Sustained-release pharmaceutical composition

Abstract

Provided are a sustained-release pharmaceutical composition of a GLP-1 receptor agonist and a preparation method therefor. The composition contains 0.05 wt% to 0.5 wt% of an active ingredient, 45 wt% to 85 wt% of a sustained-release agent, and 15 wt% to 55 wt% of a viscosity-reducing agent, or contains 0.05 wt% to 0.5 wt% of an active ingredient, and 45 wt% to 99.95 wt% of a thermal sensitive sustained-release agent, wherein the active ingredient is a GLP-1 receptor agonist, the sustained-release agent is a polyorthoester, and the viscosity-reducing agent is preferably a glyceryl ester compound. Further provided are a drug-medical device combination product containing the sustained-release pharmaceutical composition, wherein the drug is the above-described sustained-release drug, and the medical device is a jet microneedle capable of injecting high-viscosity substances, and the use of the composition in the treatment of metabolism-related diseases. The sustained-release pharmaceutical composition has significantly improved pharmacokinetic characteristics, can realize long-acting administration, improves patient compliance, and exhibits good effects in improving blood glucose control, promoting weight loss, improving blood lipid levels, etc.

Description

Sustained-release drug composition

[0001] This application claims priority to Chinese patent application 202510012854.X, filed on January 3, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of biomedical technology, specifically to sustained-release pharmaceutical compositions and their applications. Background Technology

[0003] Glucagon-like peptide-1 (GLP-1) receptor agonists are an important class of drugs used to treat type 2 diabetes and obesity. These drugs mimic the action of endogenous GLP-1 in the body, stimulating insulin secretion in a glucose-dependent manner while inhibiting glucagon release, thus effectively controlling blood sugar levels. Furthermore, GLP-1 receptor agonists also promote satiety and reduce appetite, thus showing significant effects in weight management.

[0004] However, natural GLP-1 has an extremely short half-life in vivo, only 1-2 minutes, mainly due to its rapid degradation by dipeptidyl peptidase IV (DPP-4). To overcome this limitation, researchers have developed various strategies to prolong the duration of action of GLP-1 receptor agonists, including amino acid sequence optimization, fatty acid modification, and the development of long-acting formulations.

[0005] Currently, there are several GLP-1 receptor agonists available on the market, such as liraglutide, exenatide, and smegglutide. These drugs have shown good blood sugar lowering and weight management effects in clinical practice. However, existing GLP-1 receptor agonists still have some limitations, such as high dosing frequency and poor patient compliance.

[0006] In addition, existing GLP-1 receptor agonists have shown significant effects in improving glycemic control and promoting weight loss, but their potential role in improving blood lipid levels and reducing the risk of cardiovascular disease still needs further research and exploration.

[0007] In conclusion, developing novel long-acting formulations of GLP-1 receptor agonists to improve therapeutic efficacy and patient compliance, while exploring their wide application in the treatment of metabolic-related diseases, has significant clinical implications and research value.

[0008] The background description is provided for the purpose of understanding the relevant technologies in this field and is not intended as an admission of prior art. Summary of the Invention

[0009] The purpose of this invention is to provide a sustained-release pharmaceutical composition of a GLP-1 receptor agonist, its preparation method, and its application, in order to solve the problems of high dosing frequency and poor patient compliance of existing GLP-1 receptor agonists.

[0010] To achieve the above objectives, the present invention provides a sustained-release pharmaceutical composition comprising 0.05% to 0.5% by weight of an active ingredient, 45% to 85% by weight of a sustained-release agent, and 15% to 55% by weight of a viscosity reducer. The active ingredient is a GLP-1 receptor agonist, preferably at least one selected from smegglutide, liraglutide, dulaglutide, benaglutide, exenatide, lixenatide, and polyethylene glycol loxenatide. The sustained-release agent is preferably a polyorthoester polymer, more preferably a polyorthoester, and the viscosity reducer is preferably composed of triacetin.

[0011] The present invention also provides a sustained-release pharmaceutical composition comprising 0.05% to 0.5% by weight of an active ingredient and 45% to 99.95% by weight of a thermosensitive sustained-release agent. The active ingredient is a GLP-1 receptor agonist, preferably at least one selected from smegglutide, liraglutide, dulaglutide, benaglutide, exenatide, lixisenatide, and polyethylene glycol loxenatide. The thermosensitive sustained-release agent comprises or is selected from at least one of the following: polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO) (poloxam 407), lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA).

[0012] The present invention also provides a method for preparing the above-mentioned sustained-release pharmaceutical composition. The method includes mixing a GLP-1 receptor agonist active pharmaceutical ingredient with a solution containing a sustained-release agent and a viscosity reducer; or dissolving the GLP-1 receptor agonist active pharmaceutical ingredient in a solvent, then mixing it with a sustained-release agent and a viscosity reducer, and then removing all or part of the solvent. Preferably, the mixing and solvent removal are carried out at a temperature of 50 to 80°C.

[0013] Furthermore, the present invention also provides a pharmaceutical device combination product, comprising a fluid delivery device and the aforementioned sustained-release drug composition. The fluid delivery device includes a tube for containing the sustained-release drug composition, an injection head detachably connected to or integrally formed with the tube, and a power mechanism for applying a delivery force to deliver the sustained-release drug composition. The injection head includes one or more needle elements, the orifice of which is preferably in the range of 0.1 mm to 1 mm, and the length of which is preferably in the range of 1 mm to 10 mm.

[0014] The sustained-release pharmaceutical composition or pharmaceutical device combination product of the present invention can be used to treat a variety of diseases, including obesity or overweight, diabetes, cardiovascular disease, Alzheimer's disease, non-alcoholic steatohepatitis, etc. Preferably, the dose of the active ingredient in a single standard injection dose of the drug is 3 to 25 times the dose of smegglutide in conventional smegglutide drugs.

[0015] In terms of pharmacokinetics, the drug of the present invention exhibits significantly improved characteristics after a single dose, including prolonged tmax, increased Cmax and AUC0-t, prolonged MRT and t1 / 2, increased Vz / F, and decreased CL / F. These characteristics enable the drug to achieve long-acting administration and significantly prolong the dosing interval.

[0016] Regarding therapeutic effects, when the drug of the present invention is used to treat obesity or overweight, it can achieve a significant reduction in individual body weight relative to initial body weight within 4 weeks after the start of administration, preferably a reduction of more than 2%. When used to treat diabetes, it can achieve a significant improvement in blood glucose levels within 15 days after the start of administration, including improved GTT results, reduced fasting blood glucose, and improved glucose tolerance. When used to improve cardiovascular metabolic indicators, it can achieve a significant improvement in blood lipid levels within 15 days after the start of administration, including reduced ALT activity and reduced pathological changes in liver tissue.

[0017] It is worth noting that when used for human administration, the sustained-release pharmaceutical composition of the present invention can have a dosing period of 10 to 90 days and a release time of the active ingredient of 10 to 90 days, which greatly improves patient compliance.

[0018] In summary, the sustained-release pharmaceutical composition of the present invention, through optimized formulation and preparation method, achieves long-acting sustained release of GLP-1 receptor agonists, significantly extending the dosing interval and improving patient compliance. Simultaneously, this composition exhibits excellent effects in improving glycemic control, promoting weight loss, and improving blood lipid levels, providing a new option for the treatment of metabolic-related diseases.

[0019] Other optional features and technical effects of the embodiments of the present invention are partly described below and partly apparent from reading this document. Attached Figure Description

[0020] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The elements shown are not limited to the scale shown in the drawings, and the same or similar reference numerals in the drawings denote the same or similar elements, wherein:

[0021] Figure 1A shows a schematic structural diagram of a fluid delivery device according to an embodiment of the present invention;

[0022] Figure 1B shows a schematic arrangement of needle components in a fluid delivery device according to an embodiment of the present invention;

[0023] Figures 2A to 2E show schematic structural diagrams of fluid delivery devices according to different embodiments of the present invention;

[0024] Figure 3 shows the curves of food intake changes in each group of rats in Example 10;

[0025] Figure 4 shows the percentage curves of weight change in each group of rats in Example 10;

[0026] Figure 5 shows the average levels of smegglutinin in the plasma of rats in each group in Example 10;

[0027] Figure 6 shows the changes in blood glucose levels in each group of rats during the glucose tolerance test (GTT) in Example 10;

[0028] Figure 7 shows the blood biochemical data of rats in each group in Example 10; and

[0029] Figure 8 shows HE staining images of rat liver tissue from each group in Example 10 (×200). Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings. Here, the illustrative embodiments and descriptions of this invention are used to explain the invention, but are not intended to limit the invention.

[0031] The term "comprising" and its variations as used herein signify open inclusion, i.e., "including but not limited to". Unless otherwise stated, the term "or" means "and / or". The term "based on" means "at least partially based on". The terms "one example embodiment" and "one embodiment" mean "at least one example embodiment". The term "another embodiment" means "at least one additional embodiment". The terms "first", "second", etc., may refer to different or the same objects. Other explicit and implicit definitions may also be included below.

[0032] Where numerical ranges are provided herein, it is meant that every intermediate value between the upper and lower limits of that range, and any other specified or intermediate value within that range, is included in the disclosure. For example, if a range of 10 to 20 weight percentages (wt%), i.e., 11, 12, 13, 14, 15, 16, 17, 18, and 19 wt%, is indicated, as well as a range of values ​​greater than or equal to 10 wt% up to about 20 wt% and a range of values ​​less than or equal to 20 wt% down to about 10 wt%, these are also explicitly disclosed.

[0033] The term “basically” means to a great extent or close to complete with respect to a feature or entity, that is, 85% or more.

[0034] The term “about,” especially when modifying a quantity, means a deviation of plus or minus 1%, 5%, 10%, 15%, or 20%.

[0035] The terms “preferred,” “preferred,” “optional,” or “optionally” mean that the situation described below may or may not occur, such that the description includes both the occurrence and non-occurrence of such situation.

[0036] In describing the differences in statistical experimental data, results, or parameters with test data, results, or parameters in this invention, expressions such as 'increase,' 'improvement,' 'increase,' 'prolongation,' 'decrease,' 'reduction,' 'significant,' 'significantly increased,' 'significantly improved,' 'significantly increased,' 'significantly prolonged,' 'significantly decreased,' and 'significantly reduced' refer to statistically significant differences (p<0.05). The data, results, or parameters involved in these expressions include, but are not limited to, pharmacokinetic parameters in drug testing, including time to peak plasma concentration (tmax), peak plasma concentration (Cmax), area under the curve (AUC0-last), and half-life (t). 1 / 2 The results of various indicators in the treatment effect evaluation include weight measurement, blood glucose test values ​​(including overall blood glucose level, glucose tolerance test results, fasting blood glucose value, glucose tolerance test results, area under the blood glucose curve (AUC)), blood lipid test values ​​(including overall blood lipid level, triglyceride level) and liver function test values ​​(including alanine aminotransferase activity).

[0037] definition

[0038] In this context, the “molecular weight” of a polymer (such as a polyorthoester) refers to the nominal average molecular weight of the polymer, typically determined by size exclusion chromatography, light scattering techniques, or sedimentation rate methods. Molecular weight can be expressed as number-average molecular weight or weight-average molecular weight. Unless otherwise stated, all molecular weights mentioned herein are exponential-average molecular weights. Both number-average and weight-average molecular weights can be determined using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values ​​can also be used to determine the number-average molecular weight, such as colligative measurements (e.g., freezing point depression, boiling point elevation, or osmotic pressure), or to determine the weight-average molecular weight using light scattering techniques, ultracentrifugation, or viscosity measurements.

[0039] In this document, "active agent" or "active ingredient" means any compound or mixture of compounds that produces a beneficial or useful result. Generally, "active agent" or "medicine" means any organic or inorganic compound or substance that is biologically active and suitable or intended for therapeutic purposes. As used herein, reference to a medicine, and to other chemical compounds mentioned herein, means including any pharmaceutically acceptable salt form of the compound, including isomers of applicable compounds of the present invention such as diastereomers and enantiomers, salts, solvates, polymorphs, specific crystalline forms, and racemic mixtures and pure isomers. An active agent is distinct from components such as carriers, diluents, lubricants, binders, and other formulation aids, encapsulations, or other protective ingredients. An example of an active agent is a medicine. Suitable pharmaceutical agents include locally or systemically acting active pharmaceutical agents that can be administered to a subject by injection, such as subcutaneous, intradermal, intramuscular, intraocular, or intra-articular injection, locally or intralesional (e.g., applied to abrasions, lacerations, puncture wounds, etc., and into surgical wounds or incisions). Prodrugs of active pharmaceutical ingredients and pharmaceutically acceptable salts are also included within the scope of this application.

[0040] In this article, "pharmaceutically acceptable salt" means a salt form of a drug having at least one suitable salt-forming group that does not cause significant adverse toxicological effects on patients.

[0041] In this paper, "biodegradable" refers to the degradation, decomposition, or digestion of polymers through biological environmental processes, including those of living organisms, particularly at physiological pH and temperature. As an example, the primary mechanism of polyorthoester biodegradation is the hydrolysis of bonds between and within polyorthoester units.

[0042] In this article, "polyorthoester compatibility" refers to an excipient property that, in a specific aspect of polyorthoester properties, forms a single phase when mixed with polyorthoester without causing any chemical change in the polyorthoester.

[0043] In this article, “treatment” for a disease or condition includes preventing the disease or condition from occurring in a person or animal who may be predisposed to having the disease or condition but has not yet experienced or shown symptoms of the disease or condition (preventive treatment), suppressing the disease or condition (slowing down or stopping its development), providing relief from the symptoms or side effects of the disease or condition, and alleviating the disease or condition.

[0044] In this article, "therapeutic effective amount" means the amount that is sufficient to effectively treat a disease or condition when administered to a human or animal. In this article, "standard dose" means the dose specified in the package insert of a marketed drug when administered to a human or animal to treat a disease; if the package insert specifies multiple doses or a range, then it is the maximum dose.

[0045] Currently, while GLP-1 receptor agonists (such as pre-filled smegglutide formulations) have shown good blood sugar lowering and weight loss effects in clinical practice, the high frequency of administration leads to poor patient compliance. Although there have been attempts to prolong the duration of action of GLP-1 receptor agonists through various strategies, the effectiveness still needs to be improved.

[0046] The inventors have discovered that by combining GLP-1 receptor agonists with specific sustained-release agents and viscosity reducers, not only can the duration of drug action be significantly prolonged, but the formulation can also be guaranteed to have suitable injection properties, thereby improving patient compliance.

[0047] Accordingly, embodiments of the present invention provide a sustained-release pharmaceutical composition comprising a GLP-1 receptor agonist, a polyorthoester sustained-release agent, and a viscosity reducer. Embodiments of the present invention also provide a fluid delivery device for delivering the composition, and a pharmaceutical device combination product comprising the composition and the fluid delivery device. Embodiments of the present invention further provide the use of the above composition in the preparation of drugs for treating metabolic diseases such as diabetes, obesity, and cardiovascular diseases, wherein long-acting administration is achieved through optimized dosing regimens. Embodiments of the present invention also provide the use of polyorthoesters in the preparation of sustained-release formulations of GLP-1 receptor agonists.

[0048] Sustained-release drug composition and preparation method

[0049] In one embodiment, the sustained-release pharmaceutical composition provided by the present invention includes an active ingredient (also referred to as an active pharmaceutical agent), a sustained-release agent, and a viscosity reducer.

