidylcholine, preferably soybean phosphatidylcholine, egg yolk phosphatidylcholine, or a combination thereof, more preferably soybean phosphatidylcholine; and / or The solubilizer is selected from water, bile salts, sodium oleate, dimethyl sulfoxide (DMSO), or propylene glycol. Preferably, the bile salt is selected from sodium glycocholate, sodium ursodeoxycholate, sodium ursodeoxycholate, sodium cholate, sodium chenodeoxycholate, sodium obeticholate, sodium porcine deoxycholate, and sodium deoxycholate, preferably sodium glycocholate or sodium deoxycholate, and more preferably sodium deoxycholate; and / or 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; and / or The solvent is ethanol (preferably anhydrous ethanol), N-methylpyrrolidone (NMP) or a NMP-ethanol mixture. 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).

13. The sustained-release formulation according to any one of claims 1 and 10-12 or the preparation method according to any one of claims 2-12, wherein the sustained-release formulation is an injection.

14. The sustained-release formulation according to any one of claims 1 and 10-13 or the preparation method according to any one of claims 2-13, 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: (1) The active pharmaceutical ingredient is 0.001-70 parts by weight, 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 the 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 300-800 parts by weight, preferably 400-800 parts by weight, more 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 of the above points; (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 1-150 parts by weight, preferably 1-120 or 1-100 parts by weight, more preferably 5-100 parts by weight or 10-90 parts by weight or 10-80 parts by weight or 10-70 parts by weight or 10-60 parts by weight or 10-50 parts by weight or 10-40 parts by weight, for example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140 or 150 parts by weight or any two of the above values. The sustained-release formulation has a pH value of 4.0-8.0, preferably 4.5-8.0 or 5.0-6.6, more preferably 5.3-6.6 or 5.4-6.6 or 5.5-6.6, and even more preferably 5.6-6.5 or 5.6-6.4 or 5.6-6.3 or 5.6-6.2, for example 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.

8. The range between any two point values ​​of 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, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0 or above.

15. The sustained-release formulation according to any one of claims 1 and 10-13 or the preparation method according to any one of claims 2-13, wherein the formulation comprises, or is substantially composed of, the following components having the following weight parts, or is composed of, the following components having the following weight parts: (1) The active pharmaceutical ingredient is 0.001-70 parts by weight, 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 the 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 1-150 parts by weight, preferably 1-120 or 1-100 parts by weight, more preferably 5-100 parts by weight or 10-90 parts by weight or 10-80 parts by weight or 10-70 parts by weight or 10-60 parts by weight or 10-50 parts by weight or 10-40 parts by weight, for example, 1, 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140 or 150 parts by weight or the range between any two of the above values; and The sustained-release formulation has a pH value of 4.0-8.0, preferably 4.5-8.0 or 5.0-6.6, more preferably 5.3-6.6 or 5.4-6.6 or 5.5-6.6, and even more preferably 5.6-6.5 or 5.6-6.4 or 5.6-6.3 or 5.6-6.2, for example 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.

8. The range between any two point values ​​of 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, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0 or above.

16. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is liraglutide, and the sustained-release formulation comprises 1-50 parts by weight of liraglutide, 300-800 parts by weight of soybean phosphatidylcholine (SPC), 100-500 parts by weight of medium-chain triglycerides (MCT), 50-200 parts by weight of ethanol, 10-100 parts by weight of water, and the pH of the sustained-release formulation is 4.5-7.0 (e.g., 5.5-6.5 or about 6.0); or The sustained-release formulation comprises 1-30 parts by weight of liraglutide, 300-600 parts by weight of soybean phosphatidylcholine (SPC), 150-400 parts by weight of medium-chain triglycerides (MCT), 100-200 parts by weight of ethanol, and 30-90 parts by weight of water, and the sustained-release formulation has a pH of 4.5-7.0 (e.g., 5.5-6.5 or about 6.0); or The sustained-release formulation comprises 1-30 parts by weight (e.g., about 10 parts by weight) of liraglutide, 300-500 parts by weight (e.g., about 400 parts by weight) of soybean phosphatidylcholine (SPC), 300-500 parts by weight (e.g., about 400 parts by weight) of medium-chain triglycerides (MCT), 120-180 parts by weight (e.g., about 150 parts by weight) of ethanol, and 30-50 parts by weight (e.g., about 40 parts by weight) of water, and the sustained-release formulation has a pH of 4.5-7.0 (e.g., 5.5-6.5 or about 6.0); or The sustained-release formulation comprises 1-30 parts by weight (e.g., about 20 parts by weight) of liraglutide, 500-600 parts by weight (e.g., 530-580 parts by weight) of soybean phosphatidylcholine (SPC), 150-200 parts by weight (e.g., 170-190 parts by weight) of medium-chain triglycerides (MCT), 120-180 parts by weight (e.g., about 130-160 parts by weight) of ethanol, 70-90 parts by weight (e.g., about 80 parts by weight) of water, and the sustained-release formulation has a pH of 4.5-7.0 (e.g., 5.5-6.5 or about 6.0).

17. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is telpolide, and the sustained-release formulation comprises 1-50 parts by weight of telpolide, 300-800 parts by weight (e.g., 400-700 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 200-400 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 100-200 parts by weight) of ethanol, 10-50 parts by weight of bile salts (e.g., sodium deoxycholate) or water, and the pH of the sustained-release formulation is 6.0-8.0; or The sustained-release formulation comprises 1-50 parts by weight (e.g., 5-30 parts by weight or about 10 parts by weight) of telpolide, 400-700 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 140-400 parts by weight (e.g., 200-300 parts by weight) of medium-chain triglycerides (MCT), 100-200 parts by weight (e.g., 120-200 parts by weight) of ethanol, 20-50 parts by weight (e.g., 40-50 parts by weight) of water, and the sustained-release formulation has a pH of 6.0-8.

0.

18. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is telpolide, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 5-30 parts by weight or about 5 parts by weight) of telpolide, 400-700 parts by weight (e.g., 450-600 parts by weight) of soybean phosphatidylcholine (SPC), 200-500 parts by weight (e.g., 300-400 parts by weight) of medium-chain triglycerides (MCT), 100-200 parts by weight (e.g., 120-200 parts by weight) of ethanol, 10-30 parts by weight (e.g., 10-20 parts by weight) of sodium deoxycholate, and the sustained-release formulation has a pH of 6.0-8.

0.

19. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is leuprorelin or leuprorelin acetate, and the sustained-release formulation comprises 1-50 parts by weight (e.g., about 10 parts by weight) of leuprorelin or leuprorelin acetate (calculated as leuprorelin), 300-800 parts by weight (e.g., 350-500 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 350-500 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 100-200 parts by weight) of ethanol, 10-50 parts by weight (e.g., 20-40 parts by weight) of water, and the sustained-release formulation has a pH of 5.0-7.

0.

20. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is teriparatide, and the sustained-release formulation comprises 1-10 parts by weight (e.g., about 1 part by weight) of teriparatide, 300-800 parts by weight (e.g., 350-500 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 350-500 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 100-200 parts by weight) of ethanol, 10-50 parts by weight (e.g., 40-50 parts by weight) of water, and the sustained-release formulation has a pH of 6.0-8.

0.

21. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is donepezil, and the sustained-release formulation comprises 1-50 parts by weight (e.g., about 10 parts by weight) of donepezil, 300-800 parts by weight (e.g., 350-500 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 350-500 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 100-200 parts by weight) of ethanol, 50-100 parts by weight (e.g., about 70 parts by weight) of water, and the sustained-release formulation has a pH of 5.0-7.

0.

22. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is exenatide acetate, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 1-20 parts by weight) of exenatide acetate (calculated as exenatide), 300-800 parts by weight (e.g., 500-800 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 100-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, 50-150 parts by weight (e.g., about 70-130 parts by weight) of water or bile salts, and the sustained-release formulation has a pH of 4.0-5.0 (e.g., about 4.0); or The sustained-release formulation comprises 1-50 parts by weight (e.g., 1-20 parts by weight or about 8 parts by weight) of exenatide acetate (calculated as exenatide), 300-800 parts by weight (e.g., about 600-800 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., about 100-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., about 120-180 parts by weight) of ethanol, and 100-150 parts by weight (e.g., about 110-130 parts by weight) of bile salts, and the sustained-release formulation has a pH of 4.0-5.0 (e.g., about 4.0); or The sustained-release formulation comprises 1-50 parts by weight (e.g., 1-20 parts by weight or about 10 parts by weight) of exenatide acetate (calculated as exenatide), 300-800 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 150-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, 50-100 parts by weight (e.g., about 70-90 parts by weight) of water, and the sustained-release formulation has a pH of 4.0-5.0 (e.g., about 4.0).

23. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is goserelin acetate, and the sustained-release formulation comprises 1-50 parts by weight (e.g., 1-20 parts by weight or about 10 parts by weight) of goserelin acetate (calculated as goserelin), 300-800 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 150-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, 50-100 parts by weight (e.g., about 70-90 parts by weight) of water, and the sustained-release formulation has a pH of 4.0-8.

0.

24. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is ropivacaine hydrochloride, and the sustained-release formulation comprises 1-50 parts by weight (e.g., about 5-40 parts by weight or 30 parts by weight) of ropivacaine hydrochloride (calculated as ropivacaine), 300-800 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 150-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, 50-100 parts by weight (e.g., about 70-90 parts by weight) of water, and the sustained-release formulation has a pH of 4.0-8.

0.

25. The sustained-release formulation of claim 1, wherein the active pharmaceutical ingredient is semaglutide, and the sustained-release formulation comprises 1-70 parts by weight (e.g., 5-60 parts by weight or about 60 parts by weight) of semaglutide, 300-800 parts by weight (e.g., 500-600 parts by weight) of soybean phosphatidylcholine (SPC), 100-500 parts by weight (e.g., 150-200 parts by weight) of medium-chain triglycerides (MCT), 50-200 parts by weight (e.g., 120-180 parts by weight) of ethanol, and 50-100 parts by weight (e.g., about 70-90 parts by weight) of water; and the pH of the sustained-release formulation is 5.0-6.6 (e.g., 5.3-6.6, 5.4-6.6, or 5.5-6.6).

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