Semaglutide injection for medical treatment

Abstract

The present application provides a kind of semaglutide injection for drug treatment, comprising semaglutide and one or more pharmaceutically acceptable adjuvant, semaglutide injection includes: active ingredient semaglutide;Adjuvant solution is prepared by dissolving bacteriostatic agent, pH buffering agent and isotonic agent in water for injection;The bacteriostatic agent is at least one of phenol, benzyl alcohol and m-cresol;The pH buffering agent is at least one of disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate and sodium phosphate;Isotonic agent is at least one of propylene glycol and mannitol.The present application also relates to the treatment of this drug injection is in the form of weight management, including the treatment of obesity.Can provide more excellent weight loss than liraglutide preparation and lower incidence of gastrointestinal adverse events, can effectively maintain the weight loss effect after adjusting the dosage regimen, prevent weight rebound, provide reliable strategy for long-term weight management.

Description

Technical Field

[0001] This invention relates to the field of weight loss injection technology, specifically to provide a smegglutide injection for drug therapy, which is a form of weight management, including the treatment of obesity. Background Technology

[0002] Weight management, including the treatment of obesity, remains a challenge for many. Liraglutide, a GLP-1 receptor agonist (GLP-1RA), is approved for long-term weight management in individuals with obesity or overweight and at least one weight-related comorbidity. The most common adverse event associated with GLP-1RAs is gastrointestinal disturbance, particularly nausea. Improved pharmacological treatments for weight management are still needed. Smegglutide injection's main component, smegglutide, is a GLP-1 analog with 94% sequence homology to human GLP-1. As a GLP-1 receptor agonist, smegglutide selectively binds to and activates GLP-1 target receptors, affecting blood glucose and appetite by specifically mediating GLP-1 receptors in the pancreas and brain.

[0003] The foregoing background information is intended to help those skilled in the art understand prior art that is similar to the present invention, and to facilitate the understanding of the inventive concept and technical solution of the present invention. It should be clearly stated that, in the absence of clear evidence that the above content was disclosed before the filing date of this patent application, the foregoing background information should not be used to evaluate the novelty of the technical solution of this application. Summary of the Invention

[0004] Technical issues To address the aforementioned issues, the present invention aims to provide a semaglutide composition that offers superior weight loss and a lower incidence of gastrointestinal adverse events compared to liraglutide formulations. Adjusting the dosing regimen effectively maintains the weight loss effect and prevents weight rebound, providing a reliable strategy for long-term weight management.

[0005] Technical solution (1) A semaglutide composition comprising: Active ingredient: Smeglucopyranoside; The excipient solution is prepared by dissolving antibacterial agents, pH buffers, and isotonic agents in water for injection.

[0006] The antibacterial agent is at least one of phenol, benzyl alcohol, and m-cresol; The isotonic agent is at least one of propylene glycol and mannitol; In some embodiments, the pH buffer is at least one of disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate, and sodium phosphate.

[0007] In some embodiments, the concentration of the active ingredient smegglutinin is 0.68-3.2 mg / mL.

[0008] In some embodiments, the concentration of the antibacterial agent is 4.0-5.5 mg / mL.

[0009] In some embodiments, the concentration of the isotonic agent is 10-14 mg / mL.

[0010] In some embodiments, the concentration of the pH buffer is 1.2-1.5 mg / mL.

[0011] In some embodiments, the semaglutide injection also includes a pH adjuster that adjusts the pH to 7.0-8.0.

[0012] In some embodiments, the smegglutide injection further includes a modifier, which is maltodextrin, at a concentration of 0.1-0.5 mg / mL.

[0013] (2) Use of the aforementioned smegglutinin composition in the preparation of formulations having body shaping and / or weight management effects.

[0014] In some embodiments, the formulation is an injection and / or an oral solution.

[0015] In some implementations, the weight management is selected from at least one of weight loss, treatment and / or prevention of obesity, treatment and / or prevention of overweight, and prevention of weight gain.

[0016] In some implementations, 0.25–2.4 mg of smegglutinin is administered weekly.

[0017] In some implementations, the weight management is selected from weight gain caused by at least one weight-related comorbidity, such as hypertension, type 2 diabetes, dyslipidemia, sleep apnea, and urinary incontinence.

[0018] (3) A semaglutide injection for drug therapy, comprising the aforementioned semaglutide composition.

[0019] In some implementation schemes, the specifications of semaglutide injection are based on the injection volume: semaglutide content includes: 1.5mL: 1mg, 1.5mL: 2mg, 3mL: 4mg, 3mL: 6.8mg, 3mL: 9.6mg.

[0020] In some embodiments, the semaglutide injection specification includes the following dosages and any two of the following dosages: Specification 1.5mL:1mg, four injections, once a week, each dose is 0.25mg; Specification 1.5mL:2mg, four injections, once a week, each dose is 0.5mg; The dosage is 3mL:4mg, administered four times a week, with each dose being 1mg. Specification: 3mL: 6.8mg, four injections, once a week, each dose is 1.7mg; Specification: 3mL: 9.6mg, four injections, once a week, each dose is 2.4mg.

[0021] In some embodiments, the semaglutide injection is administered subcutaneously, for example by subcutaneous injection.

[0022] In some implementations, the amount of semaglutide injection administered weekly is selected from 0.25-2.4 mg (calculated as semaglutide) and is administered to the subject.