[0050] In one embodiment, the active ingredient comprises or is composed of a recombinant long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, more preferably, the active ingredient comprises at least one of smegglutide, liraglutide, dulaglutide, benaglutide, exenatide, lixenatide and polyethylene glycol loxenatide.

[0051] In one embodiment, the recombinant long-acting glucagon-like peptide-1 (GLP-1) receptor agonist comprises or is composed of semaglutide.

[0052] Semaglutide is a recombinant, long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It undergoes acetylation at lysine 26 with the fatty acid diacid moiety. Compared to human GLP-1, it has two amino acid substitutions: Ala8 is replaced by Aib8 (2-aminoisobutyric acid), and Lys34 is replaced by Arg34. Semaglutide has the following structure, with the molecular formula C1. 187 H291 N 45 O 59 The molecular weight is 4113.58 Da.

[0053] The structure includes a modified GLP-1 polypeptide backbone and a C18 fatty acid chain covalently linked at the Lys26 position.

[0054] In some embodiments, the active ingredient comprises or is composed of liraglutide (CAS No.: 204656-20-2). Liraglutide is a synthetic GLP-1 receptor agonist with the molecular formula C172H265N43O51 and a molecular weight of 3751.20 Da.

[0055] In some embodiments, the active ingredient includes or is composed of dulaglutide (CAS No.: 923950-08-7). Dulaglutide is a fusion protein formed by the covalent binding of a modified GLP-1 analog to a modified human IgG4-Fc fragment.

[0056] In some embodiments, the active ingredient includes or is composed of benaglutide (CAS No.: 275371-94-3).

[0057] In some embodiments, the active ingredient includes or is composed of exenatide (CAS No.: 141732-76-5).

[0058] In some embodiments, the active ingredient includes or is composed of lixisenatide (CAS No.: 320367-13-3).

[0059] In some embodiments, the active ingredient comprises or is composed of polyethylene glycol loxenatide (CAS No.: 1374644-70-2).

[0060] Optionally, the sustained-release pharmaceutical composition comprises 0.05% to 0.5% by weight of an active ingredient, preferably 0.1% to 0.5% by weight, and more preferably 0.1% to 0.3% by weight. Specifically, the content of the active ingredient can be any one of 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5% by weight, or a range between any two adjacent values.

[0061] In some embodiments, the concentration of the active ingredient, namely the GLP-1 receptor agonist, is 0.1-15.0 mg / mL, preferably 0.5-10.0 mg / mL, and more preferably 1.0-5.0 mg / mL. Specifically, the concentration of the GLP-1 receptor agonist can be any one of the following values: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.34, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.2, 2.4, 2.5, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0 mg / mL, or a range between any two adjacent values.

[0062] The specific concentration of the active ingredient can be adjusted according to factors such as the type of drug, the administration site, and the therapeutic purpose, as long as the effective concentration required for treatment is achieved. For those skilled in the art, selecting a suitable specific concentration within the concentration range provided by this invention is obvious.

[0063] Furthermore, the present invention can also combine different types of active ingredients within the above concentration range according to specific treatment needs.

[0064] In one embodiment, the slow-release agent is an aggressive slow-release agent, such as selected from polyorthoester polymers, polyester polymers, or mixtures thereof, more preferably polyorthoesters. Polyorthoester polymers include homopolymers, copolymers (including random copolymers, block copolymers, alternating copolymers, and graft copolymers), and mixtures thereof. As an example, polyesters may include polylactic acid (PLA, CAS No.: 26100-51-6), polyglycolic acid (PGA, CAS No.: 26247-02-5), or copolymers thereof, such as polylactic acid-glycolic acid copolymer (PLGA, CAS No.: 26780-50-7). These materials have good biocompatibility and degradability, and their molecular weight and degradation rate can be adjusted according to specific application requirements.

[0065] Polyorthoesters used in the compositions provided by the present invention are typically composed of alternating residues derived from the reaction of diene acetals and diols, wherein the adjacent diol residues of each diene acetal-derived residue are separated from the reacted diol residues. Polyorthoesters include subunits containing α-hydroxy acids, i.e., subunits derived from α-hydroxy acids or their cyclic diesters, such as subunits containing glycolide, lactide, or combinations thereof (i.e., poly(glycol-co-lactide)), comprising all lactide and glycolide in ratios such as 75:25, 65:35, 50:50, etc. Such subunits are also referred to as latent acid subunits; due to their terminal hydroxyl groups, these latent acid subunits also fall into the more general class of "diols" used in the present invention. Polyorthoesters can be prepared as described, for example, in U.S. Patent Nos. 4,549,010 and 5,968,543. Polyorthoesters suitable for use in the compositions provided by the present invention are described in U.S. Patent No. 8,252,304.

[0066] Contains α-hydroxy acid subunit (R 1 The molar percentage of ) typically ranges from approximately 0 to 20 mol% of the total diol component (R). 1 and R 3 (As provided below). In one or more embodiments, the polyorthoester formulation contains at least about 0.01 molar percentage of α-hydroxy acid subunits. Exemplary percentages of α-hydroxy acid subunits in the polymer range from about 0 to about 50 molar percentages, or from about 0 to about 25 molar percentages, or from about 0.05 to about 30 molar percentages, or from about 0.1 to about 25 molar percentages. For example, in one embodiment, the polymer contains about 0 to about 50 molar percentages of α-hydroxy acid subunits. In another embodiment, the polymer contains about 0 to about 25 molar percentages of α-hydroxy acid subunits. In yet another embodiment, the polymer contains about 0.05 to about 30 molar percentages of α-hydroxy acid subunits. In yet another embodiment, the polymer contains about 0.1 to about 25 molar percentages of α-hydroxy acid subunits. As an example, the percentage containing the α-hydroxy acid subunit can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 molar percentages, including any and all ranges formed by combining any lower molar percentage figure with any higher molar percentage figure.

[0067] More specifically, the polyorthoester used in the compositions provided by the present invention is described by the following formula:

[0068] Where R* is C 1-4Alkyl (e.g., C1, C2, C3, or C4 alkyl), n is an integer ranging from 5 to 400, and A in each subunit is R. 1 Or R 3 That is, any monomer unit of the polymer of formula I.

[0069] In this context, A can be R. 1 Or R 3 .

[0070] In a particular embodiment, R* is an ethyl (i.e., C2 alkyl) subunit according to Formula I, wherein R* is an ethyl, corresponding to the subunit obtained by reacting the diol provided in this invention with 3,9-bis(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU), having the following structure.

[0071] For equation I, as mentioned above, A can correspond to R. 1 R 1 for

[0072] Where p and q are each independently an integer ranging from approximately 1 to 20 (e.g., each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20), and each R 5 Independently hydrogen or C 1-4 Alkyl (e.g., hydrogen, or C1, C2, C3, or C4 alkyl); and R 6 for:

[0073] Where s is an integer from 0 to 10 (e.g., selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); t is an integer from 2 to 30; and R 7 It is hydrogen or C 1-4 Alkyl (e.g., hydrogen, or C1, C2, C3, or C4 alkyl); in one or more specific embodiments, R 7 It is hydrogen. R 1 The subunit is a subunit containing an α-hydroxy acid, that is, a subunit derived from an α-hydroxy acid and its cyclic diester.

[0074] For equation I, A can also correspond to R. 3 , where R 3 for

[0075] x is an integer from 1 to 100, and in certain specific cases, selected from 1, 2, 3, 4, and 5. y is an integer from 2 to 30; and R8 It is hydrogen or C 1-4 Alkyl (C1, C2, C3, or C4 alkyl).

[0076] In a particular implementation, R 8 It is hydrogen.

[0077] In some embodiments, the polyorthoester is wherein A is R 1 Or R 3 , of polyorthoester, where R 1 for

[0078] Where p and q are each independently an integer ranging from about 1 to 20, where R is present in the polyorthoester polymer. 1 The mean of p or the mean of the sum of p and q (p+q) is approximately between 1 and 7 (e.g., 1, 2, 3, 4, 5, 6, 7); x and s are each independently an integer from 0 to 10; and t and y are each independently an integer from 2 to 30. In one or more specific implementations, R 5 It is hydrogen.

[0079] Another specific polyorthoester is in which A is R 1 Or R 3 'of those, among which R 1 for

[0080] Where p and q are each independently an integer varying from about 1 to 20, or from about 1 to 15, or from about 1 to 10, where R is present in the polyorthoester polymer. 1 The average of p, or the average of the sum of p and q (i.e., p+q), is approximately between 1 and 7. Additionally, specific ranges for x and s (for the specific embodiments described above or for any polyorthoester provided according to the invention) are those where each is an integer ranging from 0 to 7 or from 1 to 5 independently. Similarly, specific ranges for t and y are those where each varies independently from 2 to 10.

[0081] The specific polyorthoester is R 5 Those that are hydrogen or methyl.

[0082] In some specific embodiments, s and x are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8. In some specific embodiments, s is 2. In some other specific embodiments, x is 2.

[0083] Exemplary polyorthoesters contain alternating residues of 3,9-diethyl-3,9-2,4,8,10-tetraoxohelic[5.5]undecane-3,9-diyl and A.

[0084] A is as described above.

[0085] Polyorthoesters, such as those described in this invention, can be produced by adding a demonstrative diene acetal, 3,9-di(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU).

[0086] With one or more of the diols described above, such as HO-R 1 -OH or HO-R 3 Prepared via a -OH reaction. Exhibitory diols include oligoethylene glycols, such as triethylene glycol (TEG), oligoethylene glycols modified with one or more α-hydroxy acids at one or more ends, such as oligoethylene glycol glycolide or oligoethylene glycol lactide, and organic diols having a hydrocarbon core of 2 to 30 carbon atoms, such as 1,6-hexanediol, 1,10-decanediol, cis / trans-1,4-cyclohexanediol, p-menthane-3,8-diol, 1,4-butanediol, 1,5-pentanediol, 1,7-heptanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, and their cyclic equivalents, wherein the hydroxyl group can be at any two positions on a cycloalkyl or alkylene ring. Organic diols can have 2 to 20 carbon atoms. Organic diols can be linear, branched, or cyclic, and can be saturated or unsaturated. Typically, unsaturated diols will have 1-3 unsaturated elements. A particular polyorthoester may contain from about 10 to 50 total molar percentages of subunits derived from one or more organic diols with a hydrocarbon core.

[0087] Diols are prepared as described in U.S. Patent No. 5,968,543 and Heller et al., J. Polymer Sci., Polymer Letters Ed. 18:293-297 (1980), such as HO-R. 1 -OH. For example, this can be achieved by using the formula HO-R 3 The -OH diol reacts with 0.5 to 10 molar equivalents of α-hydroxy acid cyclic diesters, such as lactide and glycolide, and the reaction is allowed to proceed at 100-200°C for approximately 12 to 48 hours to prepare HO-R compounds containing polyester groups. 1-OH diols. Suitable solvents for the reaction include organic solvents such as dimethylacetamide, dimethyl sulfoxide, dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, and methyl butyl ether. Although diol products in this invention generally refer to isolated and simplified entities, such as TEG glycolide (and diol reaction products such as TEG glycolide), those skilled in the art will understand that due to the reactivity of the reactants, such as the ring-opening of glycolide, diols are actually derived from complex mixtures of reactants, which makes the term TEG glycolide (or any other term for similar products) generally refer to the average or overall properties of the products.

[0088] Specific polyorthoesters are prepared by reacting 3,9-bis(acetal)-2,4,8,10-tetraoxospiro[5.5]undecane (DETOSU) with one or more reactive diols. Polyorthoesters are typically prepared by reacting DETOSU with two or more reactive diols under anhydrous conditions. Specific polyorthoesters are also prepared, as described in U.S. Patent No. 8,252,305, by reacting DETOSU with polyethylene glycol and polyethylene glycol glycolide. Specific polyorthoesters prepared from DETOSU-polyethylene glycol-polyethylene glycol glycolide have the following molar ratio: 90:80:20, although the component ratios can be appropriately modified as described above.

[0089] Polyorthoesters formed by the reaction of DETOSU with TEG and TEG glycolide can generally be described as having the following subunits, where R 1 This corresponds to the glycol ester portion derived from polyethylene glycol glycolide (formed by the reaction of glycolide and TEG), while R 3 Corresponding to the glycol ester portion derived from polyethylene glycol:

[0090] Where A is R 1 , and R 1 for Where R 5 For hydrogen and R 6 for

[0091] The polyorthoester composition obtained is as follows: The sum of p and q averages 2, while s is 2; and when A is R 3 At that time, R 3 for Where x is 2, the resulting polyorthoester subunit or component is:

[0092] The structures of corresponding polyorthoesters prepared from the various α-hydroxy acid subunits and other diols described in this invention can be readily envisioned.

[0093] In one particular embodiment of the polyorthoester, the polyorthoester has a molecular weight ranging from about 1,000 Daltons to 20,000 Daltons.

[0094] In one embodiment, the polyorthoester described in this section is a semi-solid at room temperature and at temperatures above room temperature.

[0095] In one embodiment, R contains 80 to 100 mol% 3 , where R 3 for

[0096] Polyorthoesters with x = 2 are semi-solid at room temperature and above. Semi-solid polymers exist in a glassy or viscous liquid state. Semi-solid polymers typically exhibit a glass transition temperature (Tg) below room temperature. Below Tg, the semi-solid polymer can be considered to exist in a glassy state, while above Tg, the polyorthoester can be considered to exist in a liquid state. Semi-solid polyorthoester polymers are not thermoplastic polymers.

[0097] Generally, polyorthoesters according to any of the following formulas, Formula I, Formula II, Formula III, or Formula IV, are suitable for the compositions and / or delivery carriers provided by the present invention:

[0098] For equations I-IV,

[0099] R represents a bond, -(CH2) a -, or -(CH2) b -O-(CH2) c -; where a is an integer from 1 to 12 (e.g., selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), while b and c are independently integers from 1 to 5 (e.g., selected from 1, 2, 3, 4, and 5);

[0100] R* is C 1-4 alkyl;

[0101] R o R” and R”' are independently H or C 1-4 alkyl;

[0102] n is an integer of at least 5; and

[0103] A is a diol.

[0104] For example, the compositions and delivery systems of the present invention may be composed of polyorthoesters of formula I, II, III, or IV, wherein

[0105] R represents a bond, -(CH2) a -, or -(CH2) b -O-(CH2)c -; where a is an integer from 1 to 12, while b and c are independently integers from 1 to 5;

[0106] R* is C 1-4 alkyl;

[0107] R o R” and R”' are independently H or C 1-4 alkyl;

[0108] n is an integer of at least 5; and

[0109] A is R 1 R 2 R 3 , or R 4 ,in

[0110] R 1 It is a subunit containing an α-hydroxy acid, as described in the preceding paragraphs;

[0111] R 5 For H or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl); and R 6 Selected from the following groups:

[0112] in:

[0113] s is an integer from 0 to 10;

[0114] t is an integer from 2 to 30; and

[0115] R 7 For H or C 1-4 alkyl;

[0116] R 2 for:

[0117] R 3 for:

[0118] in:

[0119] x is an integer ranging from 0 to 200;

[0120] y is an integer in the range from 2 to 30;

[0121] R 8 For H or C 1-4 alkyl;

[0122] R 9 and R 10 Independently for C 1-12 Alkylene;

[0123] R 11 For H or C 1-6 Alkyl and R 12 C 1-6 Alkyl; or R 11 and R 12 Together for C 3-10 Alkylene; and

[0124] R 4 It is a diol residue containing at least one functional group independently selected from amide, imide, urea, and carbmate groups.