[0023] In some implementations, the weekly dose of semaglutide injection is selected from 0.25-2.4 mg, 0.25-1.7 mg, and 1.7-2.4 mg (calculated as semaglutide) administered to the subject.

[0024] In some implementations, the weekly dose of semaglutide injection is selected from 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg (calculated as semaglutide) administered to the subject.

[0025] In some embodiments, the present invention relates to a weight management method.

[0026] In some implementations, this weight management is long-term weight management.

[0027] In some implementations, the weight management is selected from at least one of: weight loss, treatment and / or prevention of obesity, treatment and / or prevention of overweight, and prevention of weight gain.

[0028] In some embodiments, the present invention relates to a method for weight loss.

[0029] In some embodiments, the present invention relates to methods for treating and / or preventing obesity.

[0030] In some embodiments, the present invention relates to methods for treating and / or preventing overweight.

[0031] In some embodiments, the present invention relates to a method for preventing weight gain.

[0032] As used herein, “overweight” means a subject’s BMI of at least 27, including any number between 27 and 30. As used herein, “obese” means a subject’s BMI of at least 30, including any number between 30 and 40. As used herein, “BMI” means a subject’s weight (in kilograms) divided by the square of the subject’s height (in meters); the unit of BMI is kg / m². 2 .

[0033] In some implementations, the method of the present invention provides improved weight loss.

[0034] In some embodiments, the method of the present invention reduces gastrointestinal adverse events in the subjects.

[0035] In some embodiments, the method of the present invention reduces gastrointestinal adverse events, such as nausea, in the subjects.

[0036] In some embodiments, the subject of the method of the present invention is a human being.

[0037] In some embodiments, the subjects of the method of the present invention are adults.

[0038] In some embodiments, the subjects treated according to the method of the invention are obese (e.g., BMI ≥ 30, or as defined herein with respect to the term “obesity”) or overweight (e.g., BMI ≥ 27 and BMI < 30, or as defined herein with respect to the term “overweight”).

[0039] In some embodiments, the subject in the method of the present invention has at least one weight-related comorbidity (such as hypertension, type 2 diabetes, or dyslipidemia).

[0040] In some embodiments, the subject in the method of the present invention has weight gain due to at least one weight-related comorbidity selected from hypertension, type 2 diabetes, dyslipidemia, sleep apnea and urinary incontinence.

[0041] (4) The preparation method of Smegglutide injection includes: under nitrogen protection, dissolving Smegglutide, antibacterial agent, isotonic agent, pH buffer and permeation enhancer in water for injection, adjusting the pH to 7.4±0.1, controlling the dissolved oxygen content to be less than 2ppm before the obtained drug solution is filtered through 0.22μm sterile filter, and using nitrogen headspace replacement during filling.

[0042] In some implementations, 0.5-2.0% (w / v) of trehalose is further included as a stabilizer to inhibit the aggregation of smegglutinin during long-term storage.

[0043] (5) The use of the aforementioned semaglutide composition in the preparation of a medicament for maintaining weight loss and preventing rebound, wherein the use of the medicament includes the following stages: Phase 1: Administer semaglutide preparation according to the dose escalation regimen until the target weight is achieved; Phase 2: After reaching the target weight, the dosing regimen will be adjusted to administer 0.25-1.0 mg of semaglutide every two weeks, or 1.7-2.4 mg of semaglutide every four weeks, to prevent weight rebound.

[0044] In some embodiments, the semaglutide formulation is an injection or oral solution containing the semaglutide composition described in the foregoing scheme.

[0045] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined to obtain specific implementation methods.

[0046] The raw materials or reagents involved in this invention are all commercially available products, and the operations involved are all routine operations in the field unless otherwise specified.

[0047] Beneficial effects According to the present invention, by using a preferred antibacterial agent such as phenol and an isotonic agent such as propylene glycol / mannitol, combined with a phosphate buffer system to stabilize the pH at 7.0-8.0 (preferably 7.4), the stability of semaglutide injection during storage is effectively ensured, reducing the risk of microbial contamination and ensuring that the osmotic pressure is similar to that of body fluids, thus reducing injection discomfort. Clinical trials have shown that subcutaneous injection of the semaglutide injection of the present invention, administered once weekly at low to high doses, produces significant dose-dependent weight loss in obese or overweight subjects, with better results than high-dose liraglutide injection. Simultaneously, the incidence of gastrointestinal adverse events (such as nausea and vomiting) caused by the present invention is relatively low, demonstrating better safety and tolerability. Adding a trace amount of maltose-β-cyclodextrin to the formulation further reduces the incidence of gastrointestinal adverse events, significantly improving patient treatment experience and medication adherence. After achieving the target weight, adjusting the dosing regimen to a low-dose every two weeks or a medium-high-dose every four weeks effectively maintains the weight loss effect and prevents weight rebound, providing a reliable strategy for long-term weight management.

[0048] The present invention adopts the above-mentioned technical solution to achieve the above objectives, which makes up for the shortcomings of the prior art, is reasonably designed, and is easy to operate. Detailed Implementation

[0049] Those skilled in the art can refer to the content of this document and appropriately replace and / or modify the process parameters to achieve the desired results. However, it should be particularly noted that all similar replacements and / or modifications are obvious to those skilled in the art and are considered to be included in this invention. The products and preparation methods described in this invention have been described through preferred examples, and those skilled in the art can obviously modify or appropriately change and combine the products and preparation methods described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0050] Unless otherwise defined, the technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention pertains. This invention uses the methods and materials described herein; however, other suitable methods and materials known in the art may also be used. The materials, methods, and examples described herein are illustrative only and are not intended to be limiting. All publications, patent applications, patent cases, provisional applications, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, the definitions included in this specification shall prevail.

[0051] Unless otherwise stated, all percentages, parts, proportions, etc. are by weight; other statements include, but are not limited to, “%”, “wt%”, “mass%” meaning weight percentage, “mol%” meaning mole percentage, and “vol%” meaning volume percentage.

[0052] When quantities, concentrations, or other numerical values ​​or parameters are given as ranges, preferred ranges, or a series of upper and lower preferred values, it should be understood that they specifically disclose all ranges formed by any pair of values ​​of any larger or preferred range limit and any smaller or preferred range limit, regardless of whether the ranges are disclosed separately. For example, when describing a range of “1 to 5 (1-5)”, the described range should be understood to include ranges such as “1 to 4 (1-4)”, “1 to 3 (1-3)”, “1 to 2 (1-2)”, “1 to 2 (1-2) and 4 to 5 (4-5)”, “1 to 3 (1-3) and 5”, etc. Unless otherwise stated, wherever numerical ranges are described herein, the ranges include the range endpoints as well as all integers and fractions within that range.

[0053] Unless otherwise specified, the materials, methods, and examples described herein are exemplary and not limiting. While similar or equivalent methods and materials can be used to implement or test the invention, suitable methods and materials are described herein.

[0054] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Furthermore, in the absence of conflict, the embodiments and features in the embodiments of this application can be combined with each other.

[0055] The present invention is described in detail below. Example 1: A semaglutide injection is provided, and the dosage and function of each component are shown in Table 1.

[0056] Table 1 - Prescription information for Smegglutinin injection in Example 1 Raw material name Theoretical dosage (35L) Actual usage (35L) effect Smegglutide 112.0g 124.6g Active ingredients Disodium hydrogen phosphate dihydrate 49.7g 49.7g Buffer salt Propylene glycol 490.0g 490.0g isotonic agent phenol 192.5g 192.5g antibacterial agent hydrochloric acid Appropriate amount 1000 mL of 0.1 M hydrochloric acid solution pH adjuster Sodium hydroxide Appropriate amount Unused pH adjuster Water for Injection Up to 35.0L Up to 35.0L solvent Note: The theoretical dosage of smegglutide is the pure amount of the active pharmaceutical ingredient, while the actual dosage is the amount of raw material added. The same applies below.

[0057] The semagrapeptide injection solution of this embodiment is prepared by the following steps: phenol and disodium hydrogen phosphate dihydrate are mixed with water for injection to obtain a concentrated excipient solution; the concentrated phenol and disodium hydrogen phosphate dihydrate solution and propylene glycol are mixed with water for injection to obtain an excipient solution; semagrapeptide (dry and pure) is mixed with water for injection to obtain a concentrated semagrapeptide solution; the concentrated semagrapeptide solution is added to the excipient solution and stirred evenly to obtain a semagrapeptide solution; then hydrochloric acid solution is added to the semagrapeptide solution to adjust the pH to 7.4, the solution is brought to a final volume, and after sterilization filtration, it is filled into 3mL borosilicate glass cartridges, sealed, and the semagrapeptide injection solution is obtained.

[0058] The concentrations of phenol, disodium hydrogen phosphate dihydrate, and propylene glycol in the injection solution were 0.0055 g / mL, 0.00142 g / mL, 0.014 g / mL, 3.2 mg / mL, and 0.1 mol / L, respectively. The entire process was conducted at 18.0–21.0 °C. The semaglutide injection solution underwent visual inspection, with the ambient temperature not exceeding 25 °C. Samples that passed the visual inspection were then loaded into disposable multi-dose pen syringes, boxed, labeled, and stored (at 2–8 °C).

[0059] Example 2: A semaglutide injection is provided, and the dosage and function of each component are shown in Table 2.

[0060] Table 2 - Prescription information for Smegglutinin injection in Example 2 Raw material name Theoretical dosage (35L) Actual usage (35L) effect Smegglutide 79.3g 88.3g Active ingredients Disodium hydrogen phosphate dihydrate 49.7g 49.7g Buffer salt Propylene glycol 490.0g 490.0g isotonic agent phenol 192.5g 192.5g antibacterial agent hydrochloric acid Appropriate amount 1000 mL of 0.1 M hydrochloric acid solution pH adjuster Sodium hydroxide Appropriate amount Unused pH adjuster Water for Injection Up to 35.0L Up to 35.0L solvent The semagrapeptide injection solution of this embodiment is prepared by the following steps: phenol and disodium hydrogen phosphate dihydrate are mixed with water for injection to obtain a concentrated excipient solution; the concentrated phenol and disodium hydrogen phosphate dihydrate solution and propylene glycol are mixed with water for injection to obtain an excipient solution; semagrapeptide (dry and pure) is mixed with water for injection to obtain a concentrated semagrapeptide solution; the concentrated semagrapeptide solution is added to the excipient solution and stirred evenly to obtain a semagrapeptide solution; then hydrochloric acid solution is added to the semagrapeptide solution to adjust the pH to 7.4, the solution is brought to a final volume, and after sterilization filtration, it is filled into 3mL borosilicate glass cartridges, sealed, and the semagrapeptide injection solution is obtained.