[0125] In some cases, the polyorthoester is a polyorthoester according to any one of formulas I-IV, where A is R 1 R 3 , or R 4 , where R 3 Selected from

[0126] in

[0127] x is an integer from 0 to 100;

[0128] y is an integer from 2 to 30;

[0129] R 8 For H or C 1-4 alkyl;

[0130] R 9 and R 10 Independently for C 1-12 Alkylene;

[0131] R 11 For H or C 1-6 Alkyl and R 12 C 1-6 Alkyl; or R 11 and R 12 Together for C 3-10 Alkylene;

[0132] R 4 It is a diol residue containing at least one functional group independently selected from amide, imide, urea, and polyurethane groups; and R 5 For H or C 1-4 alkyl.

[0133] In a specific embodiment of a polyorthoester, formula R 1 The fraction of Unit A is between 0 and 20 mole percentages.

[0134] An exemplary polyorthoester is described by formula I, II, III or IV, wherein

[0135] No unit has an equivalent to R 2 A;

[0136] R 3 for:

[0137] in

[0138] x is an integer from 1 to 100;

[0139] y is an integer from 2 to 30; and

[0140] R 6 for:

[0141] in:

[0142] s is an integer from 1 to 10;

[0143] t is an integer from 2 to 30; and

[0144] R 5 R 7 , and R 8 It can be hydrogen or methyl on its own.

[0145] Another representative polyorthoester of formula I, II, III or IV is R. 3 and R 6 Both are -(CH2-CH2-O)2-(CH2-CH2)-; R 5 is methyl; and wherein each of p and q is independently selected from polyorthoesters of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0146] In another polyorthoester embodiment of formula I, II, III or IV, R 3 and R 6 Both are -(CH2-CH2-O)9-(CH2-CH2)-; R 5 It is methyl; and the sum of p or p and q is 2.

[0147] In another variant, the polyorthoester is of formula I, II, III, or IV, and R is -(CH2). b -O-(CH2) c -; where b and c are both 2; R* is a C2 alkyl group.

[0148] Other representative polyorthoesters of formulas I, II, III, or IV, wherein R 5 It is hydrogen or methyl; R 6 for Where s is an integer from 1 to 10, or in some embodiments s is selected from 1, 2, 3, or 4; t is an integer from 2 to 30, particularly selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; R 7 It is hydrogen or methyl; while R 3 for

[0149] Where x is an integer from 1 to 10, or in some embodiments selected from 1, 2, 3, or 4; y is an integer from 2 to 30, particularly selected from 2, 3, 4, 5, 6, 7, 8, 9, and 10; R 8 It is hydrogen or methyl; R 4 Selected from aliphatic diol residues having 2-20 carbon atoms (e.g., selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbon atoms), while in some embodiments R 4 It has 2-10 carbon atoms, broken by one or two amide, imide, urea, or polyurethane groups. In some cases, A in polyorthoester is R. 1 The subunit ratio ranges from approximately 0.01 to 50 molar percentages. In some cases, A in polyorthoester is R. 1 The subunit ratio ranges from about 0 to 30 mole percentages, or from about 0.1 to 25 mole percentages. Demonstrative mole percentages include 10, 15, 20, and 25 mole percentages of polyorthoesters in which A is R. 1 The subunit. In one embodiment, the molar percentage is 20. Alternatively, in one or more embodiments, where A is R 2 The proportion of subunits is less than approximately 20%, less than approximately 10%, or less than approximately 5%, and A is R. 4 The proportion of subunits is less than about 20 percent, less than about 10 percent, or less than about 5 percent.

[0150] In some embodiments, the polyorthoesters shown as Formula I, Formula II, Formula III and Formula IV are polyorthoesters with alternating diene acetal and diol residues, each adjacent diene acetal residue pair being separated by a polyol residue, such as a diol.

[0151] Methods for manufacturing polyorthoesters are well known in the art and are described, for example, in U.S. Patent Nos. 6,613,355 and 8,252,304.

[0152] In one embodiment, the sustained-release agent is used to control the sustained-release effect of the GLP-1 receptor agonist, and its content is from about 45% to about 85% by weight, preferably from about 55% to about 75% by weight, and more preferably from about 65% by weight. Specifically, it can be any one of the following values, or a range between any two adjacent values: 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, and 85% by weight. The number average molecular weight of the polyorthoester is about 1,000 Daltons to 20,000 Daltons, preferably 2,000-10,000 Daltons, and more preferably 4,000-7,000 Daltons. Number average molecular weight can be determined by gel permeation chromatography (GPC) using polystyrene as the standard and tetrahydrofuran as the mobile phase.

[0153] In one embodiment, to adjust the rheological properties of the composition and make it suitable for injection, the composition further includes a viscosity reducer. The viscosity reducer is present in an amount of about 15% by weight to about 55% by weight, preferably about 25% by weight to about 45% by weight, more preferably about 35% by weight. Specifically, it can be any value from 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55% by weight, or a range between any two adjacent values. Preferably, the viscosity reducer is triacetin (CAS No.: 102-76-1, molecular formula: C9H). 14 O6) composition. Triacetin can significantly reduce the viscosity of the composition, thereby improving injection fluidity.

[0154] In a preferred embodiment of the present invention, the proportions of each component in the sustained-release pharmaceutical composition should be understood as approximate values. Taking a preferred proportion as an example, when the active ingredient is 0.2% by weight, the sustained-release agent is about 65% by weight, and the viscosity reducer is about 35% by weight, the content of each component may fluctuate within an approximate range (e.g., ±1%). Considering that the content of the active ingredient is relatively low (typically 0.05-0.5% by weight), this expression is clear and reasonable to those skilled in the art.

[0155] In one embodiment, the viscosity of the composition, measured at 25°C, is from 100 mPa·s to 5000 mPa·s, preferably from 500 mPa·s to 4000 mPa·s, and more preferably from 800 mPa·s to 3000 mPa·s. Specifically, it can be any value from 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and 5000 mPa·s, or a range between any two adjacent values. Viscosity measurement can be performed using a rotational rheometer at 25 ± 0.5°C, or using a Brinell conical viscometer under the same conditions, at a rotation speed of 2.5 rpm.

[0156] In one embodiment, the density of the composition is 1.1-1.4 g / mL, preferably 1.2-1.3 g / mL, and more preferably 1.24-1.26 g / mL. Specifically, it can be any value from 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, and 1.40 g / mL, or a range between any two adjacent values.

[0157] Thermosensitive sustained-release drug composition

[0158] In one embodiment, the sustained-release pharmaceutical composition provided by the present invention includes an active ingredient (also referred to as an active pharmaceutical agent), a sustained-release agent, and a viscosity reducer.

[0159] In one embodiment, the active ingredient comprises or is composed of a recombinant long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, more preferably, the active ingredient comprises at least one of smegglutide, liraglutide, dulaglutide, benaglutide, exenatide, lixenatide and polyethylene glycol loxenatide.

[0160] In one embodiment, the recombinant long-acting glucagon-like peptide-1 (GLP-1) receptor agonist comprises or is composed of semaglutide.

[0161] Other characteristics of the active ingredient can be found in the descriptions of other embodiments, and will not be repeated here.

[0162] In one specific embodiment, the sustained-release agent includes a thermosensitive sustained-release agent, the content of which is preferably from 45% to 99.95% by weight, more preferably from 55% to 99.5% by weight. Specifically, the content of the thermosensitive sustained-release agent can be any one of 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, 99.5% by weight, or a range between any two adjacent values.

[0163] The thermosensitive sustained-release agent exhibits reversible sol-gel transition behavior with temperature changes. It is liquid at low temperatures (e.g., 0-8°C), suitable for injection administration; as the temperature rises, it undergoes a solidification (including semi-solidification or gelation) transition. Specifically, the solidification (including semi-solidification or gelation) temperature (the transition temperature from liquid to solid (including semi-solid or gel)) of the thermosensitive sustained-release agent is 30°C to 45°C, preferably 35°C to 39°C, more preferably 36°C to 38°C, and even more preferably 36°C-37°C. Specifically, the solidification temperature can be any value from 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45°C, or a range between any two adjacent values.

[0164] The thermosensitive sustained-release agent may be a polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO, poloxamer 407) or a lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA). Preferably, the thermosensitive sustained-release agent is composed of poloxamer 407 or PLGA-PEG-PLGA.

[0165] The chemical structure of the PLGA-PEG-PLGA thermosensitive hydrogel is shown in the figure below:

[0166] Poloxamer 407 is a chemically stable triblock copolymer whose chemical stability gives it high stability in oxidizing, reducing, and acid / alkali environments.

[0167] In a preferred embodiment of the present invention, the thermosensitive sustained-release agent poloxamer 407 can be used as an in-situ gel for local injection. Its gel is transparent and highly hydrophilic, forming a three-dimensional mesh structure that firmly binds the drug within, thereby prolonging the drug's residence time at the affected area and improving bioavailability. Poloxamer 407 gel exhibits good tissue compatibility and significantly reduces the irritation of surrounding tissues caused by the drug dosage. Poloxamer 407 can have any of the aforementioned curing temperatures.

[0168] In another specific embodiment, the thermosensitive sustained-release agent PLGA-PEG-PLGA remains in a liquid state (sol state) below the phase transition temperature; when the temperature reaches the phase transition temperature, it rapidly gels to form a solid structure. PLGA-PEG-PLGA hydrogels are particularly suitable for local chemotherapy applications, enabling precise drug delivery to the target site and prolonging drug release time through gel formation, thereby reducing systemic side effects. By adjusting the molecular weight and copolymerization ratio of PLGA-PEG-PLGA, precise control of the drug release rate can be achieved. The thermosensitive sustained-release agent PLGA-PEG-PLGA can have any of the aforementioned curing temperatures.

[0169] Specifically, the composition of the PLGA-PEG-PLGA hydrogel can be further optimized to meet the delivery requirements of different drugs. For the PLGA-PEG-PLGA thermosensitive hydrogel, it is preferred that its purity is above 95%, its storage conditions are -20°C, and it exhibits phase transition behavior at a specific temperature.

[0170] In embodiments of the present invention, other parameters of the thermosensitive sustained-release composition may refer to those described above, or may have other parameters.

[0171] In one embodiment, the remaining amount of the sustained-release pharmaceutical composition may include excipients, unavoidable impurities, and / or residual solvents from preparation. To further improve the stability and processing performance of the sustained-release pharmaceutical composition of the present invention, one or more pharmaceutical excipients may be added to the composition, including but not limited to dissolving agents, osmotic pressure regulators, pH adjusters, or maintenance agents. The specific amounts of these excipients can be adjusted according to actual needs.

[0172] In some embodiments, the sustained-release pharmaceutical composition may be prepared as an injection.

[0173] In some embodiments, the injectable substance can be a single-dose injectable substance, such as an ampoule injectable substance, a vial injectable substance, or a pre-filled syringe injectable substance; it can also be a multi-dose injectable substance, such as a multi-dose vial injectable substance. Preferably, the injectable substance is a pre-filled injectable substance. More preferably, the injectable substance is a pre-filled injectable substance pre-loaded in a pre-filled injection pen delivery device.

[0174] In some embodiments, the content of the active ingredient of the GLP-1 receptor agonist in a single standard injection dose of a (human) single-dose injection or multiple-dose injection may be about 3 to about 25 times, preferably about 5 to about 25 times, more preferably about 5 to about 15 times, and even more preferably about 5 to about 10 times that of a standard injection dose of (human) conventional semaglutide (1.5 ml, 1.34 mg / ml semaglutide). Therefore, the active ingredient content of the GLP-1 receptor agonist in a single standard injection dose is from about 6.03 mg to about 50.25 mg, preferably from about 10.05 mg to about 50.25 mg, more preferably from about 10.05 mg to about 30.15 mg, and even more preferably from about 10.05 mg to about 20.10 mg. For example, it can be any value among 6.03 mg, 7 mg, 8 mg, 9 mg, 10.05 mg, 15 mg, 20.10 mg, 25 mg, 30.15 mg, 35 mg, 40 mg, 45 mg, and 50.25 mg, or any range between any two adjacent values.

[0175] Preparation method

[0176] The compositions of the present invention can be prepared by any suitable method to ensure uniform distribution of the GLP-1 receptor agonist in the sustained-release matrix.

[0177] In one embodiment, a GLP-1 receptor agonist is mixed into a solution to form the sustained-release pharmaceutical composition, the solution containing a sustained-release agent and a viscosity reducer. Preferably, mixing is carried out at a temperature of 50 to 80°C, more preferably at a temperature of 65 to 75°C, and even more preferably at a temperature of 70°C. More preferably, stirring is performed at said temperature for 0.5 to 6 hours.

[0178] In another embodiment, a GLP-1 receptor agonist is mixed into a solvent to form a mixture, wherein the solvent is a compound soluble in the GLP-1 receptor agonist. A solution containing a sustained-release agent and a viscosity reducer is then mixed into the mixture. The solvent is then removed, partially removed, or not removed to form the sustained-release pharmaceutical composition. Preferably, the mixing or removal of the solvent is carried out at a temperature of 50 to 80°C, more preferably at 65 to 75°C, and more preferably at 70°C. More preferably, the mixture is stirred at this temperature for 0.5 to 6 hours.

[0179] Specifically, the temperature can be any value among 50, 55, 60, 65, 70, 75, and 80°C, or any range between any two adjacent values; the stirring time can be any value among 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, and 6 hours, or any range between any two adjacent values.

[0180] Preferably, the solvent can be selected from aqueous solvents such as purified water, phosphate-buffered saline (PBS), and sodium chloride injection, or from at least one organic solvent such as dimethyl sulfoxide (DMSO), methanol, and ethanol. Preferably, the stirring is performed by mechanical stirring, magnetic stirring, or other methods, and the stirring speed is preferably 20-200 rpm, more preferably 50-150 rpm. Specifically, the stirring speed can be any value from 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, and 200 rpm, or a range between any two adjacent values.

[0181] During the preparation process, because the fatty acid modification groups on the GLP-1 receptor agonist (such as smegglutinin) molecule have hydrophobic properties, they can form non-covalent interactions with hydrophobic polyorthoesters, allowing the active ingredient to be uniformly dispersed in the polyorthoester carrier.

[0182] In some embodiments, the thermosensitive sustained-release composition can be prepared by mixing, such as low-temperature mixing. For example, at a low temperature (0-8°C), a thermosensitive sustained-release agent, such as poloxamer 407, exists in a sol state; the active ingredient, namely a GLP-1 receptor agonist, such as semaglutide powder, is added to the low-temperature thermosensitive sustained-release agent, such as poloxamer 407 sol, and mixed thoroughly. The mixture is allowed to stand to allow the GLP-1 receptor agonist, such as semaglutide, to be uniformly dispersed in the gel. The formulation is then stored at a low temperature in pre-filled ampoules for injection.

[0183] Delivery device

[0184] In several embodiments of the present invention, as shown in FIG1A, a fluid delivery device is provided, particularly a fluid delivery device for a drug or composition, which may include a tube 100 for containing fluid, the tube 100 having a first end 110 and a second end 120. As shown in FIG1A, the second end 120 may be provided with an orifice 121 for dispensing fluid within the tube. Alternatively, the second end 120 may be provided with a self-closing elastic portion.