[0061] The concentrations of phenol, disodium hydrogen phosphate dihydrate, and propylene glycol in the injection solution were 0.0055 g / mL, 0.00142 g / mL, 0.014 g / mL, 2.27 mg / mL, and 0.1 mol / L, respectively. The entire process was conducted at 18.0–21.0 °C. The semaglutide injection solution underwent visual inspection, with the ambient temperature not exceeding 25 °C. Samples that passed the visual inspection were then loaded into disposable multi-dose pen syringes, boxed, labeled, and stored (at 2–8 °C).

[0062] Example 3: A semaglutide injection is provided, and the dosage and function of each component are shown in Table 3.

[0063] Table 3 - Prescription information for Smegglutinin injection in Example 3 Raw material names Theoretical dosage (35L) Actual usage (35L) effect Smegglutide 46.7g 51.9g Active ingredients Disodium hydrogen phosphate dihydrate 49.7g 49.7g Buffer salt Propylene glycol 490.0g 490.0g isotonic agent phenol 192.5g 192.5g antibacterial agent hydrochloric acid Appropriate amount 1000 mL of 0.1 M hydrochloric acid solution pH adjuster Sodium hydroxide Appropriate amount Unused pH adjuster Water for Injection Up to 35.0L Up to 35.0L solvent The semagrapeptide injection solution of this embodiment is prepared by the following steps: phenol and disodium hydrogen phosphate dihydrate are mixed with water for injection to obtain a concentrated excipient solution; the concentrated phenol and disodium hydrogen phosphate dihydrate solution and propylene glycol are mixed with water for injection to obtain an excipient solution; semagrapeptide (dry and pure) is mixed with water for injection to obtain a concentrated semagrapeptide solution; the concentrated semagrapeptide solution is added to the excipient solution and stirred evenly to obtain a semagrapeptide solution; then hydrochloric acid solution is added to the semagrapeptide solution to adjust the pH to 7.4, the solution is brought to a final volume, and after sterilization filtration, it is filled into 3mL borosilicate glass cartridges, sealed, and the semagrapeptide injection solution is obtained.

[0064] The concentrations of phenol, disodium hydrogen phosphate dihydrate, and propylene glycol in the injection solution were 0.0055 g / mL, 0.00142 g / mL, 0.014 g / mL, 1.33 mg / mL, and 0.1 mol / L, respectively. The entire process was conducted at 18.0–21.0 °C. The semaglutide injection solution underwent visual inspection, with the ambient temperature not exceeding 25 °C. Samples that passed the visual inspection were then loaded into disposable multi-dose pen syringes, boxed, labeled, and stored (at 2–8 °C).

[0065] Example 4: A semaglutide injection is provided, and the dosage and function of each component are shown in Table 4.

[0066] Table 4 - Prescription information for Smegglutinin injection in Example 4 Raw material names Theoretical dosage (35L) Actual usage (35L) effect Smegglutide 46.7g 51.9g Active ingredients Disodium hydrogen phosphate dihydrate 49.7g 49.7g Buffer salt Propylene glycol 490.0g 490.0g isotonic agent phenol 192.5g 192.5g antibacterial agent hydrochloric acid Appropriate amount 1000 mL of 0.1 M hydrochloric acid solution pH adjuster Sodium hydroxide Appropriate amount Unused pH adjuster Water for Injection Up to 35.0L Up to 35.0L solvent The semagrapeptide injection solution of this embodiment is prepared by the following steps: phenol and disodium hydrogen phosphate dihydrate are mixed with water for injection to obtain a concentrated excipient solution; the concentrated phenol and disodium hydrogen phosphate dihydrate solution and propylene glycol are mixed with water for injection to obtain an excipient solution; semagrapeptide (dry and pure) is mixed with water for injection to obtain a concentrated semagrapeptide solution; the concentrated semagrapeptide solution is added to the excipient solution and stirred evenly to obtain a semagrapeptide solution; then hydrochloric acid solution is added to the semagrapeptide solution to adjust the pH to 7.4, the solution is brought to a final volume, and after sterilization filtration, it is filled into 3mL borosilicate glass cartridges, sealed, and the semagrapeptide injection solution is obtained.

[0067] The concentrations of phenol, disodium hydrogen phosphate dihydrate, and propylene glycol in the injection solution were 0.0055 g / mL, 0.00142 g / mL, 0.014 g / mL, 1.33 mg / mL, and 0.1 mol / L, respectively. The entire process was conducted at 18.0–21.0 °C. The semaglutide injection solution underwent visual inspection, with the ambient temperature not exceeding 25 °C. Samples that passed the visual inspection were then loaded into disposable multi-dose pen syringes, boxed, labeled, and stored (at 2–8 °C).

[0068] Example 5: A semaglutide injection is provided, and the dosage and function of each component are shown in Table 5.

[0069] Table 5 - Prescription information for Smegglutinin injection in Example 5 Raw material names Theoretical dosage (35L) Actual usage (35L) effect Smegglutide 23.3g 26.0g Active ingredients Disodium hydrogen phosphate dihydrate 49.7g 49.7g Buffer salt Propylene glycol 490.0g 490.0g isotonic agent phenol 192.5g 192.5g antibacterial agent hydrochloric acid Appropriate amount 1000 mL of 0.1 M hydrochloric acid solution pH adjuster Sodium hydroxide Appropriate amount Unused pH adjuster Water for Injection Up to 35.0L Up to 35.0L solvent The semagrapeptide injection solution of this embodiment is prepared by the following steps: phenol and disodium hydrogen phosphate dihydrate are mixed with water for injection to obtain a concentrated excipient solution; the concentrated phenol and disodium hydrogen phosphate dihydrate solution and propylene glycol are mixed with water for injection to obtain an excipient solution; semagrapeptide (dry and pure) is mixed with water for injection to obtain a concentrated semagrapeptide solution; the concentrated semagrapeptide solution is added to the excipient solution and stirred evenly to obtain a semagrapeptide solution; then hydrochloric acid solution is added to the semagrapeptide solution to adjust the pH to 7.4, the solution is brought to a final volume, and after sterilization filtration, it is filled into 3mL borosilicate glass cartridges, sealed, and the semagrapeptide injection solution is obtained. The concentrations of phenol, disodium hydrogen phosphate dihydrate, and propylene glycol in the injection solution were 0.0055 g / mL, 0.00142 g / mL, 0.014 g / mL, 0.67 mg / mL, and 0.1 mol / L, respectively. The entire process was conducted at 18.0–21.0 °C. The semaglutide injection solution underwent visual inspection, with the ambient temperature not exceeding 25 °C. Samples that passed the visual inspection were then loaded into disposable multi-dose pen syringes, boxed, labeled, and stored (at 2–8 °C).

[0070] Example 6: A semaglutide injection is provided, and the dosage and function of each component are shown in Table 6.

[0071] Table 6 - Prescription information for Smegglutinin injection in Example 6 Raw material names Theoretical dosage (35L) Actual usage (35L) effect Smegglutide 46.7g 51.9g Active ingredients Disodium hydrogen phosphate dihydrate 49.7g 49.7g Buffer salt Propylene glycol 490.0g 490.0g isotonic agent phenol 192.5g 192.5g antibacterial agent Maltodextrin 3.5g 3.5g regulator hydrochloric acid Appropriate amount 1000 mL of 0.1 M hydrochloric acid solution pH adjuster Sodium hydroxide Appropriate amount Unused pH adjuster Water for Injection Up to 35.0L Up to 35.0L solvent The semagrapeptide injection solution of this embodiment is prepared by the following steps: phenol and disodium hydrogen phosphate dihydrate are mixed with water for injection to obtain a concentrated excipient solution; the concentrated phenol and disodium hydrogen phosphate dihydrate solution, propylene glycol, maltodextrin, and water for injection are mixed to obtain an excipient solution; semagrapeptide (dry and pure) is mixed with water for injection to obtain a concentrated semagrapeptide solution; the concentrated semagrapeptide solution is added to the excipient solution and stirred evenly to obtain a semagrapeptide solution; then hydrochloric acid solution is added to the semagrapeptide solution to adjust the pH to 7.4, the volume is adjusted, and after sterilization filtration, it is filled into 3mL borosilicate glass cartridges, sealed, and the semagrapeptide injection solution is obtained. The concentrations of phenol, disodium hydrogen phosphate dihydrate, propylene glycol, maltose-β-cyclodextrin, and semaglutide in the injection solution were 0.0055 g / mL, 0.00142 g / mL, 0.014 g / mL, and 0.1 mg / mL, respectively. The concentration of semaglutide in the injection solution was 1.33 mg / mL, and the concentration of hydrochloric acid solution was 0.1 mol / L. The entire process was carried out at 18.0–21.0℃. The semaglutide injection solution underwent visual inspection, with the ambient temperature not exceeding 25℃. Samples that passed the visual inspection were then loaded into disposable multi-dose pen syringes, boxed, labeled, and stored (at 2–8℃).

[0072] Example 7: A semaglutide injection is provided, and the dosage and function of each component are shown in Table 6.

[0073] Table 7 - Prescription information for Smegglutinin injection in Example 7 Raw material names Theoretical dosage (35L) Actual usage (35L) effect Smegglutide 46.7g 51.9g Active ingredients Disodium hydrogen phosphate dihydrate 49.7g 49.7g Buffer salt Propylene glycol 490.0g 490.0g isotonic agent phenol 192.5g 192.5g antibacterial agent Maltodextrin 8.75g 8.75g regulator hydrochloric acid Appropriate amount 1000 mL of 0.1 M hydrochloric acid solution pH adjuster Sodium hydroxide Appropriate amount Unused pH adjuster Water for Injection Up to 35.0L Up to 35.0L solvent The semagrapeptide injection solution of this embodiment is prepared by the following steps: phenol and disodium hydrogen phosphate dihydrate are mixed with water for injection to obtain a concentrated excipient solution; the concentrated phenol and disodium hydrogen phosphate dihydrate solution, propylene glycol, maltodextrin, and water for injection are mixed to obtain an excipient solution; semagrapeptide (dry and pure) is mixed with water for injection to obtain a concentrated semagrapeptide solution; the concentrated semagrapeptide solution is added to the excipient solution and stirred evenly to obtain a semagrapeptide solution; then hydrochloric acid solution is added to the semagrapeptide solution to adjust the pH to 7.4, the volume is adjusted, and after sterilization filtration, it is filled into 3mL borosilicate glass cartridges, sealed, and the semagrapeptide injection solution is obtained. The concentrations of phenol, disodium hydrogen phosphate dihydrate, propylene glycol, maltose-β-cyclodextrin, and semaglutide in the injection solution were 0.0055 g / mL, 0.00142 g / mL, 0.014 g / mL, and 0.25 mg / mL, respectively. The concentration of semaglutide in the injection solution was 1.33 mg / mL, and the concentration of hydrochloric acid solution was 0.1 mol / L. The entire process was carried out at 18.0–21.0℃. The semaglutide injection solution underwent visual inspection, with the ambient temperature not exceeding 25℃. Samples that passed the visual inspection were then loaded into disposable multi-dose pen syringes, boxed, labeled, and stored (at 2–8℃).