[0185] The fluid delivery device may also include an injection head 200 detachably connected to (or integrally formed with) the tube 100, the injection head 200 including one or more needle elements 210 (jet microneedles). The one or more needle elements 210 are configured to removably engage with a self-closing elastic portion in the second end 120 or an orifice 121 for dispensing fluid 130 within the tube 100.

[0186] The fluid delivery device may further include a power mechanism 300, which includes a piston 310 disposed in the first end 110 of the tube 100 and capable of pushing the fluid 130, or is operatively connected to the piston 310 to apply delivery pressure to the piston 310 pushing the fluid 130. The power mechanism is a motorized power mechanism, that is, in the sense of this disclosure, the power mechanism does not contain manually operated components.

[0187] In some embodiments of the present invention, three self-closing elastic portions are provided in the second end, and the three needle pieces 210 are configured to be removably connected to the self-closing elastic portions in the second end 120. Specifically, the three needle pieces 210 are configured such that they are inserted into the corresponding second end 120 where the three self-closing elastic portions are provided.

[0188] In some embodiments of the present invention, the self-sealing elastic part is formed by filling silicone into a hole 121 for distributing fluid in the tube provided in the second end 120. The specific composition of the silicone is not limited here. Similarly, the hole 121 can be filled with a material other than silicone that is suitable for insertion by the plurality of needles 210. This is not limited here.

[0189] In some embodiments of the present invention, as shown in FIG1A, the piston 310 may be provided as a separate component, and the power mechanism 300 is configured to operate connected to the piston 310 to apply delivery pressure to the piston 310. Similarly, it is conceivable that in other embodiments of the present invention, the power mechanism 300 may be integrally integrated with the piston 310.

[0190] In some embodiments of the present invention, the driving method of the power mechanism 300 may include any one of compressed gas driving, spring driving, electromagnetic driving, or a combination of the above driving methods. For example, in some embodiments, the power mechanism 300 may be driven by compressed gas, such as compressed nitrogen or compressed carbon dioxide gas, or by compressed mechanical spring, or by piezoelectric actuator, without limitation.

[0191] In some embodiments of the present invention, compared to manual needle injection (where the piston inside the needle travels at a speed of approximately 0.01 m / s), the piston speed of the fluid delivery device of the present invention when the piston 310 pushes the fluid 130 in the tube 100 is greater than or equal to 10 times the piston speed of manual needle injection. The piston speed of the piston 310 when pushing the fluid 130 is 0.05 m / s to 0.50 m / s, preferably 0.09 m / s to 0.25 m / s, and even more preferably 0.14 to 0.20 m / s.

[0192] In some embodiments of the present invention, compared to manual needle injection (where the outlet jet velocity of the fluid ejected from the needle is approximately 2 m / s), the outlet jet velocity of the fluid 130 of the fluid delivery device of the present invention when it is pushed away by the piston 310 from the plurality of holes 121 in the second end 120 or one or more needle parts 210 of the injection head 200 is greater than or equal to 10 m / s, preferably greater than or equal to 50 m / s, more preferably greater than or equal to 100 m / s, and more preferably greater than or equal to 150 m / s.

[0193] In some embodiments of the present invention, at least one of the one or more needle components has an aperture in the range of 0.06 mm to 1.50 mm, more preferably in the range of 0.1 mm to 1.00 mm, and even more preferably in the range of 0.11 mm to 0.50 mm.

[0194] In some embodiments of the present invention, at least one of the self-sealing elastic part or the hole for distributing fluid in the pipe has a diameter in the range of 0.06 mm to 1.50 mm, more preferably in the range of 0.11 mm to 1.00 mm, and even more preferably in the range of 0.11 mm to 0.50 mm. The diameter can be any value from 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.22, 0.24, 0.26, 0.28, 0.30, 0.32, 0.34, 0.36, 0.38, 0.40, 0.42, 0.44, 0.46, 0.48, 0.50, 0.60, 0.70, 0.80, 0.90, 1.00, 1.10, 1.20, 1.30, 1.40, 1.50 mm, or a range between any two adjacent values.

[0195] In some embodiments of the present invention, the total fluid delivery area of ​​the plurality of needle elements or the plurality of orifices for dispensing fluid within the tube is 0.009 mm. 2 The above is preferably 0.020 mm. 2 The above, more preferably, is 0.053mm. 2 The above, more preferably 0.28mm 2 The area of ​​a single hole in the aforementioned needle or hole is 0.0028–0.035 mm². 2 Preferably, the diameter is 0.0028–0.020 mm. 2 More preferably, it is 0.0028–0.009 mm. 2 The single-hole area of ​​the needle tip refers to the single-hole area calculated from the inner diameter of the needle tip.

[0196] In this embodiment of the invention, the fluid delivery device can deliver 0.3 mm of fluid in a single pass. 3 The volume of the drug or composition (volume before delivery) is preferably 1.0 mm. 3 The volume of the drug or composition (volume before delivery) is more preferably 5.0 mm. 3 The volume of the drug or composition mentioned above (volume before delivery); in some embodiments, the fluid delivery device of the present invention can deliver a volume of drug or composition (volume before delivery) of up to 14.0 mm in a single delivery. 3 In a further embodiment, the volume (pre-delivery volume) of the drug or composition delivered in a single transaction by the fluid delivery device of the present invention can reach 46.0 mm. 3 .

[0197] In some embodiments of the present invention, at least one of the one or more needle elements 210 is substantially inserted into a human or animal body. In some embodiments of the present invention, the insertion depth of the one or more needle elements is preferably 1 mm to 10 mm. Specifically, the insertion depth can be any value from 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 mm, or a range between any two adjacent values.

[0198] In some embodiments of the present invention, the one or more needle elements 210 have different adjustable skin insertion depths. In some embodiments of the present invention, at least one of the one or more needle elements 210 has a substantial insertion depth into the inner layer of the skin of a human or animal. In some embodiments of the present invention, at least one of the one or more needle elements 210 has a substantial insertion depth into the subcutaneous layer of a human or animal. In some embodiments of the present invention, at least one of the one or more needle elements 210 has a substantial insertion depth into the muscle layer of a human or animal. In some embodiments of the present invention, at least one of the one or more needle elements 210 has a substantial insertion depth into an internal organ of a human or animal. In some embodiments of the present invention, at least one of the one or more needle elements 210 has an adjustable insertion depth.

[0199] In some embodiments of the present invention, the fluid delivery device is configured such that the diffusion volume of the fluid 130 within the body is greater than the undelivered volume. Preferably, the diffusion volume of the fluid within the body is at least 1.1 times the undelivered volume, more preferably at least 1.50 times, more preferably at least 1.80 times, even more preferably at least 2.40 times, more preferably at least 3.00 times, and even more preferably at least 3.60 times. Specifically, the diffusion volume ratio can be from 3.00 times to 10.00 times, from 4.00 times to 10.00 times, more preferably from 4.40 times to 8.00 times, and even more preferably from 5.0 times to 6.50 times. The specific values ​​listed include, but are not limited to: 4.00 times, 4.40 times, 4.60 times, 4.80 times, 5.00 times, 5.10 times, 5.20 times, 5.30 times, 5.40 times, 5.50 times, 5.60 times, 5.80 times, 5.90 times, 6.00 times, 6.50 times, 7.00 times, 8.00 times, 9.00 times, and 10.00 times, or any range between these values.

[0200] In some embodiments of the present invention, the dispersion volume ratio refers to the ratio of the volume of the dispersion region of the fluid delivered by the fluid delivery device in the body to the original volume of the undelivered fluid, that is:

[0201] In other embodiments of the present invention, the diffusion volume ratio may also refer to the ratio of the diffusion volume of fluid delivered by the fluid delivery device of the present invention in the body to the diffusion volume of fluid delivered by manual needle injection in the body, that is:

[0202] The diffusion volume of the delivery fluid can be calculated in various ways, without limitation. For example, in some embodiments of the present invention, a fluorescent marker can be added to the drug or composition in advance, and then the volume of the diffusion region can be calculated by scanning with medical imaging technology and using image analysis software, such as calculating the envelope map of the diffusion region to estimate the volume of the diffusion region.

[0203] It is understandable that when a delivery fluid enters the body through a fluid delivery device, its three-dimensional spatial distribution area increases due to the diffusion effect of the fluid within the body. This diffusion process increases the surface area of ​​the fluid, especially the drug or composition, in contact with tissues in the body, thereby improving the bioavailability and efficacy of the drug.

[0204] In some embodiments of the present invention, the outlet jet velocity v of the one or more needle elements can be configured such that the fluid jet passing through the one or more needle elements has a variety of different bulk dispersions, i.e., different dispersion volume ratios, dispersion depths, or dispersion extents; thus, in some embodiments of the present invention, the outlet jet velocities v of the one or more needle elements can be equal and have a first outlet jet velocity v1, the magnitude of which is configured such that the fluid jet passing through the one or more needle elements has different dispersions.

[0205] It is understood that those skilled in the art, under the guidance of the embodiments of the present invention, can determine the diffusion of the dermis, epidermis, subcutaneous tissue, muscle, and human organs in the body of the inoculated subject based on the needle-free delivery of the inoculated subject, including but not limited to different types of animals or patients with different physical conditions.

[0206] In some embodiments of the present invention, the orifice diameter d of the one or more needle elements 210 may be configured such that the fluid jet passing through the one or more needle elements 210 has a variety of different in vivo dispersibility, i.e., different dispersibility volume ratios, dispersibility depths, or dispersibility extents; thereby, in some embodiments of the present invention, the orifice diameters of the one or more needle elements 210 may be equal and have a first orifice diameter d1, the size of the first orifice diameter d1 being configured such that the fluid jet passing through the one or more needle elements 210 has different dispersibility, preferably, different dispersibility depths, so that the fluid jet disperses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs.

[0207] In some embodiments of the present invention, the outlet jet velocity v of the one or more needle elements 210 may be configured such that the fluid jet passing through the one or more needle elements 210 has a variety of different in vivo dispersions, i.e., different dispersion volume ratios, dispersion depths, or dispersion extents; thereby, in some embodiments of the present invention, the outlet jet velocities v of the one or more needle elements 210 may be equal and have a first outlet jet velocity v1, the magnitude of which is configured such that the fluid jet passing through the one or more needle elements 210 has different dispersions, preferably different dispersion depths, so that the fluid jet diffuses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs.

[0208] In one embodiment of the present invention, as shown in FIG1B, the injection head 200 may include a plurality of needle elements 210, for example, three annular needle elements 210 spaced apart at equal angles of 120°, thereby achieving multi-point diffusion injection. However, other arrangements of the needle elements (and corresponding orifices or resiliently closure portions) of the injection head are conceivable.

[0209] In an embodiment not shown, the injection head 200 may include a single needle element 210.

[0210] In addition to the fluid delivery device embodiment shown in Figure 1A, the present invention also provides other optional embodiments, as shown in Figures 2A to 2E. The embodiments shown in Figures 2A to 2E mainly illustrate the design of different needle component structures and have a similar working principle to those shown in Figures 1A to 1B. Features, parameters, etc., not described in detail in the embodiments shown in Figures 2A to 2E can be referred to those described in Figures 1A to 1B, and are all applicable to the injection of the sustained-release drug composition described in the present invention.

[0211] Figure 2A illustrates one embodiment of a jet microneedle fluid delivery device and its injection head structure, wherein the injection head 200 is fixedly connected to the tube 100, for example, by integral injection molding. The injection head 200 includes an integral needle tip 210 having a single drug outlet 211 located at the needle tip. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be referenced to the embodiments shown in Figures 1A and 1B.

[0212] Figure 2B illustrates one embodiment of a jet microneedle fluid delivery device and its injection head structure, wherein the injection head 200 is fixedly connected to the tube 100, for example, by integral injection molding. The injection head 200 includes an integral needle tip 210. The needle tip 210 has at least one sidewall drug outlet 212. Preferably, the needle tip 210 has a plurality of sidewall drug outlets 212 arranged around the needle tip 210, and these sidewall drug outlets may be located at different heights of the needle tip. The needle tip also has a needle tip drug outlet 211. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be referenced to the embodiments shown in Figures 1A and 1B.

[0213] Figure 2C illustrates one embodiment of a jet microneedle fluid delivery device and its injection head structure, wherein the injection head 200 is fixedly connected to the tube 100, for example, by integral injection molding. The injection head 200 includes an integral needle tip 210. The needle tip 210 has at least one sidewall drug outlet 212. Preferably, the needle tip 210 has a plurality of sidewall drug outlets 212 arranged around the needle tip 210, and these sidewall drug outlets may be located at different heights of the needle tip. In this embodiment, the needle tip does not have a needle tip drug outlet. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be referred to the embodiments shown in Figures 1A and 1B.

[0214] Figure 2D illustrates one embodiment of a jet microneedle fluid delivery device and its injection head structure, wherein the injection head 200 is fixedly connected to the tube 100, for example, by integral injection molding. The injection head 200 includes an integral needle tip 210. Compared with Figure 2B, the injection head structure of the jet microneedle fluid delivery device in Figure 2D differs in that the sidewall drug outlet holes 212 are arranged in groups, that is, sidewall drug outlet holes 212 are respectively provided at different heights of the needle tip 210. Preferably, each group of sidewall drug outlet holes 212 is arranged around the needle tip, and different groups of sidewall drug outlet holes 212 are set at different heights. Furthermore, the needle tip also has a needle tip drug outlet hole 211. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be referred to the embodiments shown in Figures 1A and 1B.

[0215] Figure 2E illustrates one embodiment of a jet microneedle fluid delivery device and its injection head structure, wherein the injection head 200 is fixedly connected to the tube 100, for example, by integral injection molding. The injection head 200 includes an integral needle tip 210. In the injection head structure of the jet microneedle fluid delivery device in Figure 2E, the sidewall drug outlet holes 212 are also arranged in groups, that is, sidewall drug outlet holes 212 are respectively provided at different heights of the needle tip 210. Preferably, each group of sidewall drug outlet holes 212 is arranged around the needle tip, and the sidewall drug outlet holes 212 of different groups are set at different heights. In this embodiment, the needle tip does not have a needle tip drug outlet. The dimensions and outlet jet velocity of the needle tip and its components in this embodiment can be referred to the embodiments shown in Figures 1A and 1B.

[0216] In different embodiments of the invention, the sustained-release composition or corresponding drug can be delivered by a fluid delivery device according to the invention having one or more needle elements (and corresponding orifices or resilient closures), which may be, for example, in the form of an injection pen, prefilled with the sustained-release composition or drug according to embodiments of the invention.

[0217] In some embodiments of the present invention, a pharmaceutical device combination product comprising a sustained-release composition or drug and a fluid delivery device according to embodiments of the present invention may also be provided, wherein the pharmaceutical device combination product is a prefilled injection pen prefilled with a sustained-release composition or drug according to embodiments of the present invention.

[0218] In some embodiments of the invention, the fluid delivery device further includes a needle kit comprising a needle sleeve for removably surrounding a first needle head on the needle tip.

[0219] In some embodiments of the present invention, the needle sheath structure may be integrated into the injection head. In other embodiments of the present invention, the needle sheath structure may be axially movable relative to the needle tip in the axial direction of the needle tip.

[0220] In some embodiments of the present invention, any of the fluid delivery devices described in the above embodiments can also be used in combination with a sustained-release drug composition. Therefore, embodiments of this application also provide corresponding drug-device combination products. In embodiments of the present invention, the drug-device combination product may include or may be a drug delivery system.

[0221] In some embodiments of the present invention, as shown in FIG1B, the injection head 200 of the fluid delivery device used in conjunction with the sustained-release drug composition is provided with three holes 121, which are arranged in a ring at equal intervals around the center of the injection head 200, and the distance between the three holes and the center is 1.25mm ± 20%.

[0222] In some embodiments of the present invention, the piston 310 of the fluid delivery device used in conjunction with the sustained-release drug composition has a pushing speed of 0.16 m / s ± 20%;

[0223] In some embodiments of the invention, the fluid delivery device used in conjunction with the sustained-release drug composition is configured such that the outlet jet velocity of the sustained-release drug composition when it is pushed away from the orifice 121 in the injection head 200 by the piston 310 is 170.00 m / s ± 20%.

[0224] In some embodiments of the invention, the fluid delivery device used in conjunction with the sustained-release drug composition is configured such that the diffusion volume of the sustained-release drug composition in vivo is greater than 1.5 times the undelivered volume of the sustained-release drug composition.

[0225] In some embodiments of the present invention, the fluid delivery device used in combination with semaglutide is configured such that the weight reduction effect of semaglutide on humans and animals is consistent with that of needle injection, preferably with a 2% improvement in weight reduction effect compared to needle injection, more preferably a 5% improvement, and even more preferably a 10% improvement.

[0226] Drug-device combination products

[0227] The present invention also provides a pharmaceutical device combination product. This combination product includes a sustained-release pharmaceutical composition and a fluid delivery device according to any one of the present invention, wherein the fluid delivery device includes a tube for receiving the sustained-release pharmaceutical composition, an injection head detachably connected to or integrally formed with the tube, and a power mechanism for applying a delivery force to deliver the sustained-release pharmaceutical composition.

[0228] The sustained-release drug composition comprises a GLP-1 receptor agonist, a polyorthoester sustained-release agent, and a triacetin viscosity reducer. The preferred GLP-1 receptor agonist is smegglutide, the content and concentration range of which have been described in detail above. The ratio of the sustained-release agent to the viscosity reducer has been optimized to ensure both sustained-release efficacy and injection feasibility.

[0229] In the fluid delivery device, a tube is used to store the sustained-release drug composition and is connected to an injection head. The injection head includes one or more needle elements with an inner diameter ranging from about 0.06 mm to about 1.50 mm and a length ranging from about 1 mm to about 10 mm. The power mechanism provides delivery force for applying and controlling drug delivery.

[0230] This combination product is designed for long-acting, sustained-release administration of GLP-1 receptor agonists, enabling sustained efficacy after a single injection and thus improving patient compliance. The content of the active ingredient in a single standard injection dose and the dosing cycle have been described in detail above.

[0231] use

[0232] This invention also relates to the use of sustained-release pharmaceutical compositions or pharmaceutical-device combinations in the preparation of products for injectable administration to treat diseases, and the use of polyorthoester polymers in the preparation of GLP-1 receptor agonist drugs for injectable administration. Through this design, the drug can achieve prolonged administration, improve patient compliance, and ensure therapeutic efficacy.

[0233] In some embodiments, the sustained-release pharmaceutical composition comprises a GLP-1 receptor agonist, a sustained-release agent, and a viscosity reducer. The specific composition and content range of the GLP-1 receptor agonist, sustained-release agent, and viscosity reducer can be found in the detailed description above. In some embodiments, the sustained-release pharmaceutical composition is the aforementioned composition. In the application of this invention, the GLP-1 receptor agonist achieves a sustained-release effect by forming a non-covalent interaction with the sustained-release agent, while the viscosity reducer ensures that the composition has suitable injectability. Preferably, the GLP-1 receptor agonist is pre-filled into a fluid delivery device in the form of a pre-filled injection pen.

[0234] Preferably, the drug is used to treat at least one of the following conditions: for the treatment of obesity or overweight; for the treatment of diabetes, preferably for the treatment of type II diabetes; for the improvement of cardiovascular metabolic indicators; preferably for the reduction of cardiovascular disease risk or the treatment of cardiovascular disease; preferably for the treatment of atherosclerosis; preferably for the treatment of myocardial infarction; preferably for the treatment of stroke; preferably for the treatment of heart failure; preferably for the treatment of peripheral artery disease; for the treatment of Alzheimer's disease; and for the treatment of non-alcoholic steatohepatitis.

[0235] Preferably, the active ingredient content in a single standard injection dose of the GLP-1 receptor agonist drug, preferably a semaglutide drug, is about 6.03 mg to about 50.25 mg, more preferably about 10.05 mg to about 50.25 mg, more preferably about 10.05 mg to about 30.15 mg, and even more preferably about 10.05 mg to about 20.10 mg. This is about 3 to 25 times, preferably about 5 to 25 times, more preferably about 5 to 15 times, and even more preferably about 5 to 10 times the semaglutide dose in a single standard injection dose of the conventional semaglutide drug. The single standard injection dose of the conventional semaglutide drug is 1.5 ml, and the concentration of semaglutide in the conventional semaglutide drug is preferably 1.34 mg / ml.

[0236] Preferably, when used to treat the disease, the drug has improved pharmacokinetic characteristics after a single dose, including prolonged time to reach peak plasma concentration (tmax), increased peak plasma concentration (Cmax), significantly increased area under the curve (AUC0-last), and prolonged half-life (t1 / 2), etc. Specific parameters have been described in detail in the foregoing section.

[0237] Preferably, the drug has at least one of the following pharmacokinetic characteristics after a single dose:

[0238] (1) Compared with conventional non-sustained-release semagrapeptide drugs, the time to reach the highest plasma concentration (t) max (Prolonged, preferably, a single injection of sustained-release drug t) max It is 1.5-10 times more potent than a single injection of non-sustained-release semaglutide; more preferably, t max It is 2-7 times; most preferably, t max The concentration of semaglutide in rats is 3-5 times that of conventional semaglutide drugs, and the standard single dose of the conventional semaglutide drugs is 0.0125 mg (corresponding to a standard single injection dose of 1.5 ml for humans). The preferred concentration of semaglutide in the conventional semaglutide drugs is 1.34 mg / ml.

[0239] (2) Compared to conventional non-sustained-release semagrapeptide drugs, the highest plasma concentration (C) max To improve, preferably, the single-injection sustained-release drug C max The dosage is 1.2-10 times that of a single injection of non-sustained-release semaglutide; preferably, 1.5-10 times; more preferably, C max It is 2-7 times; most preferably, C max 3-5 times;

[0240] (3) Compared with conventional non-sustained-release semaglutide drugs, the area under the curve (AUC) during drug delivery was significantly lower. 0-lastTo improve, preferably, AUC 0-last Reaching 18000 h·ng·mL -1 The above; more preferably, AUC 0-last Reaching 38000 h·ng·mL -1 The above; the most preferred option, AUC 0-last Reaching 64000 h·ng·mL -1 above;

[0241] (4) Compared to conventional non-sustained-release smegglutide drugs, the half-life (t) 1 / 2 (Prolonged, preferably, a single injection of sustained-release drug t) 1 / 2 The dosage is 1.2-10 times that of a single injection of non-sustained-release semaglutide; preferably, 1.5-10 times; more preferably, t 1 / 2 It is 2-7 times; most preferably, t 1 / 2 It is 3-5 times.

[0242] Preferably, when used to treat obesity or overweight, a reduction in body weight relative to initial body weight can be achieved within 4 weeks after the start of administration. More preferably, a significant reduction in individual body weight relative to initial body weight is achieved within 4 weeks after the start of administration; more preferably, the reduction is 2% or more; more preferably, it is 4% or more; even more preferably, it is 6% or more; and most preferably, it is 8% or more.

[0243] Preferably, when used to treat diabetes, improvement in blood glucose levels can be achieved within 15 days after the start of administration.

[0244] Preferably, a significant improvement in blood glucose levels is achieved within 15 days after the start of administration, and preferably, at least one of the following blood glucose characteristics is present:

[0245] (1) Significant improvement in blood glucose levels in a glucose tolerance test (GTT), preferably, within 30 minutes after glucose gavage, blood glucose levels are reduced by more than 2% compared to before administration; preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 15%.

[0246] (2) Significant improvement in fasting blood glucose level, preferably, the fasting blood glucose level is reduced by more than 0.2 mmol / L compared with that before administration; preferably, it is reduced by more than 0.4 mmol / L; more preferably, it is reduced by more than 0.6 mmol / L; most preferably, it is reduced by more than 0.8 mmol / L;

[0247] (3) The individual’s glucose tolerance is significantly improved. Preferably, the area under the glucose curve (AUC) in the glucose tolerance test is reduced by more than 5% compared with that before administration; preferably, it is reduced by more than 10%; more preferably, it is reduced by more than 15%; and most preferably, it is reduced by more than 20%.

[0248] (4) Individual blood glucose levels are maintained within the range of 5.6 mmol / L to 7.0 mmol / L;

[0249] (5) Within 120 minutes after glucose loading, the blood glucose level is restored to within 120% of the fasting level; preferably, it is restored to within 110% of the fasting level; more preferably, it is restored to within 105% of the fasting level.

[0250] Preferably, when used to improve cardiovascular metabolic indicators, lipid level improvement can be achieved within 15 days after the start of administration.

[0251] Preferably, the drug is used to improve cardiovascular metabolic indicators; preferably, it is used to reduce the risk of cardiovascular disease or to treat cardiovascular disease, wherein a significant improvement in blood lipid levels is achieved within 15 days after the start of administration, and preferably, it has at least one of the following blood lipid characteristics:

[0252] (1) Improve liver function indicators, preferably, the activity of alanine aminotransferase (ALT) is significantly reduced, preferably, the activity of ALT is reduced by more than 5% compared with that before administration; preferably, it is reduced by more than 10%; more preferably, it is reduced by more than 15%; most preferably, it is reduced by more than 20%.

[0253] (2) Reduce pathological changes in liver tissue, preferably by reducing the degree of hepatocyte steatosis and lipid droplet accumulation.

[0254] Preferably, when administered to humans, the duration of administration of the sustained-release pharmaceutical composition is greater than or equal to 10 days, more preferably greater than or equal to 10 days and less than or equal to 90 days, more preferably greater than or equal to 15 days and less than or equal to 60 days, more preferably greater than or equal to 30 days and less than or equal to 40 days, and most preferably 30 days. The time period for the release of the active ingredient from the sustained-release pharmaceutical composition is greater than or equal to 10 days, more preferably greater than or equal to 10 days and less than or equal to 90 days, more preferably greater than or equal to 15 days and less than or equal to 90 days, and most preferably greater than or equal to 30 days and less than or equal to 90 days.

[0255] To address the issues of high dosing frequency and poor patient compliance associated with existing GLP-1 receptor agonists, this invention proposes novel sustained-release drug compositions, their preparation methods, drug-device combination products, and related applications.

[0256] In an interpretive and not limiting sense, polyorthoesters offer unique advantages as sustained-release carriers. Due to the surface-dissolving properties of polyorthoesters, when a sustained-release drug composition is injected into subcutaneous tissue, a local drug reservoir is formed. This reservoir achieves slow drug release through surface dissolution, thereby continuously replenishing the drug concentration in the body and prolonging the duration of drug action. This carrier system exhibits stable release characteristics; its drug bioavailability and dissolution effect do not change with the amount of drug used, and the release rate only varies with the volume of the carrier itself. However, sustained-release compositions have high viscosity, making them difficult to deliver effectively using conventional needle-based or needle-free injection. This invention successfully achieves the effective injection of high-viscosity sustained-release compositions while ensuring ideal sustained-release effects by optimizing the composition formulation (including the ratio of active ingredient, sustained-release agent, and viscosity reducer) and combining it with a specially designed diffusion-injection fluid delivery device based on a motorized mechanism.

[0257] The sustained-release pharmaceutical composition of the present invention has the advantages of simple preparation process, convenient assembly with GLP-1 receptor agonists (such as semaglutide), and a single injection can maintain a long therapeutic effect. For example, in the treatment of obesity or overweight, the sustained-release pharmaceutical composition of the present invention exhibits unique advantages. After each dosing cycle, food intake can be continuously regulated, and a reduction in intake after injection is achieved. Notably, the present invention overcomes the problem of diminished efficacy that may occur with conventional formulations during long-term use, especially in the regulation of gastric emptying, thereby achieving a sustained weight control effect. In addition, through a reasonable dosing regimen, stable weight loss during treatment and weight maintenance after discontinuation of the drug can be achieved. In terms of blood glucose control, cardiovascular metabolic indicators, and improvement of liver function, the composition of the present invention also exhibits good therapeutic effects due to the sustained-release characteristics and sustained maintenance of drug concentration.

[0258] Example

[0259] Example 1

[0260] This embodiment describes the preparation of a sustained-release pharmaceutical composition comprising semaglutide, wherein semaglutide accounts for 0.2% of the total weight of the finished product.

[0261] Raw material: Smegglutide lyophilized powder (C005A-D230301, purchased from Hubei Jianxiang Biopharmaceutical Co., Ltd.)

[0262] Polyorthoester (POE, AP-20240313-D2, number average molecular weight approximately 4072, density 1.1556 g / mL, purchased from Beijing Nuokonda Pharmaceutical Technology Co., Ltd.)

[0263] Triacetin (CTP388, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.)

[0264] Smegglutide lyophilized powder (minimum particle size 0.20 μm, maximum particle size 73.78 μm, average particle size 2.44 μm, D50 67.21 μm) was dispersed in a mixture of polyorthoester and triacetin.

[0265] Preparation method:

[0266] 1. Weigh out the measured amount of Smegglutinin lyophilized powder;

[0267] 2. Polyorthoester and triacetin were mixed evenly at 70°C according to the weight ratio (65:35) to obtain the carrier;

[0268] 3. While stirring (1106 rpm, 20 minutes), add smegglutinin to the carrier and disperse it evenly;

[0269] 4. Use a high-speed shearing machine at 1600 rpm for 2 minutes at room temperature to ensure even mixing;

[0270] Of which, smegglutide accounts for 0.2% of the total weight of the finished product, polyorthoester content is about 65% by weight, and triacetin content is about 35% by weight (the ratio of polyorthoester to triacetin is 65:35).

[0271] The particle size distribution of the final product was as follows: minimum particle size was 0.20 μm, maximum particle size was 26.62 μm, average particle size was 1.43 μm, and D50 was 19.38 μm. At 25°C, the composition had a viscosity of 1809.1 mPa·s and a density of 1.2488 g / mL.

[0272] Example 2

[0273] This embodiment describes the preparation of a sustained-release pharmaceutical composition comprising semaglutide, wherein semaglutide accounts for 0.2% of the total weight of the finished product.

[0274] The raw materials are the same as in Example 1.

[0275] Preparation method:

[0276] 1. Weigh out the measured amount of Smegglutinin lyophilized powder;

[0277] 2. At room temperature, add the lyophilized smegglutide powder to a 10% dimethyl sulfoxide solution while stirring to ensure the drug is fully dissolved;

[0278] 3. Polyorthoester and triacetin are mixed evenly at 70°C according to the weight ratio (65:35) to obtain the carrier;

[0279] 4. Add the solution containing smegglutinin to the carrier mixture at room temperature and stir until homogeneous.

[0280] During the preparation process, smegglutide is adjusted (adapted) to account for 0.2% of the total weight of the finished product, and the weight ratio of polyorthoester and triacetin is 65:35.