[0074] Example 8: A semaglutide injection is provided, and the dosage and function of each component are shown in Table 8.

[0075] Table 8 - Prescription information for Smegglutinin injection in Example 8 Raw material names Theoretical dosage (35L) Actual usage (35L) effect Smegglutide 79.3g 88.3g Active ingredients Disodium hydrogen phosphate dihydrate 49.7g 49.7g Buffer salt Propylene glycol 490.0g 490.0g isotonic agent phenol 192.5g 192.5g antibacterial agent Maltodextrin 17.5g 17.5g regulator hydrochloric acid Appropriate amount 1000 mL of 0.1 M hydrochloric acid solution pH adjuster Sodium hydroxide Appropriate amount Unused pH adjuster Water for Injection Up to 35.0L Up to 35.0L solvent The semagrapeptide injection solution of this embodiment is prepared by the following steps: phenol and disodium hydrogen phosphate dihydrate are mixed with water for injection to obtain a concentrated excipient solution; the concentrated phenol and disodium hydrogen phosphate dihydrate solution, propylene glycol, maltodextrin, and water for injection are mixed to obtain an excipient solution; semagrapeptide (dry and pure) is mixed with water for injection to obtain a concentrated semagrapeptide solution; the concentrated semagrapeptide solution is added to the excipient solution and stirred evenly to obtain a semagrapeptide solution; then hydrochloric acid solution is added to the semagrapeptide solution to adjust the pH to 7.4, the volume is adjusted, and after sterilization filtration, it is filled into 3mL borosilicate glass cartridges, sealed, and the semagrapeptide injection solution is obtained. The concentrations of phenol, disodium hydrogen phosphate dihydrate, propylene glycol, and maltose-β-cyclodextrin in the injection solution were 0.0055 g / mL, 0.00142 g / mL, 0.014 g / mL, and 0.5 mg / mL, respectively. The concentration of semaglutide in the injection solution was 2.27 mg / mL, and the concentration of hydrochloric acid solution was 0.1 mol / L. The entire process was carried out at 18.0–21.0℃. The semaglutide injection solution underwent visual inspection, with the ambient temperature not exceeding 25℃. Samples that passed the visual inspection were then loaded into disposable multi-dose pen syringes, boxed, labeled, and stored (at 2–8℃).

[0076] Experimental Example 1: A clinical trial was conducted to evaluate and compare the dose-response of five weekly doses of semaglutide injection versus liraglutide 3.0 mg once daily in obese subjects without diabetes for 44 weeks in inducing and maintaining weight loss. The trial was designed as a 44-week randomized, double-blind, experimental, parallel-group, multicenter trial comparing subcutaneous administration of semaglutide injection once weekly at five different doses (using Examples 1 through 8, ranging from 0.25 mg / week to 2.4 mg / week) in obese subjects without diabetes. Liraglutide 3.0 mg / day was included as an activity comparator. The trial was double-blind between aggressive treatment and placebo treatment. To ensure a sufficient male sample, the trial population was not allowed to contain more than 60% females, and randomization was stratified by sex.

[0077] The primary endpoint was the relative change in body weight (%) from baseline at 44 weeks. Key secondary endpoints included the proportion of participants who had lost 5% or 10% of their baseline weight at 44 weeks, and the change in waist circumference from baseline to 44 weeks. Supportive secondary safety endpoints also included gastrointestinal adverse events (i.e., nausea, vomiting, diarrhea, and constipation). During each field visit, individual participants were asked open-ended questions about any medical problems they had experienced since their last visit. All medical problems observed by field staff or participants were reported as adverse events, and researchers assessed the severity and causality of these adverse events. For this trial, participants received field visits every 2 weeks for the first 20 weeks and then every 4 weeks thereafter.

[0078] The treatment group includes: (A) Smegglutide injection, with randomized target doses of 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg (the starting dose is 0.25 mg, and the dose is increased every four weeks, with 2.4 mg being the maximum dose); (B) Liraglutide 3.0 mg (starting dose is 0.6 mg, increasing to 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.8 mg, 2.4 mg, and 3.0 mg every two weeks, with 3.0 mg as the maximum dose).

[0079] All medications were administered subcutaneously. From the start of randomization visits, all participants in the treatment group received monthly nutritional counseling and calorie-reduced diets from a dietitian or equivalent qualified individual, as well as physical activity counseling from a qualified individual. The trial population, totaling 588 participants, was randomized. A total of 506 participants (86%) completed 44 weeks of treatment; 82 participants (14%) discontinued treatment early without a significant dose-dependent trend.

[0080] The key inclusion criteria for this trial were: male or female, aged ≥18 years at the time of signing the informed consent form; and a body mass index (BMI) ≥28 kg / m² at the time of screening. 2 The weight change was ≤5% in the 90 days prior to screening, controlled solely by diet and exercise.

[0081] The key exclusion criteria for this trial are: HbA1c ≥ 6.5% or fasting venous blood glucose ≥ 7.0 mmol / L at the time of screening, or a history of diagnosis of type 1, type 2, or a special type of diabetes; treatment with GLP-1 receptor agonists (single-target, dual-target, or multi-target) within 90 days prior to screening; obesity caused by medication or disease (e.g., Cushing's syndrome, acromegaly); or weight gain caused by non-fat content increases (e.g., edema); and treatment with other medications, products, or therapies that the investigator deems will affect the efficacy assessment of weight loss within 90 days prior to screening, including but not limited to medications, products, or therapies whose indications in the product information include overweight / obesity or equivalent meanings, and weight loss medications, products, or therapies that reduce weight. Contraindications include: use of sugar-containing medications, tricyclic antidepressants, antipsychotics, or antiepileptics (such as sodium valproate, citalopram, etc.), and systemic glucocorticoids; prior bariatric surgery (excluding those who have undergone liposuction, abdominoplasty, removal of a gastric balloon, or removal of a duodenojejunostomy tube more than 1 year ago), or planned to undergo any surgical treatment during the trial that may affect weight and efficacy assessment; prior allergy or suspected allergy to GLP-1 receptor agonists, or prior allergy to any component of the investigational drug; participation in any other trial and receiving at least one treatment within 90 days prior to screening; unstable or uncontrolled thyroid function within 90 days prior to screening, or TSH > 6.0 at screening. mIU / L or <0.4 mIU / L; a history or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN-2) prior to screening; diagnosis of malignant tumor within 5 years prior to screening (excluding cured basal cell carcinoma of the skin or cervical carcinoma in situ); any of the following major cardiovascular or cerebrovascular diseases within 180 days prior to screening: myocardial infarction, coronary angioplasty or bypass surgery, valvular heart disease or valvular repair surgery, clinically significant arrhythmias requiring treatment, unstable angina, decompensated heart failure (NYHA class III or IV), transient ischemic attack, cerebrovascular accident, etc.; severe gastrointestinal problems prior to or at the time of screening. Diseases (e.g., abnormal gastric emptying, inflammatory bowel disease); moderate to severe depression at the time of screening, or a total score of PHQ-9 ≥15 at the time of screening; or a history of other serious mental illnesses (e.g., schizophrenia, bipolar disorder); or a history of suicidal tendencies, suicide attempts, or suicidal behavior; any of the following conditions must be present before or at the time of screening: chronic pancreatitis, acute pancreatitis, symptomatic gallbladder disease (excluding cholecystectomy); any of the following conditions must be met at the time of screening: (1) systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg; (2) QTcF interval on electrocardiogram >450 ms for males or >470 ms for females; (3) eGFR <30 mL / min / 1.73 m 2eGFR is calculated according to the CKD-EPI formula; (4) ALT or AST > 3 × upper limit of normal value; (5) Serum amylase or serum lipase > 1.5 × upper limit of normal value; (6) Serum triglycerides > 5.7 mmol / L; (7) Calcitonin ≥ 50 ng / L (pg / mL); (8) HIV antibody or HCV antibody or HBsAg positive (except for those who are HBsAg positive but whose hepatitis B virus DNA quantitative test result is not higher than the upper limit of the test reference range and who did not use anti-hepatitis B virus drugs at the time of screening); history of drug abuse, drug use or alcohol dependence; total blood donation ≥ 400 mL or single blood loss ≥ 400 mL within 90 days before screening; female subjects with fertility are pregnant or lactating at the time of screening, or have positive serum HCG; or male or female subjects with fertility and their partners cannot take effective contraceptive measures during the trial and within 3 months after the end of treatment; other situations in which the researchers consider unsuitable to participate in this study.

[0082] Statistical analysis of the outcome endpoint: Table 9 shows the baseline characteristics of the subjects' weight and body mass index (BMI). The results are shown in Tables 10 and 11 of this paper.

[0083] Table 9 - Baseline characteristics of subjects in each treatment group, expressed as mean (SD).

[0084] N: Number of subjects who completed treatment; Lira: Liraglutide injection; Smegglutide: Smegglutide injection; SD: Standard deviation.

[0085] Table 10 - Weight change (%) and treatment differences from baseline to week 44 in the treatment group

[0086] N: Number of subjects who completed treatment; Lira: Liraglutide injection; Smegglutide: Smegglutide injection; SD: Standard deviation; Subjects who completed treatment: Subjects who completed treatment until the end of the trial.

[0087] The results in Table 10 show that the effect of semaglutide injection on weight loss was continuously improved by increasing the dose from a low dose of 0.25 mg to a high dose of 2.4 mg once a week, and the improvement was significantly due to the high dose of liraglutide injection.

[0088] Table 11 - Summary of gastrointestinal adverse events in subjects who completed treatment

[0089] N: Number of subjects who completed treatment; Lira: Liraglutide injection; Smegglutide: Smegglutide injection; N1: Number of subjects who experienced at least one event; %: Percentage of subjects who had at least one event.

[0090] The results in Table 11 show that the weight loss effect of semaglutide injection was continuously improved with a high dose, escalated from 0.25 mg to 2.4 mg once weekly. The increase in gastrointestinal adverse events was relatively low at high doses, 11.2 percentage points lower than with liraglutide injection. In summary, these results indicate that semaglutide injection for weight management, administered from low to high doses, leads to superior weight loss and a lower rate of gastrointestinal adverse events due to this favorable ratio between weight loss and gastrointestinal adverse events. More surprisingly, the highest weekly dose of 2.4 mg semaglutide injection outperformed once-daily 3.0 mg liraglutide injection.