[0281] The particle size distribution of the final product was as follows: minimum particle size was 0.22 μm, maximum particle size was 29.85 μm, average particle size was 1.86 μm, and D50 was 23.52 μm. At 25°C, the composition had a viscosity of 1820.3 mPa·s and a density of 1.2482 g / mL.

[0282] Example 3

[0283] This embodiment describes a sustained-release pharmaceutical composition comprising semaglutide, wherein semaglutide accounts for 0.2% of the total weight of the finished product.

[0284] The raw materials are the same as in Example 1.

[0285] Preparation method:

[0286] 1. Weigh out the measured amount of Smegglutinin lyophilized powder;

[0287] 2. Dissolve smegglutide in a 10% methanol solution at room temperature;

[0288] 3. Polyorthoester and triacetin are mixed evenly at 70°C according to the weight ratio (65:35) to obtain the carrier;

[0289] 4. Add the solution containing smegglutinin to the carrier mixture at room temperature and stir until homogeneous;

[0290] 5. Remove methanol from the solution by rotary evaporation at 30℃ for 10 minutes.

[0291] During the preparation process, smegglutide is adjusted (adapted) to account for 0.2% of the total weight of the finished product, and the weight ratio of polyorthoester and triacetin is 65:35.

[0292] When measured at 25°C, the viscosity of the composition was 1815.7 mPa·s and the density was 1.2479 g / mL.

[0293] Example 4

[0294] This embodiment describes the preparation of a sustained-release pharmaceutical composition containing smegglutide, wherein smegglutide accounts for 0.1% of the total weight of the finished product, the polyorthoester content is about 75% by weight, and the triacetin content is about 25% by weight (the ratio of polyorthoester to triacetin is 75:25). The raw materials and preparation method of this embodiment are the same as those of Example 1, but the content of the active ingredient and the ratio of sustained-release agent and viscosity reducer are different.

[0295] When measured at 25°C, the viscosity of the composition was 1805.4 mPa·s and the density was 1.2250 g / mL.

[0296] Example 5

[0297] This embodiment describes the preparation of a sustained-release pharmaceutical composition containing smegglutide, wherein smegglutide accounts for 0.05% of the total weight of the finished product, the polyorthoester content is about 65% by weight, and the triacetin content is about 35% by weight (the ratio of polyorthoester to triacetin is 65:35). The raw materials and preparation method of this embodiment are the same as those of Embodiment 1, but the content of the active ingredient is different.

[0298] When measured at 25°C, the viscosity of the composition was 1798.6 mPa·s and the density was 1.2475 g / mL.

[0299] Example 6

[0300] This embodiment describes the preparation of a sustained-release pharmaceutical composition containing smegglutide, wherein smegglutide accounts for 0.5% of the total weight of the finished product, the polyorthoester content is about 75% by weight, and the triacetin content is about 25% by weight (the ratio of polyorthoester to triacetin is 75:25). The raw materials and preparation method of this embodiment are the same as those of Example 1, but the content of the active ingredient is different.

[0301] When measured at 25°C, the viscosity of the composition was 1825.8 mPa·s and the density was 1.2353 g / mL.

[0302] Example 7

[0303] This embodiment describes the preparation of a sustained-release pharmaceutical composition comprising smegglutide, wherein smegglutide accounts for 0.1% of the total weight of the finished product, the polyorthoester content is approximately 45% by weight, and the triacetin content is approximately 55% by weight (the ratio of polyorthoester to triacetin is 45:55). The raw materials and preparation method of this embodiment are the same as in Example 1, but the proportions of the sustained-release agent and the viscosity reducer are different.

[0304] When measured at 25°C, the viscosity of the composition was 1009.2 mPa·s and the density was 1.2021 g / mL.

[0305] Example 8

[0306] This embodiment describes the preparation of a sustained-release pharmaceutical composition comprising smegglutide, wherein smegglutide accounts for 0.1% of the total weight of the finished product, the polyorthoester content is approximately 85% by weight, and the triacetin content is approximately 15% by weight (the ratio of polyorthoester to triacetin is 85:15). The raw materials and preparation method of this embodiment are the same as in Example 1, but the proportions of the sustained-release agent and the viscosity reducer are different.

[0307] When measured at 25°C, the viscosity of the composition was 2710.4 mPa·s and the density was 1.2602 g / mL.

[0308] Example 9

[0309] This embodiment evaluates the delivery effect of different injection methods for delivering high-viscosity sustained-release drug compositions and compares the performance differences of traditional needle injection, needle-free injection and diffusion microneedle injection in delivering high-viscosity formulations.

[0310] Experimental materials:

[0311] 1. Test Sample:

[0312] (1) Physiological saline (viscosity 1 mPa·s);

[0313] (2) Hydroxypropyl methylcellulose (HPMC) solution with a viscosity of 100 mPa·s, HPMC solution with a viscosity of 200 mPa·s, and HPMC solution with a viscosity of 1800 mPa·s (non-Newtonian fluid);

[0314] (3) Glycerin solutions with a viscosity of 100 mPa·s, 200 mPa·s, and 800 mPa·s (Newtonian fluids)

[0315] (4) Sustained-release drug compositions 9-1 to 9-5 prepared according to Example 1 (0.2% of the total weight of the finished product of smegglutide, 65 wt% of polyorthoester, 35 wt% of triacetin, and viscosity of 1809 mPa·s)

[0316] 2. Injection device:

[0317] (1) Needle injector: equipped with a 26G needle (0.23mm inner diameter)

[0318] (2) Needleless injector: Nozzle inner diameter 0.15mm

[0319] (3) A single-hole fluid delivery device according to an embodiment of the present invention (also known as a diffusion microneedle injector or diffusion needle injector): equipped with a 26G needle (inner diameter 0.23mm) and a needle length of 6mm.

[0320] 3. Experimental conditions:

[0321] Injection volume: 0.2 mL

[0322] Number of repetitions: Each experiment was repeated 3 times.

[0323] Test temperature: 25℃

[0324] Evaluation metric: Injection efficiency is calculated by measuring changes in quality before and after injection.

[0325] In this embodiment, the delivery efficiency of solutions of different viscosities was first evaluated in the hairless areas of 4-5 week old SPF-grade male SD rats, and the results are shown in Table 1. Then, physiological saline (1 mPa·s) was used as the test sample to evaluate the delivery efficiency in the hairy areas, and the results are shown in Table 2.

[0326] Table 1. Evaluation results of delivery efficiency of different injection methods (n=3, mean ± standard deviation)

[0327] Based on Table 1, this embodiment further evaluated the delivery efficiency of physiological saline (1 mPa·s) by different injection methods in the hairy areas of SD rats, and the results are shown in Table 2.

[0328] Table 2. Evaluation of injection efficiency of different injection methods under hairy conditions (n=3, mean ± standard deviation)

[0329] Analysis of experimental results:

[0330] 1. Evaluation of delivery efficiency under hairless conditions:

[0331] (1) When evaluated using a 26G needle (0.23 mm inner diameter), the needle-injection group showed good injection efficiency (100%) for physiological saline and hydroxypropyl methylcellulose solution. The hydroxypropyl methylcellulose solution could be injected smoothly even at a high viscosity of 1800 mPa·s, thanks to its non-Newtonian fluid shear-thinning properties. However, for glycerol solutions with Newtonian fluid properties, injection was impossible when the viscosity reached 200 mPa·s. The sustained-release drug composition of this embodiment, namely semaglutide sustained-release formulation (1809 mPa·s), is also a Newtonian fluid and cannot be delivered by needle injection. This indicates that conventional manual needle injection methods are not suitable for the delivery of the sustained-release drug composition of this embodiment.

[0332] (2) The needle-free injection group achieved good delivery efficiency for low-viscosity hydroxypropyl methylcellulose solution (100 mPa·s) at 280 N pressure, but the delivery efficiency decreased significantly with increasing solution viscosity. For glycerol solution, the delivery efficiency decreased significantly even at 280 N pressure when the viscosity reached 800 mPa·s. For the sustained-release drug composition (1809.1 mPa·s) of this embodiment, the delivery efficiency was low and unstable at 280 N pressure, and decreased further when the pressure was increased to 400 N. This may be attributed, not as a limitation, to the enhanced "skin-breaking" effect of the needle-free injector under high pressure. This indicates that the needle-free injection method is not suitable for the delivery of the sustained-release drug composition of this embodiment, and the efficiency further decreases with increasing injection pressure.

[0333] (3) The diffuse microneedle injection device (fluid delivery device according to the embodiment of the present invention) can achieve complete delivery of high-viscosity formulations (injection efficiency of 100%) under pressures of 280N and 400N. This shows that the fluid delivery device—diffuse microneedle injection technology—can effectively overcome the delivery resistance of high-viscosity Newtonian fluids and provides a reliable solution for the delivery of high-viscosity sustained-release drug compositions of the present invention.

[0334] 2. Evaluation of delivery efficiency under hairy conditions:

[0335] It is noteworthy that even for low-viscosity saline (1 mPa·s), the delivery efficiency of needle-free injection was unstable under hairy conditions (70.2 ± 18.6% at 280 N pressure and only 59.6 ± 34.9% at 400 N pressure). This may be explained, and not limited, by the fact that hair causes a loss of delivery pressure, and the uneven distribution of hair leads to greater fluctuations in delivery efficiency. Considering that the sustained-release pharmaceutical composition of the present invention is a Newtonian fluid with a viscosity (1809 mPa·s) much higher than that of saline, this result indicates that needle-free injection is less suitable for delivering the high-viscosity sustained-release formulation of the present invention under hairy conditions.

[0336] Given that the fluid delivery device according to embodiments of the present invention achieves 100% injection efficiency of the sustained-release drug composition when substantially inserted into a rat, it is expected that the fluid delivery device can also achieve 100% injection efficiency of the sustained-release drug composition under the same pressure conditions when substantially inserted into a rat in a hairy area.

[0337] This experiment systematically evaluated the delivery effects of different injection methods on solutions of varying viscosities and further validated the technology under hairy conditions. It demonstrated that the fluid delivery device of this invention—diffuse microneedle injection technology—is a preferred method for delivering sustained-release drug compositions of high-viscosity Newtonian fluids. This experiment showed that this technology not only overcomes the limitations of traditional needle-based and needle-free injections, achieving 100% injection efficiency under both low-pressure (280N) and high-pressure (400N) conditions, but also exhibits excellent stability. Particularly under hairy conditions, compared to the unstable efficiency of needle-free injection, diffuse microneedle injection maintains complete delivery, providing a reliable delivery solution for the clinical application of the sustained-release drug compositions of this invention.

[0338] Example 10

[0339] This embodiment relates to the pharmacodynamic evaluation of a sustained-release pharmaceutical composition, aiming to evaluate its therapeutic effect on obesity or overweight indications, its impact on type II diabetes-related indicators, and its improvement effect on cardiovascular metabolic indicators. This embodiment uses a diet-induced obesity (DIO) rat model to analyze the effects of different doses and injection methods on body weight, blood glucose levels, and cardiovascular metabolic indicators, in order to verify the feasibility and advantages of sustained-release formulations in clinical applications.

[0340] 1. Laboratory animals:

[0341] SPF-grade male SD rats aged 4–5 weeks were used.

[0342] 2. Experimental Groups:

[0343] Rats were randomly divided into five groups, with 10 rats in each group:

[0344] Control Case 10-1 (ND Group): This group was a normal diet control group, which was given a normal diet and injected with physiological saline (300μL) daily.

[0345] Control Example 10-2 (HFD Group): This group was a high-fat diet control group, which was given a high-fat diet daily and injected with physiological saline (300μL).

[0346] Control Example 10-3 (Group D): This group was the ordinary semaglutide injection group, who were given a high-fat diet daily and used a high-concentration ordinary (non-sustained-release) semaglutide injection preparation (0.417 mg / mL), with each injection being 300 μL.

[0347] Example 10-1 (Group A): This group was a low-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (1.25 mg / mL) prepared according to Example 4 was used, with each injection being 100 μL.

[0348] Example 10-2 (Group B): This group was a high-dose sustained-release formulation group. The patients were given a high-fat diet daily and the sustained-release injection formulation (1.25 mg / mL) prepared according to Example 4 was administered in 200 μL injections each time.

[0349] Example 10-3 (Group C): This group is the high-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (2.5 mg / mL) prepared according to Example 1 was used, with each injection being 100 μL.

[0350] 3. Experimental Design:

[0351] 3.1 Model Establishment

[0352] After one week of acclimatization, rats were fed appropriate diets according to their groups. The high-fat diet group was fed continuously for 20 weeks, and the criterion for establishing the DIO model was that the average body weight exceeded that of the normal group by 20%.

[0353] 3.2 Dosing regimen

[0354] A 5-day dosing cycle was established, with one dose administered per cycle, for a total of 3 cycles. Based on the calculation that daily administration in rats corresponds to a 6-8 day dosing interval in humans, the corresponding human dosing interval is approximately 30-40 days. The standard rat dose of semaglutide (0.025 mg) corresponds to the standard human dose. The dosage design for this experiment is as follows: Example 10-1: 0.125 mg / dose (5 times the standard dose); Examples 10-2 and 10-3: 0.25 mg / dose (10 times the standard dose); Control group 10-3 (Group D): 0.125 mg / dose. All injections were performed subcutaneously using the single-hole fluid delivery device (diffusion microneedle injector) of this invention, at an injection pressure of 280 N.

[0355] 3.3 Evaluation Indicators

[0356] (1) Weight-related indicators: Daily weight changes were recorded, and waist circumference and other vital signs were measured at the end of the experiment.

[0357] (2) Pharmacokinetic parameters: Pharmacokinetic evaluation was carried out, including the determination of time to reach peak plasma concentration (tmax), peak plasma concentration (Cmax), area under the curve (AUC0-last), and half-life (t1 / 2).

[0358] (3) Blood glucose related indicators: The improvement of blood glucose level was assessed by oral glucose tolerance test (GTT), fasting blood glucose level was detected, the area under the blood glucose curve (AUC) in the glucose tolerance test was calculated, and the blood glucose maintenance level and blood glucose recovery after glucose load were monitored.

[0359] (4) Cardiovascular metabolic indicators: The activity of alanine aminotransferase (ALT) in the serum of rats in each group was detected. At the same time, liver tissue sections were prepared, and the morphology and cell state of the liver tissue were observed after HE staining, including the lobular structure, cell arrangement and morphological characteristics.

[0360] 4. Experimental Results

[0361] 4.1 Weight changes and overall condition

[0362] The results of the weight-related experiments are shown in Table 3. Before the experiment, the average weight of rats in the high-fat diet group was significantly higher than that of the normal group by more than 20%, indicating that the DIO rat model was successfully replicated. During the experiment, rats in the ND group maintained a good mental state, moved nimbly, and had smooth and shiny fur; while rats in the HFD group had a poor mental state, dry and yellow fur, and moved slowly. After drug treatment, the mental state and fur condition of rats in all treatment groups were significantly improved.

[0363] Table 3 - Relevant conditions in rats (mean ± standard deviation)

[0364] Referring to Figures 3 and 4, the experimental results showed that the body weight of rats in control group 10-2 (HFD group) did not change significantly (0.35±1.05%), while the body weight of all drug treatment groups was significantly reduced compared with the HFD group (p<0.05). Among them, the body weight ratio of rats in example 10-3 (C group) decreased most significantly, reaching 17.17±4.63%. The body weight reduction ratios of example 10-2 (B group) and example 10-3 (C group) were 14.66±4.79% and 14.56±1.35%, respectively.