[0091] Furthermore, Table 11 shows that in Examples 6-8, the addition of trace amounts of maltodextrin to semaglutide injection significantly reduced the incidence of gastrointestinal adverse events compared to the absence of maltodextrin, decreasing it from 57.3% to 44.8%. This resulted in an overall reduction in the incidence of gastrointestinal adverse events caused by semaglutide injection, indicating that the addition of trace amounts of maltodextrin to semaglutide injection is beneficial in reducing the occurrence of gastrointestinal adverse events, thereby helping to improve patient acceptance.

[0092] Experimental Example 2: Continuing the clinical trial from Example 1, the following groups received different treatments: Example 1 group discontinued medication; Example 2 group received 0.25 mg semaglutide injection every two weeks; Example 3 group received 1.0 mg semaglutide injection every two weeks; Example 4 group received 1.5 mg semaglutide injection every four weeks; Example 5 group received 2.4 mg semaglutide injection every four weeks; and the liraglutide injection group consisted of 35 randomly selected participants who received 1.0 mg liraglutide injection every two weeks, with all other conditions identical to Example 1. After 12 weeks, it was found that Example 1 group experienced significant weight rebound due to medication discontinuation (at least 10 participants gained at least 3 kg), while no significant rebound was observed in Examples 2-5 (no participants gained more than 1 kg). The liraglutide injection group experienced varying degrees of weight rebound (at least 10 participants gained at least 2 kg). This indicates that reducing the dosage of semaglutide after reaching the target weight can effectively prevent weight rebound, while reducing the dosage of liraglutide cannot effectively prevent weight rebound, providing insights for long-term weight management.

[0093] The conventional techniques described in the above embodiments are existing technologies known to those skilled in the art, and therefore will not be described in detail here.

[0094] The specific embodiments described herein are merely illustrative of the spirit of the invention. Those skilled in the art to which this invention pertains may make various modifications or additions to the described specific embodiments or use similar methods to substitute them, without departing from the spirit of the invention or exceeding the scope defined by the appended claims.

[0095] Although the present invention has been described in detail and specific embodiments have been cited, it will be apparent to those skilled in the art that various changes or modifications can be made without departing from the spirit and scope of the invention.

[0096] While the foregoing detailed descriptions have shown, described, and pointed out novel features applicable to various embodiments, it should be understood that various omissions, substitutions, and changes may be made to the form and details of the described apparatus or methods without departing from the spirit of this disclosure. Furthermore, the various features and methods described above may be used independently of each other or may be combined in various ways. All possible combinations and sub-combinations are intended to fall within the scope of this disclosure. Many of the foregoing embodiments include similar components, and therefore, these similar components are interchangeable in different embodiments. Although the invention has been disclosed in the context of certain embodiments and examples, those skilled in the art will understand that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and / or applications, as well as their obvious modifications and equivalents. Therefore, the invention is not intended to be limited to the specific disclosure of the preferred embodiments herein.

[0097] All matters not covered in this invention are common knowledge.

Claims

1. A smegglutinin composition, characterized in that, include: Active ingredient: Smeglucopyranoside; The excipient solution is prepared by dissolving antibacterial agents, pH buffers, and isotonic agents in water for injection. The antibacterial agent is at least one of phenol, benzyl alcohol, and m-cresol; The pH buffer is at least one of disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate, and sodium phosphate; The isotonic agent is at least one of propylene glycol and mannitol.

2. The smegglutinin composition according to claim 1, characterized in that: It also includes a pH adjuster that adjusts the pH to 7.0-8.

0.

3. The smegglutinin composition according to claim 1, characterized in that: It also includes a regulator, which is maltodextrin, at a concentration of 0.1-0.5 mg / mL.

4. Use of the smegglutinin composition according to any one of claims 1-3 in the preparation of formulations having body shaping and / or weight management effects.

5. The use according to claim 4, characterized in that: The preparation is an injection and / or an oral solution.

6. The use according to claim 4, characterized in that: The weight management is selected from at least one of weight loss, treatment and / or prevention of obesity, treatment and / or prevention of overweight, and prevention of weight gain.

7. The use according to any one of claims 4-6, characterized in that: Administer 0.25-2.4 mg weekly, based on the weight of smegglutide.

8. The use according to any one of claims 4-6, characterized in that: The weight management refers to weight gain caused by at least one weight-related comorbidity, such as hypertension, type 2 diabetes, dyslipidemia, sleep apnea, and urinary incontinence.

9. A semaglutide injection for drug therapy, characterized in that, Includes the composition according to any one of claims 1-3.

10. Use of the semaglutide composition according to any one of claims 1-3 in the preparation of a medicament for maintaining weight loss and preventing rebound, characterized in that, The use of the drug includes the following stages: Phase 1: Administer the semaglutide composition according to any one of claims 1-3 weekly at a dose escalation rate of 0.25-2.4 mg semaglutide until the target weight is achieved; Phase 2: After reaching the target weight, the dosing regimen will be adjusted to 0.25-1.0 mg semaglutide every two weeks, or 1.7-2.4 mg semaglutide every four weeks, to prevent weight rebound.

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