[0365] Furthermore, referring to Figures 3 and 4, the following characteristics can also be observed throughout the entire dosing cycle:

[0366] (1) After administration again on days 6 and 11, body weight continued to decrease without a plateau. This result indicates that the sustained-release formulation of the present invention overcomes the problem of reduced gastric emptying effect that is easily observed with long-term use of conventional semaglutide;

[0367] (2) The groups of Examples 10-3 (high-dose groups) not only achieved safe medication when using sustained-release formulations at 10 times the standard dose, but also showed better weight loss effects than other dosing regimens (p<0.05, days 6, 10 and 14), further demonstrating the safety and effectiveness of the sustained-release formulations of the present invention when administered at high doses;

[0368] (3) Although the total amount of drug in groups 10-2 and 10-3 of Examples is the same, the weight reduction effect in group 10-3 is better, which may be related to the influence of carrier volume on drug release.

[0369] 4.2 Pharmacokinetic Evaluation Results

[0370] The results of pharmacokinetic experiments are shown in Table 4.

[0371] Table 4 - Pharmacokinetic parameters of smegglutide after a single dose (mean ± standard deviation)

[0372] Pharmacokinetic data showed that, compared to Control Example 10-3 (which was a high dose compared to the standard dose) and Examples 10-1 to 10-3 (AC group), the time to reach peak plasma concentration (t) was significantly prolonged. max Higher peak plasma concentration (C max A higher final area under the curve (AUC) 0-last AUC is used here. 0-t (indicated by) extended half-life (t) 1 / 2 Examples 10-1 to 10-3 (AC group) also showed a higher mean residence time (MRT) and a lower apparent clearance (CL / F) in the body.

[0373] Figure 5 shows the trend of smegglutide concentration in rat plasma over time (in days). It can be seen that the plasma concentrations of Examples 10-1 to 10-3 (Group AC) were still significantly higher on day 5 than the concentrations of the control group (Group D) on day 3. This indicates that the sustained-release injectable formulation can significantly prolong the duration of drug presence in vivo, exhibiting better drug utilization and longer-lasting effects compared to conventional injectable formulations.

[0374] 4.3 Blood glucose control effect

[0375] To evaluate the hypoglycemic effect of smegglutide sustained-release formulation, an oral glucose tolerance test (OGTT) was performed on rats in each group, and the results are shown in Figure 6.

[0376] The experimental results show that the increase in blood glucose (GLU) 30 minutes after glucose loading in Examples 10-1 to 10-3 (AC group) was significantly lower than that in Control Example 10-2 (HFD group), with blood glucose levels decreasing by approximately 30%, 47%, and 43%, respectively. Among them, Example 10-2 (B group) showed the best glycemic control effect.

[0377] Regarding fasting blood glucose levels, the treatment groups were significantly lower than the HFD group. Examples 10-1 to 10-3 (AC groups) showed a decrease of approximately 0.8 mmol / L compared to control example 10-2 (HFD group), and were similar to the levels in the normal control example 10-1 (ND group).

[0378] Regarding the stability of glycemic control, the blood glucose levels in the treatment groups remained within the normal range throughout the observation period, similar to those in the normal control group 10-1 (ND group). The blood glucose levels in each treatment group recovered well to within 20% of their fasting level 120 minutes after the glucose load, demonstrating good glycemic regulation capabilities.

[0379] In terms of glucose tolerance, the overall trend of the blood glucose curves in the treatment group was similar to that of the normal control group 10-1 (ND group), and significantly better than that of the control group 10-2 (HFD group). The area under the blood glucose curve (AUC) of Examples 10-1 to 10-3 (AC group) was reduced by more than 20% compared with the control group 10-2 (HFD group), indicating that the drug treatment significantly improved glucose metabolism.

[0380] In particular, Example 10-2 (Group B) showed the best glycemic control effect, with the flattest blood glucose curve, which was closest to that of the normal control group (ND group). This indicates that the sustained-release formulation of the present invention has a significant hypoglycemic effect, while avoiding the risk of hypoglycemia caused by excessively low blood glucose, and keeping blood glucose levels within the ideal range.

[0381] The above results confirm that the smegglutide sustained-release formulation of the present invention has excellent glycemic control effect and can effectively improve glucose metabolism function.

[0382] 4.4 Cardiovascular metabolic indicators

[0383] To evaluate the effects of the semaglutide sustained-release formulation of this invention on cardiovascular metabolism, the serum ALT activity levels of rats in each group were measured, and liver tissue pathological observations were performed. The results are shown in Figures 7 and 8.

[0384] As shown in Figure 7, the ALT activity test results indicate that, compared with control example 10-2 (HFD group), the ALT activity in examples 10-1 to 10-3 (AC group) was significantly reduced, with example 10-2 (B group) showing the largest reduction. This suggests that the dosage group has a protective effect on liver function.

[0385] Figure 8 shows HE staining images of rat liver tissue from each group (×200). The liver tissue of the normal control group (ND group) showed normal lobular structure with neatly and tightly arranged cells. In control group 10-2 (HFD group), a large number of hepatocytes showed fatty degeneration, with round vacuoles of varying sizes in the cytoplasm and obvious lipid droplet accumulation. The lipid droplet accumulation was significantly reduced in each of the examples 10-1 to 10-3 (AC groups). Although a small amount of inflammatory cell infiltration was observed in the portal area, the overall liver tissue structure was significantly improved compared to control group 10-2 (HFD group). The improvement was most significant in example 10-2 (B group), with the liver tissue structure most similar to the normal control group (ND group).

[0386] The above results indicate that the sustained-release formulation of the present invention has a good liver-protective effect and can significantly improve liver function damage caused by a high-fat diet.

[0387] Example 11

[0388] This embodiment relates to the pharmacokinetic evaluation of sustained-release drug compositions, aiming to evaluate the effect of different amounts of sustained-release agents on the pharmacokinetic characteristics of the drug in vivo.

[0389] 1. Laboratory animals:

[0390] SPF-grade male SD rats aged 4–5 weeks were used.

[0391] 2. Experimental Groups:

[0392] Rats were randomly divided into three groups of 10 each using a random number table.

[0393] Control Example 11-1: This group was the ordinary semaglutide injection group, who were given a high-fat diet daily and used high-concentration ordinary (non-sustained-release) semaglutide injection (0.417mg / mL), 300μL each time.

[0394] Example 11-1: This group is the low-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (1.25 mg / mL) prepared according to Example 7 was used, with each injection being 100 μL.

[0395] Example 11-2 (Group C): This group is the high-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (1.25 mg / mL) prepared according to Example 8 was administered in 200 μL injections each time.

[0396] 3. Experimental Design:

[0397] 3.1 Model Establishment

[0398] After one week of acclimatization, rats were fed appropriate diets according to their groups. The high-fat diet group was fed continuously for 20 weeks, and the criterion for establishing the DIO model was that the average body weight exceeded that of the normal group by 20%.

[0399] 3.2 Dosing regimen

[0400] A 5-day dosing cycle was set, with one dose administered per cycle, for a total of one cycle. All injections were performed subcutaneously using the fluid delivery device (diffusion microneedle injector) described in embodiments of the present invention (such as embodiments 9-1 to 9-3).

[0401] 3.3 Evaluation Indicators

[0402] Perform pharmacokinetic evaluation, including determining the time to reach peak plasma concentration (tmax), peak plasma concentration (Cmax), and area under the curve (AUC0-last).

[0403] 4. Experimental Results

[0404] The results of pharmacokinetic experiments are shown in Table 5.

[0405] Table 5. Pharmacokinetic parameters of semaglutide extended-release injection (n=10, Mean±SD)

[0406] The Tmax of the sustained-release formulations (Examples 11-1 and 11-2) was 24 h, significantly longer than the 6 h of the control example 11-1, indicating that sustained-release drug formulations of different concentrations all have good sustained-release characteristics. At the same time, the sustained-release formulations showed higher systemic exposure, with AUClast of 19761.43 and 28474.31 h ng / mL, respectively, significantly higher than the 11045.79 h ng / mL of the control example 11-1. In addition, the Cmax of the sustained-release formulations also increased accordingly, to 411.57 and 552.96 ng / mL, respectively, higher than the 299.89 ng / mL of the control group, indicating that sustained-release formulations of different concentrations can effectively improve the bioavailability of the drug.

[0407] Example 12

[0408] This embodiment relates to the hypoglycemic effect of a sustained-release pharmaceutical composition, aiming to evaluate the hypoglycemic effect under different active ingredient contents and different injection regimens.

[0409] 1. Laboratory animals:

[0410] SPF-grade male SD rats aged 4–5 weeks were used.

[0411] 2. Experimental Groups:

[0412] Rats were randomly divided into seven groups, with 10 rats in each group:

[0413] Control Example 12-1 (ND Group): This group was a normal diet control group, which was given a normal diet every day and injected with physiological saline (300 μL). The injection was performed subcutaneously using the single-hole fluid delivery device (diffusion microneedle injector) of the present invention (as in Examples 9-1 to 9-3), and the injection pressure was 280 N.

[0414] Control Example 12-2 (HFD Group): This group was a high-fat diet control group, which was given a high-fat diet daily and injected with physiological saline (300 μL). The injection was performed subcutaneously using the single-hole fluid delivery device (diffusion microneedle injector) of the present invention (as in Examples 9-1 to 9-3), and the injection pressure was 280 N.

[0415] Example 12-1: This group is the low-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (0.625 mg / mL) prepared according to Example 5 was used. Each injection was 200 μL and was performed subcutaneously using the single-hole fluid delivery device (diffusion microneedle injector) of the present invention (as in Examples 9-1 to 9-3). The injection pressure was 280 N.

[0416] Example 12-2: This group is the low-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (1.25 mg / mL) prepared according to Example 4 was used. Each injection was 100 μL and was performed subcutaneously using the single-hole fluid delivery device (diffusion microneedle injector) of the present invention (as in Examples 9-1 to 9-3). The injection pressure was 280 N.

[0417] Examples 12-3: This group is the high-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (6.25 mg / mL) prepared according to Example 6 was used. Each injection was 40 μL and was performed subcutaneously using the single-hole fluid delivery device (diffusion microneedle injector) of the present invention (as in Examples 9-1 to 9-3). The injection pressure was 280 N.

[0418] Examples 12-4: This group is the high-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (2.5 mg / mL) prepared according to Example 1 was used. Each injection was 100 μL and was performed subcutaneously using the single-hole fluid delivery device (diffusion microneedle injector) of the present invention (as in Examples 9-1 to 9-3). The injection pressure was 400 N.

[0419] Examples 12-5: This group is the high-dose sustained-release formulation group. The patient was given a high-fat diet daily and the sustained-release injection formulation (2.5 mg / mL) prepared according to Example 1 was used. Each injection was 100 μL and the injection was performed subcutaneously using the three-hole fluid delivery device (diffusion microneedle injector) shown in Examples 1A and 1B. The single-hole diameter was 0.1 mm and the injection pressure was 460 N.

[0420] 3. Experimental Design:

[0421] 3.1 Model Establishment

[0422] After one week of acclimatization, rats were fed appropriate diets according to their groups. The high-fat diet group was fed continuously for 20 weeks, and the criterion for establishing the DIO model was that the average body weight exceeded that of the normal group by 20%.

[0423] 3.2 Dosing regimen

[0424] Single dose.

[0425] 3.3 Evaluation Indicators

[0426] The oral glucose tolerance test (OGTT) was used to evaluate the hypoglycemic effect in each group. The OGTT was performed after drug administration, and blood glucose levels were measured at 0, 15, 30, 60, and 120 minutes.

[0427] 4. Experimental Results:

[0428] The results of blood glucose-related experiments are shown in Table 6.

[0429] Table 6. Blood glucose parameters for semaglutide sustained-release injection (n=10)

[0430] Analysis of the results of the oral glucose tolerance test in rats showed that the blood glucose level in the high-fat control group was significantly elevated during the experiment, reaching a peak of 17.5 mmol / L at 60 minutes, and remained at a high level (14.3 mmol / L) at 120 minutes.

[0431] Different injection regimens all showed varying degrees of hypoglycemic effect, which correlated with the injection dose. The higher dose group (0.250 mg) showed the most significant hypoglycemic effect, with a blood glucose curve similar to the normal control group, and blood glucose levels recovering to 7.4-7.6 mmol / L after 120 minutes. Simultaneously, at the same dose level, various configurations and pressure conditions of the fluid delivery device in this embodiment of the invention demonstrated stable blood glucose control.

[0432] These results indicate that the sustained-release formulation developed in this study has a good hypoglycemic effect and the drug delivery system is stable.

[0433] Example 13

[0434] This embodiment relates to the pharmacokinetic evaluation of sustained-release drug compositions, especially thermosensitive sustained-release drug compositions, and particularly to the pharmacokinetic evaluation of semaglutide sustained-release formulations based on poloxamer 407 thermosensitive gel, and compares them with ordinary semaglutide injection to verify their long-acting sustained-release performance.

[0435] 1. Laboratory animals:

[0436] SPF-grade male SD rats aged 4–5 weeks were used.

[0437] 2. Experimental Groups:

[0438] Rats were randomly divided into four groups of 10 each using a random number table.

[0439] Control Example 13-1 (NSRP IV Group): This group was the ordinary semaglutide injection group, who were given a high-fat diet daily and used high-concentration ordinary (non-sustained-release) semaglutide injection (0.625 mg / mL), 100 μL each time.

[0440] Control Example 13-2 (NSRP IV Group): This group was the ordinary semaglutide injection group, who were given a high-fat diet daily and used high-concentration ordinary (non-sustained-release) semaglutide injection (0.625 mg / mL), 100 μL each time.

[0441] Example 13-1 (TSG-SRP 10 / 100 group): This group is the poloxamer 407 thermosensitive gel sustained-release formulation group. The patient was given a high-fat diet daily and used a sustained-release formulation based on poloxamer 407 thermosensitive gel (made by mixing poloxamer 407 and smegglutinin lyophilized powder at low temperature (0-8℃) as described in the embodiments of the present invention), wherein the smegglutinin content was 0.625 mg / mL, and 100 μL was injected each time.

[0442] Example 13-2 (POE-SRP 10 / 100 group): This group is the polyorthoester sustained-release formulation group. The patient was given a high-fat diet daily and a polyorthoester (POE) based sustained-release formulation (0.625 mg / mL) prepared according to Example 5 was used. Each injection was 100 μL.

[0443] 3. Experimental Design:

[0444] 3.1 Model Establishment

[0445] After one week of acclimatization, rats were fed appropriate diets according to their groups. The high-fat diet group was fed continuously for 20 weeks, and the criterion for establishing the DIO model was that the average body weight exceeded that of the normal group by 20%.

[0446] 3.2 Dosing regimen

[0447] Comparative Example 13-1 (NSRP IV group) used conventional needle intravenous injection, while the other groups used the fluid delivery device (diffusion microneedle injector) of the present invention (such as Examples 9-1 to 9-3) for subcutaneous injection.

[0448] 3.3 Evaluation Indicators

[0449] Pharmacokinetic evaluation was performed, including determining the time to reach peak plasma concentration (tmax), peak plasma concentration (Cmax), area under the curve (AUC0-t), and half-life (t1 / 2).

[0450] 4. Experimental Results

[0451] The results of pharmacokinetic experiments are shown in Table 5.

[0452] Table 7 Pharmacokinetic parameters of semaglutide extended-release injection (n=10, Mean±SD)

[0453] As can be seen, Control Example 13-1 (NSRP IV group) had a very short tmax (1 h) due to direct blood entry. Although Cmax and AUC were both high, this indicates that intravenous injection can rapidly achieve higher blood drug concentrations, but cannot achieve a long-lasting effect. The tmax of Examples 13-1 and 13-2 were significantly longer than that of the NSRP group, and in particular, the thermosensitive sustained-release drug compositions, especially those based on poloxamer 407 thermosensitive gel, exhibited a sustained-release effect similar to that of the polyorthoester sustained-release formulation group of Example 13-2. The Cmax and AUC of Example 13-1 (TSG group) were also higher than those of Control Example 13-2 (NSRP group), indicating that thermosensitive sustained-release drug compositions, especially those based on poloxamer 407 thermosensitive gel, can improve drug bioavailability.

[0454] This embodiment anticipates that thermosensitive sustained-release drug compositions, especially those based on poloxamer 407 thermosensitive gel, can effectively prolong the duration of drug action, increase drug concentration, and demonstrate significant superiority over conventional semaglutide injection in terms of pharmacokinetics. It is foreseeable that, with similar or better pharmacokinetic performance, sustained-release formulations using TSG can achieve similar efficacy to POE sustained-release formulations in terms of weight control, glycemic regulation, and improvement of cardiovascular metabolic indicators.

[0455] The GLP-1 receptor agonist sustained-release drug composition provided by this invention, especially the semaglutide sustained-release drug composition, has the following significant advantages and effects:

[0456] 1. Long-acting drug delivery: By optimizing polyorthoester polymers or thermosensitive sustained-release agents as delivery agents, this invention achieves long-acting release of GLP-1 receptor agonists, significantly prolonging the duration of drug action in the body. This allows for a substantial reduction in dosing frequency, from once daily to once every 15 or even 30 days, greatly improving patient compliance.

[0457] 2. Improved pharmacokinetic characteristics: The sustained-release drug composition of the present invention significantly improves the peak plasma concentration (Cmax) and area under the curve (AUC0-t), prolongs the time to reach peak plasma concentration (tmax) and mean residence time (MRT), and achieves more stable and sustained drug plasma concentration.

[0458] 3. Significant weight loss effect: Within 4 weeks of administration, individuals using the composition of the present invention can achieve a reduction of more than 2% relative to their initial body weight, providing an effective weight management option for obese and overweight patients.

[0459] 4. Excellent blood glucose control effect: Within 15 days after administration, the composition of the present invention can significantly improve blood glucose levels, including reducing fasting blood glucose and improving glucose tolerance test (GTT) results, providing better blood glucose management options for diabetic patients.

[0460] 5. Improves blood lipid levels: The composition of the present invention can significantly reduce serum alanine aminotransferase (ALT) activity within 15 days of administration, which helps to improve the patient's overall metabolic status.

[0461] 6. Multiple therapeutic potential: In addition to treating diabetes and obesity, the compositions of the present invention also show the potential to improve cardiovascular metabolic indicators, providing new possibilities for the prevention and treatment of related diseases.

[0462] 7. Flexible administration methods: The present invention also provides a fluid delivery device for use with sustained-release drug compositions, making drug administration more convenient and precise, and further improving the convenience and effectiveness of treatment.

[0463] In summary, the GLP-1 receptor agonist sustained-release pharmaceutical composition provided by this invention has significant advantages in improving drug efficacy, prolonging dosing intervals, and enhancing patient compliance, providing an innovative solution for the treatment of metabolic-related diseases.

[0464] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A sustained-release pharmaceutical composition, characterized in that, The composition comprises: The active ingredient comprises 0.05% to 0.5% by weight, preferably 0.1% to 0.5% by weight, more preferably 0.1% to 0.3% by weight, wherein the active ingredient is a GLP-1 receptor agonist, and more preferably, the GLP-1 receptor agonist is selected from one or more of smegglutide, liraglutide, dulaglutide, benaglutide, exenatide, lixisenatide and polyethylene glycol loxenatide, and preferably the GLP-1 receptor agonist is smegglutide; The sustained-release agent is preferably about 45% to about 85% by weight, more preferably about 55% to about 75% by weight, and more preferably about 65% by weight. The sustained-release agent is preferably a polyorthoester polymer, more preferably a polyorthoester. Viscosity reducing agent, preferably from about 15% to about 55% by weight, more preferably from about 25% to about 45% by weight, more preferably from about 35% by weight, wherein the viscosity reducing agent is preferably triacetin.

2. The composition according to claim 1, characterized in that, The viscosity of the composition, measured at 25°C, is from 100 mPa·s to 5000 mPa·s, preferably from 500 to 4000 mPa·s, and more preferably from 800 to 3000 mPa·s.

3. The composition according to claim 1, characterized in that, The polyorthoester polymer material is more preferably a polyorthoester with a number average molecular weight of about 1,000 to 20,000 Daltons, more preferably 2,000 to 10,000 Daltons, and more preferably 4,000 to 7,000 Daltons.

4. A sustained-release pharmaceutical composition, characterized in that, The composition comprises: The active ingredient comprises 0.05% to 0.5% by weight, preferably 0.1% to 0.5% by weight, more preferably 0.1% to 0.3% by weight, wherein the active ingredient is a GLP-1 receptor agonist, and more preferably, the GLP-1 receptor agonist is selected from one or more of smegglutide, liraglutide, dulaglutide, benaglutide, exenatide, lixisenatide and polyethylene glycol loxenatide, and preferably the GLP-1 receptor agonist is smegglutide; A thermally sensitive sustained-release agent, wherein the content of the thermally sensitive sustained-release agent is preferably from 45% to 99.95% by weight, more preferably from 75% to 99.5% by weight; preferably, the curing temperature of the thermally sensitive sustained-release agent is from 30°C to 45°C, more preferably from 35°C to 39°C, more preferably from 36°C to 38°C, and the thermally sensitive sustained-release agent comprises or is selected from at least one of the following: Polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer (PEO-PPO-PEO) (Poloxamer 407) Lactic acid-glycolic acid copolymer-polyethylene glycol-lactic acid-glycolic acid triblock copolymer (PLGA-PEG-PLGA); Preferably, the thermosensitive sustained-release agent is composed of PEO-PPO-PEO or PLGA-PEG-PLGA.

5. A method for preparing the sustained-release pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The method includes: A GLP-1 receptor agonist is mixed into a solution to form the sustained-release pharmaceutical composition, wherein the solution contains a sustained-release agent and a viscosity reducer; or... A GLP-1 receptor agonist is mixed into a solvent to form a mixture, wherein the solvent is a compound that dissolves the GLP-1 receptor agonist. A solution-releasing agent and a viscosity reducer are then mixed into the mixture. The solvent is then removed, partially removed, or not removed to form the sustained-release drug composition. Preferably, the mixing or removal of the solvent is carried out at a temperature of 50 to 80°C, more preferably 65 to 75°C, and even more preferably 70°C.

6. A combination drug and medical device product, characterized in that, It includes a fluid delivery device and a sustained-release drug composition according to any one of claims 1 to 4, wherein the fluid delivery device includes a tube for containing the sustained-release drug composition, an injection head detachably connected to or integrally formed with the tube, and a power mechanism for applying a delivery force to deliver the sustained-release drug composition; The injection head includes one or more needle components. Preferably, the inner diameter of the needle tip is in the range of about 0.06 mm to about 1.50 mm, more preferably in the range of about 0.1 mm to about 1 mm. Preferably, the length of the needle is in the range of about 1 mm to about 10 mm.

7. Use of the sustained-release pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a product for injection administration to treat diseases, preferably, The drug is used to treat at least one of the following diseases: Used to treat obesity or overweight; Used to treat diabetes, preferably for the treatment of type II diabetes; Used to improve cardiovascular metabolic indicators; preferably, used to reduce the risk of cardiovascular disease or to treat cardiovascular disease; preferably, used to treat atherosclerosis; preferably, used to treat myocardial infarction; preferably, used to treat stroke; preferably, used to treat heart failure; preferably, used to treat peripheral artery disease; Used to treat Alzheimer's disease; Used to treat non-alcoholic steatohepatitis.

8. Polyorthoester polymeric materials, more preferably the use of polyorthoesters in the preparation of GLP-1 receptor agonist drugs for injection, preferably semaglutide drugs, wherein the polyorthoester polymeric material in the drug is preferably a sustained-release agent with a polyorthoester content of about 45% to about 85% by weight, preferably about 55% to about 75% by weight. Preferably, the GLP-1 receptor agonist drug, and more preferably semaglutide drug, is pre-filled into a fluid delivery device in the form of a pre-filled injection pen. Preferably, the drug is used to treat at least one of the following diseases: Used to treat obesity or overweight; Used to treat diabetes, preferably for the treatment of type II diabetes; Used to improve cardiovascular metabolic indicators; preferably, used to reduce the risk of cardiovascular disease or to treat cardiovascular disease; preferably, used to treat atherosclerosis; preferably, used to treat myocardial infarction; preferably, used to treat stroke; preferably, used to treat heart failure; preferably, used to treat peripheral artery disease; Used to treat Alzheimer's disease; Used to treat non-alcoholic steatohepatitis.

9. The composition according to any one of claims 1 to 4, the pharmaceutical-device combination product according to claim 6, or the use according to claim 7 or 8, characterized in that, The active ingredient content in a single standard injection dose of the GLP-1 receptor agonist drug, preferably a semaglutide drug, is about 6.03 mg to about 50.25 mg, preferably about 10.05 mg to about 50.25 mg, more preferably about 10.05 mg to about 30.15 mg, and even more preferably about 10.05 mg to about 20.10 mg. This is about 3 to about 25 times, preferably about 5 to about 25 times, more preferably about 5 to about 15 times, and even more preferably about 5 to about 10 times the semaglutide dose in a single standard injection dose of a conventional semaglutide drug. The standard human injection dose of the conventional semaglutide drug is 1.5 ml, and the concentration of semaglutide in the conventional semaglutide drug is preferably 1.34 mg / ml.

10. The composition according to any one of claims 1 to 4, the pharmaceutical-device combination product according to claim 6, or the use according to any one of claims 7 to 8, characterized in that, The drug has at least one of the following pharmacokinetic characteristics after a single dose: (1) Compared with conventional non-sustained-release semagrapeptide drugs, the time to reach the highest plasma concentration (t) max (Prolonged, preferably, a single injection of sustained-release drug t) max It is 1.5-10 times more potent than a single injection of non-sustained-release semaglutide; more preferably, t max It is 2-7 times; most preferably, t max The concentration of semaglutide is 3-5 times that of conventional semaglutide drugs. The standard single-dose injection dose for humans is 1.5 ml, and the preferred concentration of semaglutide in conventional semaglutide drugs is 1.34 mg / ml. (2) Compared to conventional non-sustained-release semagrapeptide drugs, the highest plasma concentration (C) max To improve, preferably, the single-injection sustained-release drug C max The dosage is 1.2-10 times that of a single injection of non-sustained-release semaglutide; preferably, 1.5-10 times; more preferably, C max It is 2-7 times; most preferably, C max 3-5 times; (3) Compared with conventional non-sustained-release semaglutide drugs, the area under the curve (AUC) during drug delivery was significantly lower. 0-last To improve, preferably, AUC 0-last Reaching 18000 h·ng·mL -1 The above; more preferably, AUC 0-last Reaching 38000 h·ng·mL -1 The above; the most preferred option, AUC 0-last Reaching 64000 h·ng·mL -1 above; (4) Compared to conventional non-sustained-release smegglutide drugs, the half-life (t) 1 / 2 (Prolonged, preferably, a single injection of sustained-release drug t) 1 / 2 The dosage is 1.2-10 times that of a single injection of non-sustained-release semaglutide; preferably, 1.5-10 times; more preferably, t 1 / 2 It is 2-7 times; most preferably, t 1 / 2 It is 3-5 times.

11. The composition according to any one of claims 1 to 4, the pharmaceutical-device combination product according to claim 6, or the use according to any one of claims 7 to 10, characterized in that, The drug is used to treat obesity or overweight, wherein a significant reduction in individual weight relative to initial weight is achieved within 4 weeks after the start of administration; preferably, the individual weight is reduced by more than 2% relative to initial weight; more preferably, the individual weight is reduced by more than 4% relative to initial weight; even more preferably, the individual weight is reduced by more than 6% relative to initial weight; and most preferably, the individual weight is reduced by more than 8% relative to initial weight.

12. The composition according to any one of claims 1 to 4, the pharmaceutical-device combination product according to claim 6, or the use according to any one of claims 7 to 10, characterized in that, The drug is used to treat diabetes, preferably to treat type II diabetes, wherein a significant improvement in blood glucose levels is achieved within 15 days after the start of administration, and preferably it has at least one of the following blood glucose characteristics: (1) Significant improvement in blood glucose levels in a glucose tolerance test (GTT), preferably, within 30 minutes after glucose gavage, blood glucose levels are reduced by more than 2% compared to before administration; preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 15%. (2) Significant improvement in fasting blood glucose level, preferably, the fasting blood glucose level is reduced by more than 0.2 mmol / L compared with that before administration; preferably, it is reduced by more than 0.4 mmol / L; more preferably, it is reduced by more than 0.6 mmol / L; most preferably, it is reduced by more than 0.8 mmol / L; (3) The individual’s glucose tolerance is significantly improved. Preferably, the area under the glucose curve (AUC) in the glucose tolerance test is reduced by more than 5% compared with that before administration; preferably, it is reduced by more than 10%; more preferably, it is reduced by more than 15%; and most preferably, it is reduced by more than 20%. (4) Individual blood glucose levels are maintained within the range of 5.6 mmol / L to 7.0 mmol / L; (5) Within 120 minutes after glucose loading, the blood glucose level is restored to within 120% of the fasting level; preferably, it is restored to within 110% of the fasting level; more preferably, it is restored to within 105% of the fasting level.

13. The composition according to any one of claims 1 to 4, the pharmaceutical-device combination product according to claim 6, or the use according to any one of claims 7 to 10, characterized in that, The drug is used to improve cardiovascular metabolic indicators; preferably, it is used to reduce the risk of cardiovascular disease or to treat cardiovascular disease, wherein a significant improvement in blood lipid levels is achieved within 15 days after the start of administration, preferably having at least one of the following blood lipid characteristics: (1) Improve liver function indicators, preferably, the activity of alanine aminotransferase (ALT) is significantly reduced, preferably, the activity of ALT is reduced by more than 5% compared with that before administration; preferably, it is reduced by more than 10%; more preferably, it is reduced by more than 15%; most preferably, it is reduced by more than 20%. (2) Reduce pathological changes in liver tissue, preferably by reducing the degree of hepatocyte steatosis and lipid droplet accumulation.

14. The composition according to any one of claims 1 to 4, the pharmaceutical-device combination product according to claim 6, or the use according to any one of claims 7 to 13, characterized in that, When administered to humans, the sustained-release drug composition is administered for a period of 10 days or more, preferably 10 days or more and 90 days or less, preferably 15 days or more and 60 days or less, preferably 30 days or more and 40 days or less, and most preferably 30 days.

15. The composition according to any one of claims 1 to 4, the pharmaceutical-device combination product according to claim 6, or the use according to any one of claims 7 to 14, characterized in that, When administered to humans, the active ingredient is released from the sustained-release pharmaceutical composition for a period of 10 days or more, preferably 10 days or more and 90 days or less, preferably 15 days or more and 90 days or less, and preferably 30 days or more and 90 days or less.

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